Summit Therapeutics PLC Sponsored ADR Aktie

Great. Good morning, everyone. It's my pleasure to introduce the Summit Therapeutics team. With us, we have Bob Duggan, Co-CEO with Maky Zanganeh, Co-CEO; Manmeet Soni, CFO; Allen Yang, CRDSO; and Dave Gancarz, CBSO.

To start here, a big picture question. Ivo is the leading PD-1 or L1 VEGF asset in development and China-based Phase III frontline lung cancer survival data was just recognized by the plenary at ASCO. Walk us through your overall strategy here, including across the various tumor types and combination approaches as you look to maintain your position and expand upon global development?

Yes. We're trying to keep that a little bit close to our chest because every time we announce something, our competitors announce the same thing and say we're going to do it as well. But when we think about PD-1, VEGF, first of all, I think that PD-1 versus PD-L1 does make a difference. I don't know if it changes too much your strategy, but it might change your overall baseline efficacy.

But with that said, 3 years ago, when we were looking at this asset, we did the boil the ocean exercise. We looked at all the PD-1 indications, all the VEGF approved indications. There was a lot of sort of history around those 2 targets that they are validated targets. And we looked at where we could go and where we can contribute. So part of that is you look at PD-1, you look at VEGF, you look at where those agents are approved, the overlap like lung cancer seems like a great target, and we're going after lung cancer.

And what's interesting about the class is that when you look at the data that Akeso has generated, there are some targets that are very interesting, right? So that was very surprising to me that there was so much activity in CRC. We knew that there was an Avastin effect, but I think it's beyond that. So CRC is something that we've disclosed.

We have an interest in head and neck cancer, right? So that study has been announced as well. And so we have that ongoing collaboration with Illumina -- the Illumina study with GORTEC. So we're going after head and neck cancer. I think people weren't understanding that until they saw this recent data at ASCO showing the activity. So any PD-1 VEGF, we're very interested in. Lung is our core, right? That is the biggest indication in PD-1s. And so we think owning that space is very important. That's why we have the HARMONi-3 study, the HARMONi-7 study, the HARMONi study.

The only indication that can rival that in unmet need is probably CRC, microsatellite stable CRC, and that's why we have the GI3 indication going. I think the GORTEC study head and neck is also very important, not as large an indication. But if you look at all the other indications, we are actively looking at them. A lot of times, it becomes a business decision, how much better than pembro do you think we're going to be. And that's always our competition, it seems like in most indications. And if you're expecting me to name those indications that we're planning in the next year, I'm sorry, I can't give those to you today. Yes.

As a stand-alone company without a multinational partner, do you think that your balance sheet and strategic perspectives alone are intact? And I guess, really, how do you think about it as you look to address the $90 billion plus checkpoint oncology market?

Yes. We've always said we'll be -- there will be dilution here. It could be 5%, it could be 10%. On an annualized basis, you should invest with that. We'll do our best to better that as we can. This is a business that either going alone, you can partner with someone that can assist you with sales and marketing or you can merge all 3 of those opportunities, we will factor in. We're here for patients first. We also are here to make sure that wealth is created not only for patients, but for all participants.

So we think we're doing a good job with that. We think there's plenty of opportunity there. And we think we are the causative source as to any of the 3 choices. And right now, we enjoy the position we're in. Clearly, on the big pharma side, OS is a major factor. But we have on the drug 2 OS readouts, one nominal. So we have 3 OS. No one else has touched that. No one else has touched pembro. We're 36% less chance, 34% less chance of death with a pembro equivalent.

We think we're actually in a very profound and positive position moving forward. So we have an ATM. We have access to capital. We're in touch with those on the Street that can provide that. I've participated in each of the fundraisers and would look forward to continuing to do so. So I hope that gives you some color.

And just to frame the discussion we're going to have here, what are the key events and milestones that we should be focusing on over the next 12 months?

Yes. So certainly, we have -- over the course of 2026, we have our final PFS readout for HARMONi-3 squamous. Shortly thereafter in the first half rather of 2027, we have the non-squamous readout for PFS as well. So in terms of short term, we have immediately 2 market opportunities reading out in the second half of this year, first half of next year. And then we also have our BLA in the post-TKI EGFR mutant with PDUFA date of November of this year.

And Salveen, if I may say as well, the trials still going. I mean we are really enrolling the patients very fast. Some of the trials really 6 to 9 months is ahead of schedule on the non-squamous. The HARMONi-7 is moving very fast and CRC as well. That has to be in consideration of what Dave is talking on the readout very soon, hopefully.

In the HARMONi-6 overall survival data that was presented at ASCO, Ivo demonstrated a 34% survival benefit over Tevimbra, a hazard ratio of 0.66. Can you frame the results in the context of your global programs and speak to any KOL feedback post the plenary session?

Sure. So I want to pause for a second with what you just said. This is the first randomized Phase III study to ever go head-to-head with PD-1 plus chemo and show a statistically significant, clinically meaningful overall survival benefit, full stop, right? There's never been a drug that has been able to replace PD-1 inhibitor therapy and show both a PFS and OS benefit in this case. And that's really important because we replace the PD-1 therapy in this setting.

And so with that, there's now an overall survival benefit. So when coming into ASCO, it was really important. One of the remaining questions was, hey, you've shown strong PFS benefits. HARMONi-A was statistically significant. HARMONi showed the nominal p-value that implied significance. But in the frontline lung setting, this is really the cornerstone of where pembro and the other PD-1 inhibitors have really dug their heels in, in terms of entrenched. This has now gone -- ivonescimab has gone head-to-head against the PD-1 regimen and shown a statistically significant overall survival benefit. So I think that's really important to be clear on.

I think with respect to what does this mean for the program globally, you certainly don't feel worse going into the rest of the program now knowing that, right? And so that certainly improves confidence with respect to what does this mean globally. I think there's also a really important concept here as well, people talk about, hey, there's a VEGF inhibitor as a part of -- or VEGF inhibition is a part of the novel mechanism of ivonescimab. Historically, we've seen VEGF inhibition degrade from PFS to OS.

And one of the things that you heard us talk about over the past 6 months is that's not something that we expect in the frontline setting. What we now have coming out of ASCO is a PFS benefit and an OS benefit that statistically are highly consistent and highly correlated, right? So 0.60 in PFS, 0.66 in OS. But what that really represents is, statistically, are numbers that are very close together and highly correlated. So we're not seeing a big gap between PFS and OS. That's the key takeaway, right?

As we talk about -- I think I'm going to get here, but one of the questions that we tend to get a lot from the Street is, hey, what's a clinically meaningful benefit? What does this mean in the West? What do you need to achieve? And we've always been pretty clear that from a KOL perspective, community perspective, the academic and treating community at large, 0.8 hazard ratio in overall survival was kind of a gold standard benchmark. What we now show is a wide buffer with respect to what we see in the HARMONi-6 trial from what that OS gold standard benchmark is. And we also see highly correlated PFS to OS.

So as we take that forward, we now have more confidence with respect to the global applicability of ivonescimab in terms of its ability to show an overall survival benefit based on a few of those points. So you asked more broadly, there's been some noise with respect to the forest plots of the HARMONi-6 trial showed a benefit for all patients. No patients crossed the hazard ratio bound of 1. And so -- but hey, maybe somewhere within the 20 or so cohorts, we saw one that was a little bit a little bit more spread than others, and that was age. And so I want to hit that point head on as well because I think that's something that people have spoken to.

And so one, all patients received the benefit period, right? There were no patients who had a hazard ratio that crossed 1. Secondly, as we talked about at ESMO last year, there was -- when you do not stratify for every subgroup or every variable, you will have some imbalances across those. And specifically with those patients greater than 65 in the tisle arm, the Tevimbra side, and those patients greater than 65 in the ivo arm, there was an imbalance, and there were prognostic factors or those components that maybe favor the outcome more so on the Tevimbra side.

So for example, the median size of the lesion was larger in that subgroup in the ivo arm. There were more distant metastases. There were more brain metastases at baseline in the ivo arm. And so those sorts of things can happen in a randomized Phase III study. What we still saw even with that was a benefit for ivo in all scenarios.

Finally, this is the fourth Phase III. So not only by starting, do I talk about this is the first trial ever to go head-to-head against PD-1 plus chemo in solid tumors and show a statistically significant benefit. There was another study that went head-to-head against pembro in the HARMONi-2 study that was monotherapy ivo, monotherapy pembro and showed the benefit in PFS. We just haven't reached the OS readout yet. That showed highly consistent results greater than less than 65.

There also are the HARMONi and the HARMONi-A, the second and third Phase IIIs to read out, those also showed highly consistent benefit less than and greater than 65. So 3 other Phase III studies, all showing a consistent benefit less than and greater than 65. And so when we look across this, the question becomes, hey, is this something that worries you? No, it doesn't at this point in time because we have the totality of the evidence across all 4 Phase III clinical trials is very strong.

Yes. And I would just add, Salveen, when I was talking to physicians after the meeting, they're very excited about ivo, right? I think Summit has a tradition of drawing very tough sort of discussions in our presentations.

But I think she sort of missed the point of that in the presentation, right? We've now proven an OS benefit. The PFS can transition to OS benefit. It works as a monotherapy. It works well in combination with chemotherapy. That doesn't mask the benefit of ivonescimab. And I think that presentation sort of sets ivo as the leading molecule in a new class of agents. And that was the importance of that presentation, right, that you sort of totally missed.

It's not just about lung cancer. It's about all the PD-1 VEGF indications that are addressable. It's not a question of does this drug work? It clearly validates the class. It's just how big is this class going to be. And that's the more important question.

To follow up here in your HARMONi-3 study, the global lung cancer trial, how are you accounting for imbalances on baseline characteristics? And I'm saying this in the context of the translation from the HARMONi-6 trial to yours where the U.S. patient [indiscernible] China?

Yes. So the HARMONi-3 and HARMONi-6 study are very similar in the sense. In tradition, in China, they do cap enrollment at 75. That's not an unusual thing. That's common and same for Chinese studies. In the U.S., we tend to be more sort of liberal in terms of the age.

First of all, I want to say that, that was the only study that showed a difference in the hazard ratio of age. The other thing I wanted to point out, it still showed a slight benefit. The hazard ratio was still under 1. There was no detriment, right? So traditionally, what you do in the study is you balance for criteria that you think may impact the outcome, the location of metastases, the region as well as the PD-L1 expression. So those things are accounted for as in stratification factors for randomization. To date, we have not seen age as an important factor.

And the other thing, too, discuss that made a big point of bringing this out, but had she looked back at the ESMO presentation in 2025, where they presented a PFS, they saw this age. The hazard ratio was 0.88 for the age greater than 65, but they had accounted for that by imbalances in terms of other criteria, brain metastases, size of the lesions and so forth. So again, I think there's always going to be the statistical noise. But if you look at that forest plot, there's nothing that crosses over to the right side or goes above 1. Everything is still under 1. So we still expect there to be a benefit broadly across patient groups.

Go ahead.

Yes. The only other thing I would add to that, Salveen, right, it's really important to remember that overall across the study, across the 2 arms, those are balanced. Those pieces are balanced. It's when you get into a subgroup and then you look at the balance across that subgroup. So across our HARMONi-3 study, just like in HARMONi-6 , in totality across the ivo arm in total and the tisle arm in total in their study and our study across the ivo arm in the pembro arm, those criteria are balanced.

For the HARMONi-3 study, you recently disclosed in the squamous population interim PFS analysis, and it did not achieve statistical significance despite read-through from HARMONi-6. Can you speak to what drove the divergence here? Was it event maturity, the higher statistical bar or other factors such as control arm performance or regional differences?

Yes. And it's a good question. And I think one -- so we really haven't given details with respect to the statistical plan, but I'll make 2 points, one of which is we had one specific purpose when we were looking to include this, and this was a late addition to the study with respect to the interim analysis. And that was we already have a substantial lead within the class.

And so this was an opportunity really to take the readout in the second half of this year that's already planned and look to accelerate that by even more time, roughly 2 months or so in order to have a conversation earlier with the health authorities. So any time you have an opportunity to speak with the health authorities with a statistically significant primary endpoint, that was a calculated risk that was taken.

Obviously, follow-up time was a little bit different with respect to HARMONi-6 within our study and whatnot. But I think the calculated risk was for that very specific purpose. I think overall, as we look at the final analysis at the end of 2026, there is a meaningfully different bar in terms of the threshold to achieve there.

And so that's also an important point. It's not the same bar looking again and hoping to change things. This is a meaningfully higher bar in the interim than what we'll see in the final. And obviously, now that you have the information with respect to ASCO, the high correlation between the PFS and OS is also very relevant as well.

What do you view as the bar for the final PFS analysis in the second half? And how should we calibrate the probability of success here?

Yes. I think we've seen overall the data -- so if you take what we saw in HARMONi-6 and then you take also HARMONi and HARMONi-A, HARMONi-2, all of the data is pointing to and trending to the same direction. So we have over 4,000 patients who have been treated in clinical studies with ivonescimab to date between Summit and Akeso. And so the totality of that information, we're able to look at and really understand across pathology, across tumor types, early-stage, late-stage clinical trials, so on and so forth.

And that -- the totality of that evidence really points us into where our confidence is on the trial as a whole. I think if we look at individual points for thresholds, I think it's obviously important to set up statistically significant and clinically meaningful trials that show a statistically significant and clinically meaningful bar. And so that really becomes our threshold for both PFS and OS.

And how are you thinking about the interim OS read at the same time?

Yes. And that's a great question, right? And so the second half of this year is the final PFS. So historically, within trials, we look at OS as well to ensure that you don't have any sort of detriment to survival. We are not looking at the interim overall survival in the second half of this year as a be-all-end-all make or break for that endpoint because we have additional looks set up in the future. And so it will be important to show that there's no detriment there.

However, what I don't want that to be misconstrued as is any lack of confidence in that endpoint. So there are other in-class trials that are being run in the Phase III setting. So Bristol-Myers and BioNTech are running their study in frontline non-small cell lung cancer as well. They have taken out an overall survival as a primary endpoint, and they have a PFS sole primary endpoint. We have not. We have a PFS OS primary endpoint.

The reason why we will maintain overall survival as primary endpoint is because we strongly believe in that endpoint for this drug in this setting, in this trial. And so -- and we see that validated through the results of HARMONi-6 as well. So we have no hesitation whatsoever with respect to where we are looking with respect to ivonescimab in the future.

Great. And one last question here on HARMONi-3. So for the non-squamous cohort, we'll see final PFS analysis in the first half of '27. What gives you confidence in the readout and maybe speak to the mechanistic or structural differences between the squamous and non-squamous population? Allen?

Yes. So when I started oncology, which was like a long time ago, they were actually treated as one group. So a couple of things. I think let's talk about the differences and why we're confident. So the chemo backbone is a little bit different. For a non-squamous, they use pemetrexate instead of a taxane. The methotrexate stays on as maintenance, right?

So traditionally, adenos or non-squamous tend to do better in terms of OS and PFS with treatment. With that said, we're confident because if you look back at the Phase II data, there was a benefit, right? If you look at the HARMONi-2 data, which was monotherapy ivonescimab versus monotherapy pembrolizumab, it showed a very clear benefit both in the squamous group and the non-squamous group, and that benefit was about the same, right?

So finally, when you look at the study, we believe that it will work. There are some adjustments you have to make because non-squamous patients do better overall. They get a little bit more chemotherapy. So the treatment effect may be a little bit harder to detect, but that's why the non-squamous cohort is larger in size, right? And it may not be that you need more power, you just want to bring those events in soon enough that you can see it in a reasonable amount of time.

Now finally, the leap from squamous to non-squamous histology is actually not that big. I get the concern, but think about the jump from squamous non-small cell lung cancer to microsatellite stable colorectal adenocarcinoma, another adenocarcinoma, we see good activity there. Again, I think the biology is such that this molecule is going to be broadly applicable. And I want to say that we have the superior molecule as well.

Yes. The one thing I would add to that as well is when we look at the Phase II data that was generated in both settings, right? And so when we initially entered into the deal with Akeso, there was strong squamous Phase II data in frontline lung cancer in combination with chemotherapy. Because of the enrollment pattern, they had -- our partners at Akeso had enrolled the squamous cohort first and then the non-squamous cohort was enrolled afterwards. And so the data took a little bit more time to mature.

So in addition to what Allen said with respect to HARMONi-2, the other thing that's really important is the Phase II data in both squamous and non-squamous was very [indiscernible] forward with the Phase III.

Our partners at Akeso effectively replicated what they saw in Phase II. That was the AK112-201 study, where there was an 11.1 month PFS benefit in the Phase II and an 11.1 month PFS benefit in the Phase III HARMONi-6 study. And so -- and then we saw overall survival at ASCO. And so when we look at the non-squamous cohort, we also see highly encouraging data in that setting as well. And so part of that is also -- it's everything that Allen spoke to in addition to some Phase II data underneath that to support them.

Bob and Maky, with multiple PD-1 VEGF drugs in development here, how do you support the view that ivo is not just first-in-class, but also best-in-class? And what data would prove this differentiation? And in that context, interesting to see the CRC data at ASCO versus competitors.

You jump, and I'll follow up.

Okay. I mean it's for sure, once you have a drug that is going to perform, it's very obvious that left and right, you're going to have other pharma, biotech, they are going to start to develop other molecules. The interesting part was when we started with the VEGF/PD-1, nobody was there. Nobody believed in us. And it was like 2.5 years ago. And that was really difficult even at this moment of time to enroll one patient.

Now you are everywhere. Everybody is talking about VEGF/PD-1, which is great for us because that shows that we were right at this moment of time, and we continue to keep our position and being leading in this process. I always say, you know what, we will see at the end how everything will go. Every single patient deserves any drug that works -- but at this moment of time, especially, I can say the data of Pfizer versus us. You see the overall response rate.

For sure, there's a lot of different things behind the trials that I know that Allen can talk more in detail, but that shows as well that even in this regard, at minimum in this therapeutic area, we are leading even on the safety and efficacy process. So yes, other drug existing. We continue to execute. We focus our attention to where we are, our drug, our clinical trials. And as I mentioned multiple times, and I'm very proud to say that you cannot right now find any VEGF/PD-1 inhibitors or this bispecific that is in multiple clinical trials. I mean we have 47 sponsored trials, 15 Phase III, 155, including all of the collaborations if it's with other ADC, if it's the KRAS inhibitors, if it's IST program.

So that is really -- I mean, it's interesting right now, we are enrolling. But in 2, 3 years from now, even 1 year from now, you will see one data after the other will hit the market. And that is the beauty of the strategic work that the team did during this past 2 years.

And as well, I can say is even from financial part, you will see it very cost effectively we are doing all of our trials. I mean Akeso leads with the Phase II, we catch it on the Phase III. The IST program is really giving us a lot of information while we are moving along the way. The collaboration with the big pharma right now is as well something that over time, you will see how we did our deal of collaboration. So all of them, I can say, I'm proud of the way that the team worked, and I'm sure this one will never stay behind the cloud. We'll convert it soon enough.

Our team, the top 10 people have worked together for over 10 years, and we've had extraordinary success where others wouldn't go. We didn't succeed by following. We succeeded by leading. We went to China when only Chinese went to China. 4 years ago and the American press was like allergic to it. That's not the case now. There's not one big pharma company that won't straight out admit that China is the leading developer of novel therapies. And it's not because some of them don't have American citizenship. It's not because some of them weren't educated in America because they're hard-working, smart human beings benefiting the rest of us. And it's not that others won't catch up.

We saw the bispecific tetravalent. I think very few people knew what stood for, knew what it meant. Akeso is the source of the bispecific tetravalent. Pembro is a monospecific bivalent and there is no comparison between the 2. If you need an enemy going after cancer, you're going to pick the bispecific every single time.

So we made 2 immediately great calls there. Paid $0.5 billion, raised $500 million overnight without commissions, launched into the partnership with Akeso. 70% of what we -- 80% of what we remain to owe them is on revenue payout, the $10 billion, $20 billion, $30 billion. These are monies that I really, as I sit here, hope we pay. We pay those monies, and we're not sitting here at an $11 billion market cap.

5 years ago, SpaceX had a $0.25 billion market cap and it is sitting there probably within the next few days at $1.7 trillion. I will just tell you that bispecifics tetravalent will dose over 1 million people before anyone will colonize Mars. But pick what you want here, but this is a business that is every bit as big as the GLP. The GLPs are at $100 billion and prices are coming down.

We're also at that $90 billion, $100 billion market cap and someone is going to get value to paid for it. Pembro will generate over $60 billion in the next 3 years, the tail end of what it produced. Meanwhile, we're trading at $11 billion, and we have the lead. There was an ad by Merck at ASCO saying 20 years of pembro success. Now is the time for a little change in the approach and then went dot, dot, dot, and it's a subcu therapy. And I put after dot, dot, dot, ivonescimab. So we'll see how this turns out.

But this team that is in front of you today and those behind us have an unbelievably impeccable track record in a very challenging business. And we've come up spades, spades and spades, and we're going to do the same thing on this one. And those that own it, congratulations. And those that don't, you should probably look at doing it. That's my advice.

If I could just add and sort of extend what they said. So Bob has said that we're first-in-class, best-in-class, right? We're first-in-class because Bob and Maky had the foresight to sort of see this asset years ahead of everybody else. They went to China, found this asset [ that nobody had hears of ], we're 2 to 3 years ahead of everybody, right? So we have a BLA under review. We have our second Phase III readout that's going to read out by the end of the year, approximately at the end of the year.

And our closest competitor is probably going to have their first Phase III readout in 2028. So we're way ahead in terms of being the first-in-class. We are clearly, I think, also the best-in-class. And I'll little geek out here, but I'm kind of cautious because every time we say we have cooperative binding, they say, "Oh, I don't believe in cooperative binding." Now they all say they have cooperative binding, right? We say that there's internalization. They say there's internalization, right? So some food for thought here.

PD-1 and PD-L1 will make a difference in this class of agents, right? If you say that they're the same, they're not. If you believe internalization is a key component of the MOA, whether you target PD-1 versus PD-L1 is going to be important. PD-1 addresses the T lymphocytes, which my team calls serial killers. They keep killing and killing and killing. If you target PD-L1 and you get internalization, and that's important, then you get degradation of the drug, you're going to limit your internalization. You're only going to internalize in the tumor cell there directly, right? And then you lose the drug and you lose the effect.

The other thing is that PD-L1 is expressed broadly across different tumor types. Now PD-L1 expression levels are going to make an important role, but it's a numbers game when you look at PD-1 versus PD-L1. If you look at the sort of third agent in the field, I think the clinical data is empirically showing that we're superior. They target PD-1, but it's very clear that they can't dose at what we can dose and the clinical efficacy, although only in Phase II so far, doesn't seem to be comparable to us as well.

And therefore, I think I've always said this, because of the bispecifics, because of the tetravalent technology, the format and the targets will matter unlike PD-1s, right? That was a commodity. Here, the technology that Akeso has built is, I think, superior and best-in-class.

Salveen, I love Allen's passion. As soon as he starts, he can never stop. And to answer Bob's question, I believe [indiscernible] in the market as you see me in the mood. I mean you cannot put me in this box to send me to spaceship. So...

Allen came in and interviewed, just I really had no idea, even how to pronounce his name. And we had a great interview. I said, why did you come to us? He said, "Well, I quit my out of the company. I said, why did you quit?" He said, "I disagreed with the Chief Executive Officer." I said who was right? He said, "I was." I said "You're hired." This guy is one sharp guy. Dave Gancarz is one sharp guy.

Salveen is one sharp lady, Maky Fortune billionaire and Manmeet is, really brilliant. So you've got brilliant people doing the right thing. We thinking the same way you do. I don't take a salary. I make or break it just the way you make or break. This is either going up and I win or it's going down, I lose, and we're not going to lose. We got plenty of ways to make this go right. So thanks for your attention. Thanks for your past support. And I think if we're here next year, this place will be packed.

And one quick last question for Manmeet here. Given the planned Phase III expansions we just talked about in the commercial build-out, how should we think about cash runway?

So we have been pretty efficient in our capital allocation, right? Running 4 Phase IIIs by ourselves. Our run rate for last quarter was $120 million. We ended last quarter with over $600 million in cash. And as Bob said, there is no scarcity of cash, and it's our choice at what time we want to raise and we will keep doing. We did -- in every year from last 3 years, we have raised $0.5 billion approximately every year, which is sufficient for us to keep it.

We don't want to keep like billions of dollars in the balance sheet because we believe in the drug, and there are so many more milestones which are coming in the next 12 to 18 months, which will give us ample opportunity to raise money.

For commercialization going there, yes, we are preparing. We have hired our commercial leadership team and market access team is already in the field. We have started our -- a lot of activities on that part, which is a long lead time. Otherwise, we will continue to allocate commercialization spend as we see appropriate, but there is no concern.

We -- in this company, I think we make budgets for the sake of budget. But if there is a value add for ivonescimab, we just clear it, right, over here. There is nothing like a budget that stops our people for doing something, whether it's collaborations or whether it's anything.

Okay. With that, thank you so much. Really appreciate the time today.

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the Summit Therapeutics ASCO 2026 Update Call. [Operator Instructions] I would now like to turn the call over to Dave Gancarz, Chief Business and Strategy Officer. Please go ahead.

Good morning, and thank you for joining us. Team Summit is pleased to be hosting this call from Chicago, where the oncology community has gathered for what has already been an exciting ASCO 2026 Congress. This meeting continues to showcase the rapid pace of innovation across cancer research and treatment, and we're energized to be a part of this important scientific and clinical discussion directing the next wave of medicines for patients with cancer.

We issued 2 press releases over the weekend relating to encouraging Phase II data in metastatic colorectal cancer and, of course, the historic results of the Phase III HARMONi-6 trial featuring Ivonescimab presented as part of yesterday's plenary session at ASCO. The Phase II CRC data is a global data set, including patients enrolled in the United States and China, and the HARMONi-6 study was conducted exclusively in China, sponsored by our partners at Akeso.

All data in the HARMONi-6 study was exclusively generated, managed and analyzed by Akeso. The press releases are available on our website, www.smmttx.com. Today's call is being simultaneously webcast, and an archived replay will also be made available later today on our website.

Joining me on the call today is Bob Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Maky Zanganeh, our President and Co-Chief Executive Officer; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; Dr. Bilal Piperdi, our Chief Medical Officer; Dr. Allen Yang, our Chief R&D Strategy Officer; and Dr. Howard Jack West, our VP of Global Medical Affairs. I am Dave Gancarz, our Chief Business and Strategy Officer. Before we get started with the call, I would like to note that some statements made by our management team and some responses to questions that we make today may be considered forward-looking statements based on our current expectations.

Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties.

Summit undertakes no obligations to update these forward-looking statements, except as required by law. One item of note, this presentation is being webcast with slides, so we'll be referring to slides being displayed on the webcast link. I'd encourage you to use the webcast link to see the slides being presented this morning that will accompany our comments.

Following comments from our team, we will take questions. And with that, I would like to hand it over to Dr. Jack West to walk through the beginning of the presentation.

Thank you, Dave. Yesterday, as you are aware, ivonescimab data were featured in a presentation as part of the plenary session at ASCO. The presentation titled ivonescimab + chemo chemotherapy versus tislelizumab + chemotherapy in previously untreated advanced squamous non-small cell lung cancer, overall survival results of the Phase III HARMONi-6 trial was delivered by Dr. Shun Lu, MD, PhD, Principal Investigator of HARMONi-6, Director of the Lung Cancer Center at Shanghai Chest Hospital and tenured Professor.

Prior to discussing the results of the study, we will reinforce the study design and baseline characteristics that were discussed at ESMO last fall as well as published simultaneously in the first paper for the study in the Lancet. The study was highly significant in its primary endpoint of progression-free survival.

And of course, the focus of the data release was the overall survival data from this study. Revisiting the schema for the HARMONi-6 trial, this study evaluated ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, a PD-1 inhibitor in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous non-small cell lung cancer, irrespective of PD-L1 expression.

HARMONi-6 is a single region multicenter Phase III study conducted in China and sponsored by Akeso with all relevant data exclusively generated, managed and analyzed by Akeso. Key eligibility criteria are shown here. Patients were randomized 1:1 and stratified by stage of cancer and PD-L1 tumor expression at baseline.

Patients received either ivonescimab at 20 milligrams per kilogram + carboplatin-paclitaxel or tislelizumab + carboplatin-paclitaxel for up to 4 cycles, then received either ivonescimab or tislelizumab as maintenance therapy for up to 24 months.

Treatment was to be discontinued for intolerability, progressive disease or initiation of new antitumor therapy. The study's single primary endpoint was progression-free survival by independent radiologic review committee. The focus of today's progression will be overall survival. The trial included a total of 532 patients.

Baseline characteristics show that this was a predominantly male population, nearly all with Stage IV disease, and it's important to underscore that these patients with advanced squamous non-small cell lung cancer included patients with characteristics that have traditionally been considered as potentially associated with bleeding on anti-angiogenic therapy.

Specifically, approximately 2/3 had a central tumor, 17% had encasement of major blood vessels in the chest, 9% had tumor cavitation and nearly 1 in 3 had a history of some hemostasis. The breakdown of PD-L1 expression showed approximately 40% had a PD-L1 negative cancer with the remaining 60% of PD-L1 positive cancers showing 40% in the low range of 1% to 49% and about 20% with high PD-L1 expression of 50% or greater.

The median follow-up time of this current data cut is 21.4 months. At the planned interim analysis of the study, the trial was positive for overall survival with a hazard ratio of 0.66 and a corresponding p-value of 0.0017 and representing at least a 4-month difference in median survival, though this remains early at this time.

The curves separate early at approximately 6 months after treatment begins and continues to expand with additional time. Landmark 2-year overall survival rates were 64.7% for those patients receiving ivonescimab compared to 48.6% for those receiving Anti-PD-1 therapy with tislelizumab.

This represents the first randomized Phase III study conducted in driver mutation negative frontline non-small cell lung cancer against another PD-1 therapy in combination with chemotherapy to achieve a statistically significant benefit in overall survival.

When we look at various subgroups, it's important to highlight that the size of the subgroups is smaller by definition and not designed to show statistical significance on their own. The subgroup analysis for overall survival confirms the benefit in 3 planned subsets as indicated by point estimates for each subgroup landing on the left side of the dividing line favoring ivonescimab, overall, showing that the study results were observed broadly and not driven by a specific subset or subsets of patients.

These overall survival curves show benefit in patients with negative, low and high PD-L1 expression. Representing PD-L1 TPS scores of less than 1%, 1% to 49% and 50% or more, respectively, at baseline. Patients with negative PD-L1 tumor expression had a hazard ratio of 0.64. Those with low PD-L1 tumor expression had a hazard ratio of 0.67 and those with high PD-L1 tumor expression had a hazard ratio of 0.64.

In other words, ivonescimab with chemotherapy demonstrated benefit compared to tislelizumab with chemotherapy across the entire spectrum of tumor PD-L1 expression.

Ivonescimab continued to demonstrate an acceptable and manageable safety profile in the HARMONi-6 study, consistent with previous Phase III studies of ivonescimab + chemotherapy. No additional safety signals were noted in the HARMONi-6 study. Treatment-related serious adverse events occurred in 41.4% of patients receiving ivonescimab + chemotherapy and 34.3% of patients receiving tislelizumab + chemotherapy.

Treatment-related adverse events leading to discontinuation in the study occurred in 5.3% of patients receiving ivonescimab + chemotherapy compared to 4.5% for those receiving tislelizumab + chemotherapy. The most common treatment-related adverse events in both arms were commonly associated with platinum doublet chemotherapy and included anemia, decreases in neutrophil counts and white blood cell counts.

Most of the possibly VEGF-related adverse events occurring in the ivonescimab + chemotherapy arm were classified as Grade 1 or 2. Grade 3 or higher hemorrhage events were observed in 2.6% of patients in the ivonescimab + chemotherapy arm compared to 0.8% of patients in the tislelizumab + chemotherapy arm of the study. In summary, ivonescimab provided a statistically significant and clinically meaningful overall survival benefit for patients with advanced squamous non-small cell lung cancer as first-line treatment in the HARMONi-6 trial with a hazard ratio of 0.66, which was consistent across all key subgroups, including those with negative, low or high PD-L1 tumor expression.

Regardless of PD-L1 tumor expression, patients received consistent benefit. Ivonescimab's strong performance across all levels of PD-L1 expression is important as ivonescimab appears to provide clinically meaningful improvements to patients irrespective of PD-L1 expression. Ivonescimab was well tolerated with low rates of adverse events leading to discontinuation or death, both comparable to the tislelizumab + chemotherapy arm.

Prior to HARMONi-6, there were no known Phase III clinical trials in non-small cell lung cancer that have shown a statistically significant improvement in both PFS and now OS compared to PD-1 or L1 inhibitor therapy in combination with chemotherapy in a head-to-head comparison. Following the success of Akeso's HARMONi-2 study in China, where the PFS benefit was observed in a monotherapy setting for patients whose squamous or non-squamous tumors were positive for PD-L1 expression.

This is the second time in which ivonescimab-based regimens have become the first known investigational therapy to demonstrate a statistically significant benefit compared to standard of care PD-1 or L1 inhibitor-based therapies. This underscores the specific value that ivonescimab and the HARMONi-6 regimen could bring to patients in this setting with the opportunity to include a differentiated mechanism of action for physicians and patients to choose from.

We believe that ivonescimab has the potential to become a new standard of care for advanced squamous non-small cell lung cancer, and we look forward to the near-term readouts for our global Phase III study, HARMONi-3, evaluating ivonescimab in frontline non-small cell lung cancer.

With today's positive HARMONi-6 overall survival update, we gain even more confidence in the potential for ivonescimab to make a meaningful difference in the lives of patients with lung cancer. On that note, we want to extend a heartfelt thank you to the patients and their families, the clinical site personnel and the Akeso team for contributing to and conducting the HARMONi-6 trial.

Additionally, it is worth highlighting that the Lancet published a full HARMONi-6 manuscript concurrent with yesterday's plenary session. And with that, I'd like to turn it back to Dave.

Thanks, Jack. I'd like to echo Jack's comments around our gratitude to the patients who enrolled on HARMONi-6, their family members, trial site personnel, investigators and, of course, the Akeso team. We are highly encouraged by the read-through of this study to HARMONi-3 in frontline all-comers non-small cell lung cancer as well as HARMONi-7 in non-small cell lung cancer with high PD-L1 expression.

Anti-PD-1 therapy with or without chemotherapy, depending on PD-L1 status is the overwhelming standard of care in frontline lung cancer without driver mutations. Ivonescimab, both as monotherapy and in combination with chemotherapy, now compared favorably in both settings in Phase III studies conducted in China.

While additional HARMONi-3 data will be important to see in the coming quarters, the consistent, statistically significant, clinically meaningful results in progression-free survival and overall survival in HARMONi-6 and the PFS and OS data generated to date from HARMONi-2 are very encouraging when we look to our ongoing global frontline lung cancer studies and beyond.

One additional point I'd like to ensure we go over. There were some commentary with respect to subgroup analysis -- to the subgroup analysis hazard ratios that were disclosed in the forest plot for overall survival related to results by age groups presented yesterday.

As you may recall from ESMO 2025, while patients under 65 and over 65, both showed a PFS benefit from ivonescimab + chemotherapy as compared to tislelizumab + chemotherapy, the effect was seen less in older patients. An analysis was performed by Akeso to review differences in baseline characteristics between those over 65 in the Ivo arm versus the tisle arm to understand this difference.

In doing so, multiple imbalances were noted, including target lesion size and the presence of brain metastases. This was specifically addressed previously during the ESMO 2025 presentation. Correcting for these baseline differences explained the substantive portion of the difference in hazard ratios by age for PFS, and it is important to see that written on the slide on the screen right now.

If you are on the webcast, the slides from ESMO 2025 note that when adjusting for these covariants, the adjusted PFS hazard ratio for those patients greater than 65 years old was 0.69. Note that for both PFS and OS, not even considering the imbalanced baseline characteristics, the older subgroup did not show any detriment. Once adjusted for these baseline differences, the hazard ratio for PFS was normalized to the overall population. Therefore, the difference noted appears to be more -- most likely driven by the imbalance baseline characteristics.

These differences were seen in PFS and could be seen in the OS forest plots as well and can happen in clinical trials. Each subgroup is not powered and is not necessarily balanced for baseline characteristics. And if prognostic factors are not balanced, a subgroup can be impacted as we described previously last October.

Importantly, remember that HARMONi-6 is the fourth Phase III study conducted evaluating ivonescimab. In the first 3 studies, results for patients under and over 65 were very comparable. In the global HARMONi study, the longer-term follow-up of OS showed a numerically better hazard ratio for those patients over 65. So HARMONi-6 is the only study where we see this difference and this unpowered subgroup had imbalanced baseline characteristics. Let's move on and discuss the continued deep experience we have with ivonescimab. Ivonescimab has read out 4 Phase III clinical studies to date, all 4 of which had positive data, leading to 2 approvals in China thus far. At this time, a total of 15 Phase III clinical trials have either been announced, are currently ongoing or have read out in multiple tumor types.

47 clinical trials have been initiated since 2019 between Summit and Akeso, evaluating ivonescimab in a variety of solid tumors. When considering investigator-initiated and collaborative studies, a total of 155 clinical trials are now listed on clinicaltrials.gov. The enthusiasm demonstrated by investigators around the world to generate data and seek positive signals for patients facing high unmet medical needs really speaks to the opportunity and optimism surrounding ivonescimab.

Together with our partner, Akeso, we have enrolled over 4,000 patients in either Summit-sponsored or Akeso-sponsored clinical trials around the world. Commercially, in China, over 70,000 patients have received ivonescimab.

Turning to our pipeline and our global Phase III HARMONi study. In April, we provided an update with respect to the squamous cohort of this study. We added to our protocol an interim analysis for PFS for the specific purpose of providing a potential opportunity for earlier regulatory discussions, specifically with the U.S. FDA.

To achieve statistical significance at this early interim look, there was a meaningfully higher bar compared to the upcoming planned final PFS analysis based on minimal alpha spent on the interim analysis. The interim PFS analysis was reviewed by an independent data monitoring committee or an IDMC, and the committee recommended the study continue as planned.

Importantly, no safety concerns were noted and the study continues to be double-blinded. In line with prior guidance, we expect the final progression-free survival and interim overall survival analysis for the squamous cohort in the second half of this year. For the non-squamous cohort, we expect the final progression-free survival analysis to occur in the first half of 2027.

The study continues to be double-blinded, and we do not have further information regarding the results of the study. We look forward to the results of the final PFS and interim OS in the second half of this year. With respect to the non-squamous cohort of HARMONi-3, we have completed screening for patient enrollment and expect to complete enrollment of the 1,000 patient cohort this month.

We continue to enroll in HARMONi-7 and HARMONi-GI3, look forward to continuing our work with GORTEC in head and neck cancer as well as RevMed with Novel RAS inhibitors, kicking off the GSK collaboration testing ivonescimab with ADCs and expanding the number of collaborations we have with other agents with novel mechanisms of action.

With that, I'd like to turn it over to Allen to review the Phase II CRC data in combination with FOLFOX chemotherapy, the backbone chemotherapy, our Phase III HARMONi-GI3 clinical study. Allen?

Thanks, Dave. At this year's ASCO conference, ivonescimab data in colorectal cancer was also featured from the global Phase II study, AK112-206, which evaluates 2 doses of ivonescimab, 20 milligrams per kilogram and 10 milligrams per kilogram in combination with FOLFOX chemotherapy as first-line treatment in patients with microsatellite stable metastatic colorectal cancer.

The study was conducted in China and the U.S. Akeso had previously disclosed encouraging Phase II study data with ivonescimab in combination with different chemotherapy regimens in microsatellite stable CRC. The standard of care chemotherapy in first-line metastatic setting is most often FOLFOX. And so we expanded the Phase II study to include 2 cohorts of ivonescimab at different doses in combination with FOLFOX.

This was the basis for our Phase III study, HARMONi-GI3, as Dave alluded to. This also represents global data as a mix of patients were enrolled from the U.S. and China for these 2 arms. In this analysis, all patients experienced a reduction in tumor burden compared to their baseline assessment.

The addition of ivonescimab to FOLFOX delivered deep and durable response rates and responses were consistent across the 2 dose levels. In the overall study population, ivonescimab + FOLFOX chemotherapy achieved an objective response rate of 70.8% and a disease control rate of 100%.

Treatment responses in the higher dose of ivonescimab + FOLFOX arm were more durable than the lower dose of ivonescimab + FOLFOX with a duration response landmark estimate at 9 months of 79.1% and 41.5%, respectively. For patients in the higher dose ivonescimab arm, the landmark PFS rate at 9 months was 76.1%. While progression-free survival remains immature, the high proportion of patients progression-free at 9 months is encouraging.

The study demonstrated an acceptable and manageable safety profile for the ivonescimab regimen and no new safety signals were observed. This was consistent with previous studies of ivonescimab, including Phase II data in metastatic microsatellite stable CRC and demonstrate the potential for a favorable benefit risk profile for ivonescimab + FOLFOX in this study. In total, including both arms, 20.4% of patients experienced serious treatment-related adverse events associated with either ivonescimab or chemotherapy. There were no ivonescimab-related deaths and one ivonescimab-related discontinuation, supporting the tolerability and ability to manage these adverse events.

These support continued expansion of ivonescimab clinical development in metastatic colorectal cancer. They also support the design of our global Phase III HARMONi-GI3 study in microsatellite stable metastatic colorectal cancer that is currently enrolling. We are pleased with these results at ASCO and are excited about the potential to help patients facing colorectal cancer.

The disease has a particularly poor outcome in the metastatic disease setting with a 5-year survival rate between 13% and 18%, underscoring the urgent need for improved treatment options. Before concluding the call, I wanted to take the opportunity to remind everyone of our upcoming catalysts and recent accomplishments.

As we've discussed on past calls, we will continue to provide further details on additional new global studies throughout the year as they are ready to share. To date, we have initiated global Phase III studies in non-small cell lung cancer, colorectal cancer and head and neck cancer through our partnership with GORTEC.

We look forward to continuing to grow our global pipeline and explore ivonescimab's potential to help more patients in new tumor settings. For HARMONi-3 trial -- for the HARMONi-3 trial evaluating ivonescimab with chemotherapy in frontline all-comers non-small cell lung cancer, we have completed enrollment in the squamous cohort.

We are now completing enrollment for the non-squamous cohort and expect to conclude enrollment this month. As I mentioned earlier, the final PFS and interim OS analysis for the squamous cohort are expected in the second half of this year for the non-squamous cohort and the final PFS analysis is expected in the first half of 2027. Turning to our BLA filing. Based on our Phase III HARMONi study seeking approval for ivonescimab + chemotherapy in the EGFRm-mutated non-small cell lung cancer setting Post-TKI, the submission is currently under review with the U.S. FDA. The agency has provided a target PDUFA date of November 14 later this year.

We continue to grow our commercial capabilities as we prepare for the anticipation of ivonescimab's potential first U.S. approval and potential launch later this year. Okay. I'd like to give it back to Dave Gancarz.

Thanks, Allen. On today's call, we've covered ivonescimab's accomplishments thus far in the clinic, but this is only the beginning of a vast potential market opportunity set for ivonescimab across solid tumors. We have discussed this several times before, but with each successful data set, it becomes -- the reality becomes closer.

Ivonescimab has the potential to be a platform blockbuster drug. Ivonescimab is well positioned to make a significant impact across the solid tumor treatment landscape between checkpoint inhibitors and Anti-VEGF therapies with an estimated total addressable market to be in excess of $100 billion globally. Looking only at the checkpoint inhibitor market for non-small cell lung cancer, market estimates for immunotherapy are expected to exceed $20 billion per year by 2028.

On the slide you see on the screen now, in many solid tumor settings where Anti-PD-1 and Anti-VEGF therapies are highlighted, PD-1 and PD-L1 indications in green and Anti-VEGF indications in purple. The ones highlighted in yellow represent the indications where we are currently running Phase III trials for ivonescimab globally, lung and colorectal cancers.

Clearly, there are several additional opportunities for ivonescimab, including, in addition, novel settings where neither have been affected, such as EGFRm mutant on small cell lung cancer. Ivonescimab's differentiated profile, as we saw with HARMONi-6 achieving a statistically significant, highly clinically meaningful PFS and OS benefit supports this platform potential across multiple indications, each of which could be blockbuster opportunities on their own. We have only just begun to see the potential of ivonescimab to help patients with solid tumors. These are exciting times at Summit, and we encourage you to stay tuned to our journey as we continue to expand the ivonescimab clinical development plan in new tumor settings.

We'll now turn the call back to the operator to see if there are any questions that our team can help answer. If you could please open the line for questions.

[Operator Instructions] Your first question comes from the line of Tyler Van Buren with TD Cowen.

Congratulations on the tremendous and potentially practice-changing data presented this weekend. Just can you provide your latest thoughts on how you believe the PFS hazard ratio and now the impressive OS hazard ratio for HARMONi-6 will translate to the ongoing HARMONi-3 trial?

And as the follow-up to that, what is -- specifically, what is your confidence that Ivo is performing similarly to HARMONi-6 in the ongoing HARMONi-3 trial, considering the fact that it passed on the recent interim PFS analysis?

Thanks, Tyler. I think with respect to the overall confidence on HARMONi-3, as we mentioned on the call as well as we've mentioned a few times historically, the purpose for that interim analysis was specifically as we look at the landscape overall competitively, there are multiple PD-1, VEGF in class of which we are significantly in the lead.

And so we've looked at an opportunity to take the final PFS timing in the second half of this year and with -- and look to accelerate the timing by which we could speak to the U.S. health authorities and affect the regulators and in that case, specifically the FDA. And so with the minimal alpha allocation, we looked to perform that interim analysis, as I mentioned on the call.

And so the -- and as I said earlier, the IDMC looked -- recommended to continue and recommended no changes to the study. With that, we have no change in terms of our overall confidence because what we did in that process was not change the final PFS threshold in effect. It was extraordinarily minimal in terms of the cost on the final.

So as we look now at the data from HARMONi-6, we see 2 things. We see a highly statistically significant PFS and a highly statistically significant OS. And so that in the same setting gives us a lot of confidence as we look at the translation overall from one study to another in that same setting that we have -- are very well positioned with respect to the second half of this year.

I'd also remind if we look back at the gold standard endpoint of OS, when we look at the HARMONi and the HARMONi-A studies, we had remarkably consistent median OS from the East and the West as well as highly consistent hazard ratio. So we've seen in the past consistency overall between data with ivonescimab in China as compared to globally.

And then the final point I would make is, overall, again, we've had 4 Phase III readouts in total. All 4 have been positive. And so when we look at the trajectory of that data, it's all pointing in one direction at this point, and that's been positive.

And so from that perspective, while no one has a clear crystal ball, it is very much -- as we look at the data, we see everything moving and aligning in the same direction from that perspective.

Dave, I'd like to add, Tyler, thanks for the question. Akeso has been a terrific partner. So the HARMONi-6 and HARMONi-3 trials are very similar, if not almost identical. In addition, Akeso has helped us enroll patients from China for the HARMONi-3 study. So about 1/3 of those patients will be from overlapping sites and investigators with the HARMONi-3 and HARMONi-6 study. So the one thing I'd also like to point out is we took a calculated risk trying to bring this drug to patients earlier.

But the enrollment for the squamous cohort just recently completed. And therefore, that data was immature. We understood that risk, but we took it. Obviously, we were not happy with the results, but we thought that was important for patients. But as the data matures, we expect our data to strengthen, although we haven't seen it.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

Congratulations on the data here. Two for me. One is, how do you think the strong squamous results read through to the non-squamous portion of the study? And secondly, at the presentation, the presenter noted that the median OS was reached with the last patient event. Could you put that finding in context and expectations for OS upon additional maturation?

Thanks, Salveen. Why don't we start with the first question that you asked there with respect -- can you repeat the first question? I just want to make sure I got the full context on the first question.

Sure. Just how to think about the read-through from the squamous result to the non-squamous portion of the study?

Very good. And so I think it's important. I'll give a little bit of history here, Salveen, because I think this is good context overall. When we look at the history of HARMONi-3, for example, we started in squamous, and that was generally because when we entered into our transaction with Akeso, the Phase II data in squamous in combination with chemotherapy was very strong and was maturing. And so we immediately -- and I think Bob has alluded to this a few times in the past, it was very important that we -- when we entered into the transaction with Akeso that we started very quickly in terms of establishing a presence with the PD-1, VEGF bispecific.

And so the squamous data in Phase II was mature. It was highly encouraging, and that's what prompted an immediate opening of that study. As we then looked at the non-squamous portion, it was just simply less mature at that point in time, and so it was in our pipeline in terms of addressing.

Fast forward now to the middle of 2024, we see the positive data from HARMONi-2 that showed monotherapy Ivo performing well in both squamous and non-squamous histologies. At that same time in 2024, the Phase II non-squamous data in combination with chemotherapy was also maturing, was highly encouraging.

So I say all that because when we get to now HARMONi-6 and your question with respect to the read-through, that HARMONi-6 data was highly validating to the Phase II data that was seen in AK112-201, the Phase II study. And so we saw highly encouraging Phase II data in squamous -- that then translated to the HARMONi-6 success that we've seen now.

We have highly encouraging Phase II data in non-squamous as well. And so that data becomes a little bit more validated as well with the Phase III replicating the Phase II data. And when I say replicating, for example, the median PFS was nearly identical between the Phase II and the Phase III. And so what we're seeing is the data that we've relied on in terms of the encouraging opportunity in non-squamous, that Phase II data has been -- that same study has been shown to replicate Phase II to Phase III.

Obviously, it's frontline lung cancer as well. And so highly encouraging opportunities are present and the existing Phase III data in squamous is highly encouraging. So there's -- there's certainly nothing negative with respect to the non-squamous portion. I'll turn it over to Jack for the second half of that question with respect to...

[Remind me?].

Yes, with respect to the last patient who passed away leading to the median.

The highlight there is that at that part of the curve, it's a very small number of patients. And so a single patient death among 4 patients at that time led to a drop just below the median, but that's a very unstable finding. In fact, it is defining the lower limit of the confidence interval for that median, which means it can only improve from what that is, and that's exactly what Akeso, I believe, expects will be the case as the data mature and there is a much larger population to draw from who gets out to and beyond the median that point.

So that is the lowest number that would ever be seen and we might anticipate based on the patterns that, that isn't truly a representative number and that it's going to end up with further follow-up as a stronger difference in terms of absolute number of months between the 2 arms.

And Salveen, this is Allen. I'd add to -- I understand the question about squamous translating over to non-squamous being non-squamous is a greater unmet need in Western markets. I want to point out the HARMONi and HARMONi-A studies. Those were non-squamous histologies with the same chemo backbone, even though they are EGFR mutant non-small cell lung cancer.

And again, all the strong ivonescimab data in complete different tumor types of CRC, TNBC. So the drug is active. So the jump from squamous to non-squamous histology is small compared to the breadth of this molecule.

That's right. And I think the other piece I would add on top of Jack nice explanation, when you look at the curve overall, what you are seeing is the curve separating at 6 months, but then continuing to expand. And that's really what reflects the hazard ratio of 0.66 and that 34% relative improvement in reducing the risk of death.

Yes. Obviously, the median is just one point in time, but that shape of the curve as everyone highlighted, including in the plenary session, is widening as the patients continue over time and the curve moves to the right. So that median kind of underrepresents the benefit that was really seen.

Yes. So when you look at the baseline tislelizumab + chemotherapy, which performed either on par with or slightly above historical results with respect to the RATIONALE-307 study, which is the pivotal study in which tislelizumab + chemo was approved. That relative improvement of 34% relative improvement on top of that 22, 23-month benchmark, you would certainly expect that to be a bit higher than the 4 months.

Just the math would tell you it's closer to 7 to 8. And so when you look at the median follow-up time of 21 months and change, what this really represents because those curves are widening further with more time, that hazard ratio in respect of confidence interval and thus the p-value becomes statistically significant, showing that there's clearly the benefit already with more opportunity to continue to look at longer-term follow-ups, if you will.

But this is the final -- this is the primary overall survival analysis. It is statistically significant and highly statistically significant at that. And I think that 34% relative risk reduction is the important part to look at.

Your next question comes from the line of Yigal Nochomovitz with Citi.

Congrats on the very, very strong result at ASCO. Thanks for also mentioning the covariate analysis that you did at ESMO with regard to the PFS. I'm just curious if you were to apply that same math and logic to OS, what the conclusions may be? And curious as to why the ASCO discussion didn't put forward that piece of analysis.

And then also, could you just clarify as to why the interim was triggered at 204 versus the planned 225 events as defined in the protocol for the study?

Thanks, Yigal. And so I think the -- so -- and we appreciate the comment with respect to the covariate analyses. And so importantly, there was not a separate covariate analyses run at this point with respect to overall survival.

However, the baseline characteristics to be very clear, don't change over the course of the study, right? These are the baseline characteristics of the patients entering in. And so the baseline characteristics at the PFS analysis remain, of course, consistent with those at the overall survival analysis.

And that's why we thought it was important today to remind everyone of this particular topic, which was discussed back in October of 2025, where those imbalanced characteristics -- baseline characteristics within the greater than 65 year-old patients between Ivo and tisle is very relevant.

So as you saw that translate from an PFS hazard ratio of about 0.88 down to about 0.69 when you took into account the fact that those in the Ivo arm had higher rates of brain metastases, had larger target lesions at baseline, right, those baseline characteristics when adjusted, normalize the difference between those under and over 65.

I think it's also -- it is really important also to note that this is the fourth Phase III study conducted with ivonescimab. The other 3 did not show any detriment when looking at those over 65 as compared to those under 65. And so this is where it's important to remember, these are non-powered subgroups as well.

And so you don't have necessarily balanced baseline characteristics amongst the subgroups and you also aren't powering your study to reflect the results of those patients. So we see other studies. For example, there are studies that have been run where highly statistically significant overall survival benefit. FLAURA2 is an example of this where the results in first-line EGFR mutant non-small cell lung cancer, osimertinib + chemo versus osimertinib monotherapy, about 1/3 to 35% of those patients were enrolled in Asia ex-China, but that specific subgroup, that region showed a hazard ratio of 1.00.

Representing 1/3 of the patients or more enrolled in that study. However, I don't think anybody would argue that osimertinib + chemotherapy works in China, but not in the rest of Asia from that perspective and then also works in the U.S. and Europe. So I say all that just to provide example -- an example of a place where when you look specifically at a subgroup and then you try to extract too much from that, it's very difficult to do because you don't balance for everything else that goes into a very well-designed and robust clinical study.

And so as we think about that, there was no detriment to patients over 65 either from a PFS or an OS perspective. And I think that's really important to point out.

I'll take the next question and you can add. So Yigal, thanks for the question. The other question was about why they did the OS analysis slightly around that - it was 204 and versus 220, it's not uncommon. It's a goal, and it's often hard to predict how many patients you'll have at the time of the analysis because there's a cleaning and sort of preparation and the locking of the database.

So as long as you're within -- well within 10%, that's not unusual. I can't comment that question is probably best for Akeso partners. But it's often as part of a regulatory discussion, there may be a query from a regulatory agency. That's the reason I see that they would slightly vary from their targets.

Your next question comes from the line of Brad Canino with Guggenheim Partners.

Congrats to you, your team and your partner on those data. The 0.66 hazard ratio and the at least 4-month benefit, can you contextualize these results within the past frontline squamous lung trials that have changed practice? And then you always get a lot of questions on the translation of that benefit to HARMONi-3.

But do you need to translate that magnitude? Or is there some margin where even a lower result could be significant enough to still change practice?

Yes. This is Jack. I will feel that I spend a lot of my time talking with my colleagues who are clinical oncologists. And I would say that a huge amount of the excitement about HARMONi-2, I know I'm going back in time, was just that as impressive and as integral as pembrolizumab has been a sense that it was an impenetrable plateau that we might never exceed in our careers and just seeing the capacity to do better than that is remarkable and all of the potential opportunities to exceed that with pembro or potentially other checkpoint inhibitors. Squamous, in particular, is a setting that has been -- has had a dearth of developments over time as compared to non-squamous, where there's new driver mutations and targeted therapies that chip away.

But squamous has really been left without many new opportunities. And that would make any development especially welcome. Seeing a PFS benefit is not negligible. And in many settings of oncology, that is eagerly accepted as enough to adopt a new therapy. I think that in lung cancer, non-small cell, at least particularly, we often impose a higher bar of overall survival.

That said, if it is a hazard ratio below about 0.75 or 0.8, that is enough for nearly every oncologist I speak with to consider that to be very clinically relevant, clinically meaningful and worth adopting as a new treatment. I would also say that when I've spoken with and seen results of survey questions from colleagues about, well, if you see a PFS benefit, but the overall survival may or may not be statistically significant, but trending in the right direction, you get a splay a mix of different opinions about whether that is clearly enough. But about half of my colleagues really feel that PFS benefit and even a modest trend of improvement in overall survival is perfectly welcome first to their patients; and secondly, themselves because this is not a comparison against placebo or chemotherapy alone.

This is the first time we're seeing an improvement against such a high bar, and it's not accompanied by a counterbalancing major liability and toxicity. So people are saying, if this is compared to pembro or tislelizumab and you clearly exceed on PFS and it's in the right direction for OS and not accompanied by a problematic increase in toxicity, why would my patient not want to pursue that option.

So yes, there's going to be a range in what clinicians require to adopt something. I would say the results we saw yesterday would be on the very far end of that range and really not controversial, but with a lot of room to see less than that and still be enough to motivate patients and most oncologists or many oncologists to readily adopt an improvement in some, even if not every parameter across the board.

Your next question comes from the line of Mohit Bansal with Wells Fargo.

My congratulations as well. So I would love to talk a little bit about the median follow-up at the point of interim in HARMONi-3 versus HARMONi-6. To what extent you can comment on that? And was there a difference between the median follow-up in HARMONi-3 interim versus 6 interim that could explain why you did not hit the interim at that time point?

Yes. This is Dave. I'll jump in and then I'll ask Bilal to provide any additional color. So what I would say overall is enrollment patterns are a little bit different as we know in any study in China versus any study globally, the enrollment patterns are a little bit longer. So what you will see in general, when you look at enrollment in a global study is a little bit more back-ended enrollment, one; and two, longer period of time.

I'm making very general comments with respect to enrollment in a global study as compared to China, where you tend to ramp up very quickly and enroll the duration of the study over a shorter period of time. And so while Mohit, we're not going to give particular color in terms of here's median follow-ups and very specifics related to HARMONi-3, it would be incredibly unusual to provide that commentary on an interim look.

But what I would say is there are patterns that you can look at across global studies in general across studies conducted in a single region and particularly in China in general, where the distribution of events, the follow-up time will be a little bit different just naturally just based on the traditional patterns that you see for enrollment. And then I'll ask Bilal if there's anything else you'd like to add.

Thanks for the question. I agree with Dave. I think more important rather than the median is the pattern of enrollment. And so sometimes it's a little hard to translate one to the other. For the last interim for HARMONi-3, we took a calculated risk because we want to get this drug earlier to the patients. And I think we're really trying out. We are very confident with how this is going towards the final analysis.

Your next question comes from the line of Cory Kasimov with Evercore ISI.

This is Josh on for Cory Kasimov. Given there's precedence of China-only trial allowing for approval in the EU, such as RATIONALE-307, wondering if there's any plans to use the HARMONi-6 data set to look for [indiscernible] in the [EU?]. And if not, how could these results help with the HARMONi-3 application?

Thanks for the question, Josh. I think I'll make a couple of points here. So obviously -- so when we entered into the great partnership with Akeso, one of the things that we were pretty clear on with respect to the U.S. individually was that we never had an intent to take a single region study conducted outside of the U.S. and look to bring that specifically in China and then look to bring that to the FDA for approval.

I think the FDA had made plenty of comments prior to that, that, that was not what they were looking for. We then, of course, open the HARMONi-3 study. With respect to HARMONi-3, that will be the primary study for which we would seek approval, especially in the United States.

But there's complementary considerations. There's another randomized Phase III in the same setting, particularly in the squamous cohort of HARMONi-3. So from a package perspective, HARMONi-6 could be included to strengthen that overall package. And so the other piece is when we look at, to your point, Josh, questions in other geographic locations, those are things that we can continue to consider. And so obviously, we're running HARMONi-3 in Europe as well. So that's part of the calculus that needs to go into this. And part of this is also is we have -- if you take the totality of events, we completed enrollment in the first quarter of this year for the squamous cohort.

And then also this data is -- it was a late breaker at ASCO. So it's pretty fresh in terms of what we have here. And so part of that, as we look at next steps, we'll consider multiple options. But it's important that we have the global HARMONi-3 data reading out in the second half of this year. And so we can look at combining packages in certain ways, but this is also -- unlike the RATIONALE-307, there wasn't necessarily a study being run in those regions at the same time, which is where we were always -- we've talked very consistently about our strong strategic and operational desires to bring ivonescimab around the world.

And so with that, we can look at whether it makes sense to combine those packages based on what things look like when we get to the second half of this year as well, which make that a much more straightforward question to answer.

Your next question comes from the line of Ren Benjamin with Citizens.

Add my congratulations as well. I guess the question I have is kind of given all that you know now for the HARMONi-6 study and the required kind of amount of follow-up, which occurred for the interim OS to hit statistical significance.

Can you maybe talk us through your thoughts as to why maybe you wouldn't delay the reporting of the interim OS for HARMONi-3? How do you maybe optimize so that you have the right amount of follow-up and the right amount of events that might occur so that both PFS and OS are potentially hitting in the second half of this year?

And maybe as a follow-up, I think you mentioned the OS significance boundary was like 0.049 for this HARMONi-6 study. Do we -- is it fair to apply kind of a stat since you've never specified the step plan that we see in HARMONi-6 to HARMONi-3 and why you would choose a one-sided test over a 2-sided test?

You added a couple of questions in there. I think...

I did, sorry, Dave.

So I think one of the points with respect to the one-sided test versus the two-sided test, I mean I think that's probably a little bit -- I think there's a little bit of noise in one of the media coverage articles. I don't think that's a particularly relevant aspect here.

The idea of both HARMONi-3 and HARMONi-6 is looking to show statistical superiority over PD-1 + chemotherapy. And so that is -- we're not looking at it the other way around. So the difference -- there's really no functional difference between the 2. The it's just a different way to describe the results of the same test. With respect to the stat plan for HARMONi-3. I appreciate the question. But I think as I mentioned a couple of times and as we've talked about as a group and its common across nearly all interim analyses, we don't plan to provide individual details on the individual statistical plan for the study, and that includes both the previous interim PFS look as well as the upcoming interim OS look.

I think the third piece, I think, which is important is your question with respect to the bar in the interim OS at the end of this year, less the bar in terms of what the thresholds are, but the ability to compare the follow-up time in HARMONi-6 or other studies and looking at the timing of HARMONi-3.

So HARMONi-3, as we've talked about, this is an interim OS analysis, but it's also the final PFS analysis. And so those are effectively tied together. So we'll look at the final PFS analysis based on our prespecified number of events, and that will -- that's looked at the end of -- those events look like they'll come in the second half of this year, and that's the end of the testing for PFS. And traditionally, when you look at a final PFS analysis, you also, at that same time, have a look at interim OS or you have a look at OS on an interim basis.

So I would say we should set no expectations that the idea is an interim OS look at the second half of this year is a make or break look. But I think it will be very informative in terms of what that looks like from overall survival. And that will also take place at a median follow-up time that's less than what the HARMONi-6 follow-up time was.

And so HARMONi-6, I believe, completed enrollment in January of 2025. This analysis had a data cutoff that was presented yesterday at the end of February 2026. And so you've got last patient in plus about 13 months there. We talked about the fact that we completed enrollment in the first quarter of this year. And then we're saying that this final PFS and interim OS will take place in the second half of this year.

So while you don't know necessarily when in the second half, it's obviously going to be less than 13 months. of median follow-up time. So we think that's very informative in terms of what directionally where OS looks. But I certainly wouldn't go into this with the expectations that we feel that OS as an endpoint is make or break in the second half of this year.

We have a look just like most trials do at OS at the time of the final PFS, which is prespecified, and that's what we're looking at the second half of this year. And so within that interim OS gives us directional inference in terms of where we go from what that data looks like to describe the OS at this point.

Your next question comes from the line of David Dai with UBS.

I also want to add my congratulations on the data. So one thing you mentioned, Dave, was that there was imbalance between the 65 years of age and under 65 based on lesion size and brain mets. So how do you think this might impact patient selection for HARMONi-3 trial? And do you expect to exclude some patients with these kind of covariants for HARMONi-3 trial?

Yes. I understand your question, David. So -- and I appreciate what you're asking. Importantly, HARMONi-3 remains completely blinded. So if we step back, what you aren't able to define within subgroups before -- as you look at the data is what different covariables will be unbalanced within the arm.

So I think it's a little bit of a speculative question of will different subgroups, which are not stratified in the trial, will they contain imbalance baseline characteristics. Again, I would say -- so there's no way to know that before you go into a trial. But I would also say that's where looking at subgroups can be helpful.

And I think as Jack mentioned in his comments, but they're not powered for individual results, right? And so what you're looking for is do you see a subgroup with a hazard ratio over 1 and particularly -- directionally well over 1 that gives you pause to say clinically, is there something here that may be more informative maybe than what we had thought hypothetically going into a study.

I want to be very clear. All subgroups had a hazard ratio of less than 1. All subgroups received benefit from ivonescimab + chemotherapy in comparison to tislelizumab + chemotherapy. All subgroups trended were the left of the line on the forest plot, right?

So there were no subgroups that were detrimental when received or had a detriment from ivonescimab as compared to PD-1. That's a really important context here. And so even with the imbalance of these variables, we did not see a detriment to any of these patients, right? It was a smaller improvement, but an improvement nonetheless, right? And I think that's the difference here that I want to make sure we don't lose sight of. This isn't an example where we're looking at a subgroup with a 1.3 hazard ratio and saying, hey, we really need to take a step back and understand if there's something there. And so there's no way to know a priority going into a study the Western patients versus the Eastern patients or the PD-L1 high versus the PD-L1 low will ultimately have more brain metastases versus less or whatnot because that's not really what's planned for.

But I think that where -- that's where we'll see that data that comes through. But it is very important that all subgroups were less than one, and therefore, none of these imbalances actually led to a detriment.

Yes, Dave...

I was just going to add one thing too to reassure you. There are criteria which we believe could impact the outcome. And so things like brain metastases as well as PD-L1 expression levels are stratified for in the HARMONi-3 study.

Yes. Just to add on Jack, this is Bilal here. And if you look at the 95% confidence interval, I think the overlapping between the 2 age groups further strengthen that. I mean this could be fairly random.

Your next question comes from the line of Dara Azar with Stifel.

Congrats on the data. Could you please characterize the growing separation of the OS curves? Do you attribute this to ivonescimab or the histology more? And how strong is the case to see a similar phenomenon in non-squamous non-small cell considering HARMONi-2 OS hazard ratio translation from PFS was a little bit different in that mixed histology study.

This is Jack. I think that the most noticeable thing, again, when you see the separation becomes clearer as the chemotherapy has been completed. Chemotherapy is kind of a normalizing effect. And then you -- once you're at the point where you're directly testing the ivonescimab against the other immunotherapy and tislelizumab, the longer you go, the more that differential becomes apparent.

I think that with non-squamous non-small cell lung cancer, it's different because there's going to be ongoing maintenance pemetrexed. And so that may still have some kind of normalizing or effect that may -- that will change it from a paradigm where there's a prolonged period of just ivonescimab as monotherapy in the maintenance setting against pembrolizumab.

So it will be a little different, but you still see the separation occur, and I am optimistic that that's what we will see, especially as if patients are fortunate enough to be doing well without progression, in some cases, patients will have pemetrexed discontinued due to cumulative myelosuppression issues, renal issues and even though pemetrexed is generally considered a very well-tolerated therapy, it has cumulative toxicities if patients are on it for enough of a period that it really becomes longitudinal.

So there will still be patients who are just ongoing essentially monotherapy of in HARMONi-3, ivonescimab against pembrolizumab. But the separation, I think, will be there, but it will be a little different question in the non-squamous population, both because of the underlying differences in biology and because there is not a maintenance chemo component in squamous.

And again, I think the only thing I would add is really the -- again, we go back to the highly encouraging Phase II data generated in the space where we saw very -- and some of this was disclosed as recently as ELCC 2024 and obviously, that's highly encouraging data as well that helps provide additional comfort on that front as well in terms of the applicability of ivonescimab + chemotherapy in the non-squamous cohort.

I'd now like to turn the call over to Dave Gancarz for closing remarks.

I want to take the time to thank everybody for attending today's call. Obviously, the historic results of HARMONi-6 is we've gone over multiple times, is a day for celebration across both Summit team, and I want to once again congratulate our partners at Akeso for a wonderful results.

This is a hazard ratio of 0.66 is not something to shake a stick at. But not only that, this is the first trial to go head-to-head against a PD-1 + chemotherapy in frontline driver mutation negative non-small cell lung cancer and show a statistically significant benefit, not only in PFS, but now overall survival.

And that is not -- as Jack was very eloquently describing earlier, not a borderline case and not anything other than something to be fully celebrated. So we want to take the time to thank you for attending today's call. An archived version of the webcast will be available on our website, and enjoy the rest of your day. And for those of you here in Chicago, we hope you have a wonderful rest of your ASCO.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

All right. We'll go ahead and get started. Good afternoon, everyone. Thanks for being with us. This is the second day of the Citizens Life Sciences Conference here in Miami. It's my pleasure to welcome Summit Therapeutics joining us here. Joining us is Dave Gancarz, CBO and Strategy Officer; as well as Allen Yang, Chief Medical Officer. So thank you guys both for being here. I never know exactly who's in the audience who knows the Summit story, who may not. I don't know who's listening in on the webcast as well. So I always like to start these discussions off with maybe a 2- to 5-minute overview of Summit as a whole.

Sure. And really appreciate, Reni. Thank you for the invitation, and happy to be here. So Summit Therapeutics focuses primarily on our main pipeline asset, which is ivonescimab. So we entered into a strategic partnership with Akeso Bio in December of 2022. That deal went effective in January 2023 for ivonescimab. So Summit Therapeutics has the rights to ivonescimab in North America, South America, Europe, Africa, the Middle East and Japan. So major markets effectively outside of China and Korea.

And so as we look through the strategic process, what that involved was getting going in late-stage clinical studies as soon as possible. So part of the impetus behind that deal was really a significant amount of data that was highly encouraging in Phase II in order to allow for that immediate progression into the pivotal studies. And so immediately upon in-licensing ivonescimab, we began by expanding the HARMONi-A study into the global HARMONi study. And that was performed over the course of '23 and '24.

And so we've read that data out, and that was positive with results displayed at World Lung last year. And so that was statistically significant in progression-free survival, although not statistically significant in overall survival in the primary analysis and part of that due to the follow-up period with respect to Western patients based on kind of expanding that study from a China-specific study into a global study. That became with additional follow-up time of Western patients, showing a nominal p-value of less than 0.04.

And so as we look through the strategic steps for ivonescimab, frontline solid tumors was the core of the priority. And so we went -- shortly after initiating the HARMONi study, we launched HARMONi-3 in frontline non-small cell lung cancer in combination with chemotherapy. While that started as a squamous specific study, that ultimately became squamous and non-squamous. And so we had mature Phase II data in squamous -- frontline squamous non-small cell lung cancer in the AK112-201 study. That prompted us to go immediately into the squamous cohort once we saw the data from the Phase III HARMONi-2 study in China as well as maturing data from the 201, that same Phase II study in the non-squamous cohort that went into both histologies.

So that brings us to a full frontline chemo combination study. We also have the HARMONi-7 study, the monotherapy non-small cell lung cancer study in PD-L1 high-expressing populations. And then recently, we initiated the HARMONi-GI3 study, which is a global study in microsatellite stable colorectal cancer. So 4 Phase III studies are sponsored by Summit at this point, 3 in non-small cell lung cancer and one in MSS colorectal cancer. And so where do we sit then today based on some of the work that we've done as well as our partners at Akeso.

So between the 2 companies, 4 Phase III clinical studies have read out at this point, 4 Phase IIIs have read out with positive data. So it's been a good start from that perspective. And so all 4 were positive with respect to progression-free survival. And in addition, so HARMONi-A was statistically significant in overall survival in China post-TKI EGFR mutant lung cancer. 3 of the 4 have had some level of readout in overall survival. All 3 of those have had a hazard ratio less than 0.8, if you will, that generally accepted clinically meaningful threshold for overall survival when we speak to physicians, KOLs, investigators and so on and so forth.

So as we look forward, we have quite a bit coming now in 2026. And so that includes the squamous cohort of the HARMONi-3 study has now completed enrollment. So we'll look to an interim PFS analysis in the second quarter and then a final PFS and an interim OS analysis in the second half of 2026. And then the non-squamous cohort completes enrollment in the second half of this year and then final PFS, interim OS -- or final PFS in the first half of 2027 and then there is an interim OS planned. And so we haven't definitively guided in terms of when that is.

And so that puts us in a pretty good position with respect to upcoming events. We have the PDUFA for the BLA with respect to the HARMONi study in November of 2026 as well. So several catalyst events in '26. And then I think finally, the larger point, if you look at the totality of ivonescimab, 10 Phase IIIs currently being run by our partners at Akeso. We have the 4. There's a fifth that's a head and neck frontline study that's multiregional. And so that is being performed by a cooperative group in CorTec, called the Illuminate study. So 15 Phase IIIs throughout.

Over 4,000 patients have now been dosed in clinical studies sponsored either by Summit or Akeso. And Akeso has achieved approval in China for ivonescimab in 2 settings, and that has led to over 60,000 patients who have now been treated in a commercial setting in China. So good uptake there.

I think the final point I would highlight is the enthusiasm across solid tumors from investigators. So over 140 clinical trials are registered on clinicaltrials.gov. And so a little over 40 of those are sponsored by either Summit or Akeso. So that means there's a significant amount of interest globally, both in our regions as well as in China with respect to investigators initiating -- investigator-initiated trials in order to evaluate ivonescimab in several settings beyond those of which we've discussed.

I think -- thank you very much, right, for that overview. We'll dig in a little bit more on maybe some specific HARMONi studies because I always get the nomenclature a little bit mixed up 2, 3a, right, all this stuff. But I think we unanimously hear that this could be one of the game-changing molecules in IO, right? So there was KEYTRUDA, Opdivo, right, Yervoy. And people have always been trying to improve upon that, right? Those are phenomenal molecules. I don't want to say it was. They are phenomenal molecules. We've been trying to improve on it forever, whether it's other checkpoints, right, combinations and the like. And it seems like ivonescimab has really potentially cracked the nut. So can you just tell us the uniqueness of this molecule? I know everyone knows it's a bispecific, but the uniqueness of the molecule. And if you had to pick like out of the many studies you highlighted, had to pick one study to showcase the ORR, the PFS and the OS, what would it be?

Okay. I shall take that. So in terms of the molecule itself, it has 2 validated targets, PD-1 and VEGF. And I think what was underappreciated at the time when that molecule came out is like, "Well, why can't you just give pembro and bevacizumab together? And there were studies with atezo/bev that went around and showed maybe some activity, no clear better activity than pembro alone.

But I think what people underappreciated was that the way the molecule was designed. It wasn't just targeting the molecules. It's the way that it targeted. So we talk about cooperativity. And when I talk about cooperativity, there's 2 types of cooperativity with one we call sort of allosteric cooperativity where the PD-1 binding increases the binding of VEGF and the VEGF binding increases the binding of PD-1. So you get the tightest binding where you have both ligands present, which is the tumor microenvironment.

The other thing that's underappreciated is that it's a tetramer, so it has 2 VEGF binding sites, 2 PD-1 binding sites. VEGF-A is actually a dimer. And what's been well shown is you can actually cross-link one IVO to VEGF to another IVO to another VEGF to another IVO. This is what we call associative cooperativity. And this cross-linking does 2 things. It presents these high-affinity PD-1 binding sites. So you can imagine multiple PD-1 binding sites binding to a T cell. But we now have evidence that it actually causes clustering of the PD-1 receptor on the cell membrane, and that leads to actually internalization and degradation of the PD-1 receptor. And we believe that's going to be important as well.

And I think the take-home message is that unlike the PD-1/PD-L1 story from the previous checkpoint inhibitor era, where there's about a dozen approved and they seem to be interchangeable, the format is going to be very important. We think ivonescimab is not only the first-in-class, but probably the best-in-class. However, there's not enough data for the other molecules to sort of compare it to. But I think as more data evolves and more data is compared, you'll see that the format matters.

The one study that I think sort of demonstrates this the best is the HARMONi-2 study run by Akeso. That was a pure experiment. We always knew that, that was going to be important. That study was ongoing at the time of the deal, where Summit licensed this from Akeso, Monotherapy pembrolizumab versus monotherapy ivonescimab. Clear in non-small cell lung cancer, sort of a showdown between the 2 drugs. What we were very interested is looking at the data, not only was it -- would it win, we assumed that we would have an advantage and those patients that had low PD-L1 expression because of the VEGF.

But what was interesting was that IVO beat pembro not only in the low PD-L1 expressing, but also the high PD-L1 expressing. So we know that IVO was making the PD-1 aspect of the molecule better. And now there's good evidence that it's not only the sort of mechanical cooperativity, but there's probably some biological cooperativity because VEGF probably plays a role in immune sort of exhaustion and so forth. So we're very excited about the molecule. The molecule has performed very well and several studies have been positive now.

And can you just remind us of kind of the delta? Like that's a great example, right, head-to-head. Everyone asks in the [ IVO ] space, like do you have monotherapy activity? And this like concretely showed you, right? So now when you're going into chemo combinations or ADC combinations, no one can sit back and debate, "Oh, does it have monotherapy activity." So can you just remind us of that benefit that you saw over KEYTRUDA?

Yes. So the -- you know the number...

Yes, hazard ratio in the monotherapy study, PFS was 0.51, so about a 49% improvement over monotherapy pembrolizumab. I think equally as important, following on to what Allen said was then that was tested in the chemo combination setting as well, right? And so the HARMONi-6 study read out in frontline chemo combination non-small cell lung cancer, head-to-headed PD-1 plus chemotherapy. And so that also showed a significant improvement that was clinically meaningful hazard ratio of 0.60.

And so now we're seeing activity clearly in monotherapy head-to-head to Allen's point with respect to that monotherapy activity. But now in the -- what is the overwhelming backbone therapy in solid tumors, PD-1 plus chemo, a clear separation of those curves within the HARMONi-6 study performed by our partner, Akeso in China that showed clear benefit in that chemo combination study as well.

So everyone kind of asks us about the HARMONi study, right? So this is what you just -- you filed on. You have a BLA in November -- sorry, PDUFA date in November. It was a very anticipated data set, right? And it was bittersweet, like you hit in PFS, but the first look at OS didn't meet. But then as you mentioned, the second look did meet. Normally, one would require some encouragement from the FDA, from investigators, something to kind of give you the gumption to go ahead and still file, right? And you did. Can you just give us maybe a little bit of the background or why did you decide to just go ahead and file for this indication?

Yes. So a couple of key points, right, in terms of the setting. So this is the post-TKI setting for EGFR-mutated non-small cell lung cancer. And so osimertinib, either as a monotherapy through the FLAURA trial or in combination with chemotherapy through the FLAURA-2 study. So that's an EGFR TKI, is standard of care as well as the MARIPOSA regimen of amivantamab and lazertinib. So that's your kind of frontline standard of care. Second or post the TKI regimens are really a dearth of opportunity for those patients, right? And so that's amivantamab plus chemotherapy is the only post-TKI fully approved regimen at this point.

And so part of what becomes important, one, is taking a look at what's out there from a landscape perspective or from what patients and physicians have the opportunity to in one regimen. I think there's general understanding in terms of some of the tolerability concerns within that regimen. And so when we look at the results of the HARMONi study, we see very reasonably consistent, if you will, results from an efficacy perspective, statistically significant PFS and then not statistically significant, but a good trend in OS, both with hazard ratios in the 0.7 in that, but neither statistically significant from the statistical analysis perspective.

And so very comparable on efficacy. And then we look at the tolerability, and we do see a difference in terms of a tolerability profile for the ivonescimab plus chemotherapy arm that's -- we get feedback from physicians that there's a high level of tolerability there. And so anecdotally, we hear feedback with respect to treating physicians on the HARMONi studies, it was IVO plus chemo compared to placebo plus chemo. And oftentimes, those physicians wouldn't know which of the 2 arms the patients were on initially because they weren't seeing tolerability concerns that would traditionally come from add-on therapy. So a good kind of read-through in terms of that.

So when we looked at the opportunity, we saw a lot of enthusiasm from physicians. We saw the package that we're able to have in totality, and we thought that, that was highly relevant to patients and physicians, and that drove the decision.

Okay. I don't want to speculate on the regulatory interactions and what might be an ODAC panel or not an ODAC panel. So we'll leave it at that. That's going to come one way or another in November. We do hear from clinicians and KOLs, especially when they're on scientific boards of other companies, when they're giving advice, they're already thinking about IVO being there and being one of the frontline molecules. So that's already a good step of approval, I think, for it.

Let's talk about HARMONi-3 just in the 8 minutes or so we have left. Some people kind of challenge us, right? They're like, well, in HARMONi, they should have just waited longer with OS. They shouldn't have unblinded it together. How do we know that something like that isn't going to happen in HARMONi-3. HARMONi-3 now is the global study you guys have run, right, following HARMONi-A, right, which had both patients from China as well as global. This is all you. How are you feeling about the statistical analysis? You just -- I think at the most recent earnings call said that we're going to have an interim analysis in the second quarter. It was a surprise to me, maybe not to other people. Kind of just take us through how confident you feel about the stat plan and your pacing of the unveiling of data?

Yes. So importantly, the HARMONi study was sequential enrollment to China and then expanding into the U.S. and Europe, right? And so this is a global study from the start with HARMONi-3. So that involves multi regions around the world, Asia, the Americas, Europe, but it's a traditional global study from that perspective. When we look at the recent announcement, as you referenced with respect to the interim PFS, important to note that there are 2 Phase III studies that have replaced PD-1 and have been successful, right?

And so those are the HARMONi-2 and HARMONi-6 studies. The only replacing of PD-1 to be successful is an ivonescimab-based regimen or base study, right? And so both of those were successful in PFS at the interim PFS analysis. And so when we talk about learning from the data, we've said this a lot in terms of the importance of learning from the data being generated by our partners at Akeso and learning from data that we're generating here, always applying that information. This is an example we read out the HARMONi-6 study at ESMO last fall and taking a look, seeing another study hit at the interim PFS that became important in terms of leveraging that information with respect to our design.

The other piece in terms of why do that is the easiest way to have a conversation with the health authorities, in particular, the FDA is to go with a statistically significant primary endpoint, right? And so that -- what that effectively does is pulls in that conversation with the health authorities in terms of a statistically significant primary endpoint should that come true within the interim analysis. And then that allows for accelerating that conversation and what does it look like in terms of bringing this opportunity forward to patients as well.

And so we learned from the data that has been generated previously, not once but twice against -- head-to-head against PD-1 and then said, how do we make this regimen available to patients as soon as possible.

Have you provided any more detail in terms of what the alpha spend is for this interim, if it hits, obviously, everyone knows what happens there. But if it doesn't hit, does it preclude you from other further analysis? Like how should we be thinking about that?

Yes. No. So this is an interim analysis. We haven't given details with respect to statistics other than to say the interim analysis is a higher bar, if you will, than the final analysis, right? So no, there's nothing that would preclude moving forward with the preplanned final analysis that we had talked about previously in the second half of this year. So nothing changes that. It's a higher bar at the interim. So certainly nothing that would say not meeting the interim then leads to the inability to hit the final analysis.

One thing we've also said is in effect, we did not move the bar very much at all in the final analysis to kind of maintain where we were to not really change probability of success throughout 2026, but bring in an opportunity at a higher bar based on what we've seen head-to-head with IVO against PD-1s historically. And that gave us the confidence to add in that step, if you will. In effect, if you think about it, there's no better read-through to a randomized Phase III study than a randomized Phase III study using your own compound in a very similar regimen with an extremely similar control arm.

And so we saw HARMONi-6, and that was highly positive, and that gives us the confidence to pull in an interim PFS analysis and then take that opportunity to go forward in order to accelerate. I think some will say, "Hey, are you hedging?" Not at all. In reality, we're not moving anything with respect to the final in terms of the bigger picture. But what we are doing is bringing in an opportunity a little bit sooner.

I think it's important for investors to also realize that enrollment for these large studies, this is a fairly large study, right? And...

Yes, there's 600 patients in this cohort.

Enrollment went pretty rapidly, right? And you've been able to maintain these. Normally, we see companies that are pushing out for one enrollment issue or another. You guys went very quickly. You're bringing in this interim into the second quarter. So now just help me understand or just correct me if I'm wrong, interim in the second quarter, final in the second half, interim OS in the second half and then final OS in the first half of next year, possibly?

Haven't talked about final OS yet. So we were always very clear when we guide, we want to be reasonably certain about something and so that we're not constantly moving things around, to your point, in terms of changing timing. And so we haven't given timing with respect to final OS, but there would be an interim OS look in the second half of this year as well as the final PFS, if necessary, in the second half of this year. But then what we've said is the non-squamous portion also, that completes enrollment in the second half of this year to be able to look at final PFS and then shortly around that period an interim OS.

So both squamous and non-squamous, right, coming out, which is great. Everyone is going to be looking out at that. We only have about -- I could talk to you guys for a long time about this. So we're really fascinated by the molecule. We love the data that we see. It seems like it's going to be a game changer. But I guess I'd love to maybe take a step back and think about strategy a little bit.

We know from Merck how they were able to get KEYTRUDA to be the best-selling checkpoint inhibitor, right, by a significant amount, right? It's not like there weren't fast followers, right? But clearly, there was a game plan there. As you think about IVO, is it this BLA that's coming up? Is it the squamous, non-squamous data from HARMONi-3? What is it that kind of triggers you to really kind of go out and get the broadest footprint possible for IVO? Is that even like part of the plan? Or do you want to kind of slowly grow this and just have maybe a partner come in and take over? Give us an idea as to how you're thinking about this.

Yes, I'll name a couple of bullet points, and I want to make sure Allen has a chance as well. So a couple of important things. Cornerstone indications for the PD-1 VEGF class are non-small cell lung cancer as it was for the PD-1 class. And then a place where PD-1s were not successful in microsatellite stable colorectal. First 2 tumor settings that we took a look at is others, if you will, in class are looking at starting Phase III clinical studies in first-line non-small cell lung cancer. We're now talking about readouts in that path forward. So that's a pretty significant difference with respect to placement there. And then obviously, we are enrolling now in the colorectal setting as well.

What differentiates here? So 4 Phase IIIs have read out for ivonescimab. There are 4 that have read out for the class, right? And so only ivonescimab has had a readout, 4 for 4. So Allen made a really important point. These are not monoclonal antibodies interchangeable. And so if you make a difference to the molecule construct, that -- when you're 4 for 4 at ivonescimab and you're going to make a change to that, there's more room to go down than there is to go up. That's one.

Two, the 10 Phase IIIs being run by Akeso right now. That speaks to the broad applicability of ivonescimab because there's obviously data supporting moving ahead there. So that's another differentiator. We do plan to go much more broadly, but what we are going to do is kind of give you that information as we're ready to enroll as opposed to showing everybody else where to go and where to start planning, right? So that becomes important. Anything else that?

Yes. No, I would just say that we're going after all of those, right? Like I think Dave mentioned that non-small cell lung cancer is our anchor or cornerstone indication, right? With the studies we have on hand, we will probably sort of corner the market on metastatic non-small cell lung cancer, right? And that's probably about 80% of the market.

The one indication that could actually be bigger than non-small cell lung cancer is microsatellite stable colorectal cancer. And so we have a Phase III, and we're ahead on that as well. So I think those are the important cornerstone or anchor indications, right? If you look at how Merck beat atezo and nivo in the old days, it was because they won in lung cancer, right, even though all 3 of them started about the same time.

Now we're looking across all the indications, right? So with our Akeso partners, we're running 4 global Phase IIIs. They have over 10. So there's like 15 Phase IIIs running. You should probably ask yourself like why aren't we doing certain indications? Like Akeso is doing TNBC. They're doing small cell lung cancer, right? They're doing pancreatic cancer. It's not that we're not able to join those studies. We think that the standard of care in those diseases are going to change. And so maybe we're waiting for something to happen there. And then the other indications, you'll hear more. I think Maky, our CEO, sort of alluded to that you'll hear more Phase IIIs out there. So the idea is to go after all of these things in parallel.

And I think it's important for investors to also know that you guys are disciplined with your -- with the utilization of your cash. You've set up some collaborations with Revolution Medicines and GSK so that you're not necessarily growing this R&D engine to come up with new ADCs or new combination metrics. There are potential partners there to work with?

But that's an important point also because what we're not going to try to do is force the optimization of our own pipeline, right? So we're going to follow the science. We're going to go out. We're going to combine with several different ADCs. We've seen there isn't a single ADC platform that is optimized across solid tumors. So we can combine with platform A in this setting, platform B in this setting. And that, to your earlier point, what led KEYTRUDA to be as explosive as it ultimately ended up being. Merck was able to go after each of those different combination agents or different settings based on following the data as opposed to trying to optimize within its own pipeline that may not be the optimal combination in each setting.

Terrific. Dave, Allen, thank you very much for coming. I apologize for going over time, but really appreciate it.

Thank you.

Thank you.

All right. Good afternoon everyone. Tyler Van Buren here, senior biotech analyst at TD Cowen. Thank you very much for joining us here at TD Cowen's 46th Annual Healthcare Conference. For our next session, it's a privilege to have a fireside chat with Summit Therapeutics, and it's my pleasure to introduce Dave Gancarz, the Chief Business and Strategy Officer; and Allen Yang, the Head of R&D Strategy. Dave and Allen, it's a privilege to have you guys here. Thank you very much for joining me.

Thank you, Tyler. Really appreciate the invite.

So maybe we'll start, we've got a lot of questions, but maybe we'll start with just 1 high-level question, to set a foundation. Again, I'm sure most are aware at this point, but maybe you could just briefly recap the Akeso partnership for ivonescimab, how Summit's role has evolved over time as the program has progressed into late-stage development and global studies and now regulatory review.

Sure. No, I appreciate the question, Tyler. So we entered into the deal with Akesobio, who are our partners based in China for ivonescimab, a PD-1 VEGF bispecific antibody. That deal was signed in December of 2022. And then after traditional customary review that it went effective in January 2023. Akeso at that point was running 2 Phase III studies in non-small cell lung cancer, one post-TKI, EGFR-mutant non-small cell lung cancer and then one in frontline PD-L1 positive non-small cell lung cancer. So effectively HARMONi-A and HARMONi-2. As we entered into the transaction with Akeso, our immediate intent was to also move into late-stage development immediately. So we expanded HARMONi-A into a global study and that became HARMONi as well as looking to start immediately into frontline non-small cell lung cancer, and that was the chemo combination squamous cohort of HARMONi-3.

And so we -- part of the benefit in working with such great partners at Akeso, a significant amount of data had been generated at the time and also very quickly, and then they've continued to invest heavily in ivonescimab given the plethora of products that they have in progress and now approved at different stages in China. And so we work very closely with Akeso on an ongoing and regular basis. And now as we've introduced our third and now fourth Phase III clinical study globally. So HARMONi in post TKI EGFR mutant lung cancer, HARMONi-3, which was then expanded into 2 cohorts, squamous and non-squamous chemo combination frontline non-small cell lung cancer, HARMONi-7 in PD-L1 high non-small cell lung cancer. That's the monotherapy setting.

And then finally, recently last quarter, we introduced the first-line microsatellite stable colorectal cancer study as well. And so that's IVO in combination with chemotherapy compared to standard of care bevacizumab plus chemotherapy. And so we've announced that we intend to continue to expand that clinical development pipeline, as you alluded to, Tyler. So we also announced last week on our earnings call, the Illuminate study, which will be a cooperative group study based -- a multiregional study in Europe and China, and we'll consider expanding that into the United States as well, and that's in frontline PD-L1 positive head and neck squamous cell carcinoma. And so that's the first study that we've announced in 2026, and we've mentioned that we continue -- we plan to continue to announce additional studies as those are ready to launch as well so.

Great. And we'll get into each of those studies and indications in just a moment. But I wanted to spend a little bit on the molecule's design and the clinical implications given the data that you all and Akeso have reported a lot of PD-1 VEGFs out there now following in your footsteps. As we spoke about the other day, following earnings, it's very possible that ivonescimab may have kind of just hit the goldilocks level in terms of its design. And as you think about cooperative binding and daisy chaining. So just maybe elaborate on the molecule and how that's been in your opinion, supported by the data that you've seen so far?

Yes. Thanks for the question. So I think it's now a validated class of agents, the PD-1 VEGF, right? So there's now multiple Phase III studies that show a benefit of PD-1 VEGF bispecifics over PD-1. So I think the class is derisked. The one thing I'd like to communicate is that ivonescimab is unique. And unlike the history of PD-1s, which was the first generation of checkpoint inhibitors where the PD-1 seem to have similar data and almost interchangeable. There was a question of PD-1 versus PD-L1. With the bispecifics, because of this cooperativity the format will matter, okay? So ivonescimab is designed around VEGFA binding sites and PD-1 binding sites. Some of the other molecules will try to bind PD-L1 and not PD-1. Some of the other molecules won't have the daisy chaining ability, right?

So we know that there's what we call intramolecular cooperativity, the binding of PD-1 increases the binding of VEGF in vitro and VEGF increases the binding of PD-1, but then there's this also unique feature of daisy chaining with some of those molecules don't daisy chain and I think that will impact the efficacy. And we're beginning to see differences arise. The last part I'd say about the format being important is where the binding is. So some molecules have an X shape where there's a VEGF and then the PD-1.

And then there are some that have the VEGF PDL-1, but then there are some that have like a super wide structure where they have a PD-1 and a VEGF. And we think that will be important as well. And they may daisy chain a little bit differently. And I think the daisy chaining is important in terms of increasing the cooperativity for binding a PD-1, but we now know that it has to do with sort of how it interacts with the PD-1 on the surface of cells, and that may cause sort of down regulation and degradation of the receptor. We believe that's going to be important in the future as well.

Now given that complexity, it's not just a molecule blocking the receptor, right, it seems to be that there's some dynamic structures to this, and that will be important. And the format will matter. And I think there's enough differences in the different company's formats that will make clinical impacts as well.

Great. So let's start with second-line lung cancer or the EGFR mutant second-line setting, obviously, positive studies with HARMONi-A and then HARMONi, the global study that you all ran. So the FDA accepted the BLA. We have a PDUFA date now. So can you walk through the interactions that you have with the FDA as part of that filing, the acceptance and how things have progressed to the extent that you can share those details with us.

Yes. So similar to what we mentioned last week on the earnings call. So we have continued to have very fruitful conversations with the agency. We don't get into kind of the meeting-by-meeting discussions at this point. But the review time line was provided, and that includes the PDUFA date of November of 2026. And so we continue to look forward to the continuation of the review by the agency. And so we have the utmost respect for the FDA as I think we've been very clear on. And so with that, we don't necessarily go back and forth in terms of discussing meeting by meeting publicly, but what it does is it informs the continuation. Obviously, the acceptance was announced also recently and then there's a traditional cycle that comes with that mid-cycle review meetings, late cycle review so on and so forth after the application orientation meeting earlier on in the cycle. So there's that normal process set up, and we look forward to continuing to work with the agency through that process.

Great. So I'm convinced you guys should get approval. Based upon the product that's out there and its safety profile and your data, but maybe for the audience, you can elaborate about the HARMONi data, response, PFS, OS and what -- where your conviction lies following the data that you guys should get approval?

Yes, it's a great question, Tyler. So if we step back, right, there have been 4 Phase III clinical studies that have read out at this point with ivonescimab, 3 of which were in China in single region, randomized Phase IIIs and then the global HARMONi study, a multiregional Phase III. 4 Phase III clinical studies that have read out, 4 Phase III clinical studies that have read out with positive data. So that's a pretty good batting average with which to start. When we dive specifically into HARMONi. So we had a statistically significant progression-free survival benefit. And obviously, our -- as we continue to review the overall survival benefit was not statistically significant at the time of the primary analysis with additional follow-up of Western patients and part of that dealt with the delay in enrollment in the West. It was a Phase III study that had never been tested in the West.

And so that delayed enrollment about 4 months or so in terms of physicians getting comfortable with the data, getting comfortable with the bispecific molecule, risk of metastases to the brain and the ability to control that bleeding so on and so forth. And so once we kind of accounted for that long-term follow-up, we had the nominal p-value of 0.03, which implies the benefit for overall survival as well. And that threshold below the magical clinical meaningful 0.80 was seen in both the primary analysis and the long-term follow-up.

When we look at what's in the field right now, right, there's 1 fully approved regimen that's the amivantamab plus chemotherapy regimen. So that was approved on a progression-free survival benefit, a trend but not statistically significant overall survival benefit. So very much akin in terms of efficacy data. And then when we look at the safety profile, there's been some well-established tolerability concerns with respect to amivantamab. We believe that the data that's been shown in the HARMONi study as well as HARMONi-A, HARMONi-2, HARMONi-6, have shown a very manageable safety profile. And we think when we look at the totality of the evidence, that's meaningful with respect to the need out there in terms of options for patients and physicians to choose from. We also -- overall response rate was numerically higher in the ivonescimab-arm duration of response did not have overlapping confidence intervals in terms of ivonescimab versus the chemo-only arm.

And so as we look at the data, we see very clear risk benefit profiles that favor ivonescimab as compared to standard of care chemotherapy in the study as well as what we see and then just in the marketplace, what's available for patients and the need for additional options, we think the study showed that this regimen has a nice place there. And I think that's been generally consistent with the feedback we've gotten from KOLs in that space as well with respect to the desire for optionality and that this regimen has shown what they're looking for in terms of that optionality.

What about the enrollment in U.S. versus ex U.S. and that split as well as the consistency of the data between the Western and the Eastern populations. Do you believe that based on everything you know that the FDA is kind of comfortable with that enrollment split and that the data are constant enough for approval?

I mean, with respect to the enrollment split so we saw about 38% in the West, about 62% in the East. That's reasonably consistent in terms of many of the EGFR mutant trial. So EGFR mutation positive lung cancer is -- has a bit of a higher prevalence in patients of Asian descent as opposed to many western patients. And so we typically do see a higher enrollment in Asia in EGFR mutant non-small cell lung cancer in general. So that 50% to 65% is a reasonable range in terms of what's seen from an enrollment percentage there. So I don't think there's been a lot of question with respect to enrollment splits by any stretch.

I mean, I think when you bring up consistency, we talk about gold standard of overall survival in terms of what that looks like. it's really difficult to make an argument that the data is not consistent. It's actually more consistent than is often seen in randomized Phase IIIs in general, from a regional breakdown, especially when those individual regions are not powered, median overall survival in the West, 17 months for the ivonescimab plus chemo arm compared to 14 months for the placebo median overall survival in the East, 16.8 months versus 14 months incredibly consistent from a numerical median perspective, hazard ratios in Kaplan-Meier curves, I think if you overlay them when you look at earlier maturity versus including later maturity with Western patients, remarkably consistent.

And I think we've shown that in a couple of presentations as well. So I think the consistency has been established pretty solidly. And so now it's really making that case with respect to the benefit risk profile for the application.

Yes. And just adding to what Dave said, the number of patients, right, that as you said, the EGFR-positive non-small cell lung cancer is more prevalent in Asia. But those numbers of 150 patients from the West were pretty sort of negotiated with the agency. So we think that we've met that obligation. There was never that number designed to show independent sort of statistical significance in a region, but just to show consistency of the results globally.

Okay. That's very helpful. What's your latest perspective on the market opportunity in this setting for Summit in the Western population?

Sure. I think we've spoken earlier. When you look at the vast amount of settings by which we believe ivonescimab has the opportunity. So when you look across, not only non-small cell lung cancer, but when you go beyond lung cancer into those tumors that are PD-1 sensitive or checkpoint inhibitor sensitive, those that are VEGF-sensitive as well as places like EGFR mutant non-small cell lung cancer, which doesn't have an approval in either a checkpoint inhibitor or anti-VEGF therapy. That total available market, this is about 3% of that. And so from that perspective, it's a small portion of the overall opportunity for ivonescimab. However, it's an opportunity to lay the groundwork, right? And so it's a thoracic oncology indication. So you're able to build experience with thoracic oncologists.

We look to our next readout that's in frontline non-small cell lung cancer in the squamous histology cohort. And so the opportunity to really work with thoracic oncologists have that availability of the drug to be able to use and administer in patients and understand is always helpful in terms of setting the ground for the next step. Obviously, there's commercial underpinnings as well that come with that interactions with payers, health systems and so on and so forth as well.

Yes. As a clinician, it is a rare population, but it is the same physicians that treat the EGFR positive in the frontline. But as Dave said, it's an opportunity to enter the market early but the HARMONi-3 readout is going to be critical for us.

That's great. So we'll go ahead and move to the front line then. Was there in the audience at the plenary session at ESMO when you guys gave that presentation, again, remarkably consistent, beautiful PFS separation across the subgroups, as you guys have shown in prior trials. And you mentioned on the recent earnings call that you're now doing a PFS interim analysis in Q2 with HARMONi-3 in squamous population. So as you split it around ESMO. So maybe you could talk about what changed there? And what is giving you confidence to take that earlier interim analysis in Q2 based upon the historical data and HARMONi-6,etcetera.

No, it's a great question. So when we look at the historical readouts that have taken place to date so there's been 2 randomized Phase III studies that have gone head-to-head against the PD-1. So HARMONi-2 IVO monotherapy, pembro monotherapy, and then that's in the PD-L1 positive frontline lung cancer. And then HARMONI-6 that you're alluding to, Tyler read out last fall at ESMO. IVO plus chemo versus PD-1 plus chemo frontline squamous, right? And so HARMONi-6 is pretty much a direct read-through in terms of HARMONi-3. There isn't much better of a read-through in terms of a Phase III study than a randomized Phase III done with effectively incredibly similar combinations in an incredibly similar setting, right?

And so -- when we look at HARMONi-2 and HARMONi-6, both were highly statistically significant in PFS, both achieved that at an interim PFS look, right? And so one, when we look at the opportunity to accelerate the timing. It's one following the data that's been generated by our partners at Akeso. So we said we'll continuously learn from the data generation from our partners.

We've now seen 2 randomized Phase IIIs hit the interim PFS. And so that begs the question in terms of almost why not as opposed to why here. But secondly, and very importantly, what it also does is it accelerates the conversation with the health authorities, right? You can have discussions with the health authorities, but it's a different conversation when you go in with this is a statistically significant positive primary endpoint in a Phase III study. That's a different conversation, right? And so with an interim PFS, that analysis to be conducted in the second quarter, as we said, that accelerates the opportunity to potentially have a conversation with the health authorities based on potentially positive readout in that scenario.

Great. And as we think about that interim analysis, is it fair to say that the duration of follow-up and the number of events is going to be designed to be very similar to what you saw with the positive in terms of HARMONi-6 and HARMONi-2 potentially a little bit?

Yes, I don't know that we've commented specifically in terms of expectations on like median follow-ups or whatnot. We started enrolling the squamous cohort of HARMONi-3 a little bit earlier than the nonsquamous when we -- as I mentioned in the opening there. But nonetheless, I think we're confident with respect to what we've seen in HARMONi-2 and HARMONi-6 and then what that should read through based on the similarities of the study.

Okay. Yes. If I could 30 seconds just tie it together. You asked like what is the partnership with Akeso. They've been a great partner. They provided a lot of data. They continue to provide great Phase II data, Phase III data. But if you look at what we've done with HARMONi-3, I mean, that study was designed before any of these studies read out. But then the Akeso HARMONi-2 study readout. This is when we have the confidence to throw in the nonsquamous cohort there, right? Because we saw in HARMONi-2, there didn't -- the efficacy benefit existed in both histologies, right? And now the HARMONi-6 data has read out very strongly in combination with chemo, and that's a very similar population to the HARMONi-3. So I think that informs that decision, and as Dave alluded to, the goal is to bring this to patients earlier, right, as fast as possible, right?

And as Dave said, you can have that discussion. PFS and OS are dual primary endpoints. When you have one of those endpoints hit, it becomes a positive study, and you can have that pre-BLA meeting. Prior to having that data in hand, you can't have a BLA meeting, right?

And for HARMONi-3 and squamous, which is reading out first. What do you think is the bar for PFS and OS in order to file and receive approval? And remind us when OS is coming.

Sure. So the last question is easier. So interim OS consistent with the previous disclosure and what we said about the final PFS analysis in the second half of 2026, right? In terms of bars, I think as opposed to -- I never want to speculate in terms of the agency and what specific directions and part of that is it's a total package consideration, safety data becomes very important and then the end points reading out in each is important. When we talk to KOLs and physicians, what they've said pretty consistently in terms of what they're looking for about 0.75 for PFS, about 0.8 for OS. Those -- when you have dozens and dozens and ultimately, hundreds of conversations with KOLs as well as significant high treating physicians.

They tend to coalesce around those 2 points. And obviously, the study takes that into consideration in terms of this design as well.

Would you say that, that KOL feedback on PFS and OS in terms of expectations is pretty consistent with the non-squamous population and maybe you could remind the audience when we're going to get that data as well.

So for clinicians, yes, I mean, I think that seems reasonable. I mean if you go back in history, like the 25% improvement in PFS and 20% improvements is this dates back to prior to these targeted therapies and immunotherapies back in the old days when you had chemotherapy, what's the bar that wouldn't change your practice? That seemed to be a reasonable bar. I mean what we're seeing with ivonescimab has been better than that. So we're hoping that we can beat that minimum, but it's more of a what you say, and it seems to go across products. It's not specific to IVO. And then the other question was?

The timing of the PFS OS for non-squamous.

Yes. So we've said the plan is to complete enrollment in the second half of 2026 and that would lead to a planned PFS analysis in the first half of 2027. We've been a little bit less specific in terms of overall survival, not because there's not one plan. We're just still it's still in the first quarter of '26 and so as we look at the first half of '27, we have the plan, but we want to make sure we get to the number of events before we give any formal guidance with respect to that timing. But in general, final PFS would be in the first half of '27.

Yes. So the enrollment started after the squamous, and it's been very brisk, but it is a larger sample size. So it's hard to give specifics, but it seems to be enrolling very well.

All right. That's good to hear. So I guess just -- so HARMONi-2 ivonescimab is obviously already proved on the basis of that in China. So Akeso doesn't necessarily have to update that OS data, HARMONi-6.

But you're going to ask anyway.

Yes. Well, no expectations for HARMONi-2, but what about HARMONi-6, right? Akeso might update that. And again, it's not in your hands, but is the -- is it fair to say that we might get HARMONi-6 and we're probably not getting HARMONi-2 or.

So I'll remind you that this is Akeso study, and they haven't issued formal guidance with respect to either study in terms of an OS update. What I would say is the protocol has been published with respect to HARMONi-6 and that's a larger sample size as well. And that's an important distinction between HARMONi-2 and HARMONi-6. The HARMONi-6 study is a bit of a larger sample size so you can kind of infer from looking at the protocol, there's likely a '26 event somewhere in there. HARMONi-2 because that was -- as I mentioned in the beginning that study was in flight when we did the deal.

So right, that's specifically designed single region, exclusively in China, PFS, not really thinking about global implications. That study reads out positively and everybody goes, great, but we're changing the goalpost after the study. We want to talk about OS like yourself. And so what that -- it's a fair question, but I think if we look back in terms of history, what that goalpost did effectively move after. So in fairness to our partners at Akeso, they really haven't provided guidance, and we won't leapfrog above them. HARMONi-6, that was kind of upsized in order to take into account some of these conversations.

Okay. Fair enough. We have 4.5 minutes to talk about all the other indications. Frontline lung cancer is huge. I think everyone knows that. So let's move to colorectal. Why did you guys choose that as the first expansion indication beyond lung? How is that program progressing? And when could we get data?

So we -- it is funny. I was about to say we just began enrollment in that study. So I appreciate that when will we get data. So we're not quite there yet in terms of guiding on that point. But look, I think a couple of important points, right? So microsatellite stable colorectal cancer, not a PD-1 indication, right? That's a historical VEGF indication. We had very encouraging Phase II data there. We tested that, as we mentioned, in multiple -- with multiple chemotherapies. We provided the FOLFOXIRI data in conjunction with our partners at Akeso and ESMO 2024, continue to enroll that both in China and the U.S., with additional cohorts for different chemotherapies settled on the FOLFOX6 regimen based on discussions with KOLs review of the data, that's matured a bit.

We're highly encouraged that led to the go-forward there. It's also a cornerstone opportunity. That's a significant number of patients, that's an unmet need. There hasn't been a lot of progress in the last 20 years in terms of MSS CRC, a couple of EGFR inhibitors, right, but not the broader market for all patients there. And so that's a significant opportunity for patients with a need, and it's another cornerstone opportunity for ivonescimab.

So Tyler, maybe I can let your appetite for when we will look at data. So a couple of things. So remember, we are very excited about this CRC because it indicates that ivonescimab is unique, right? At the simplest way you can think of it is the VEGF component is competing on bevacizumab. But we think that there may be something unique about ivonescimab and sort of cracking that immunotherapy going into these colder tumors. So as Dave mentioned, there was FOLFOXIRI data published by Akeso in ESMO 2024, which was the excitement clinically that led to the GI-3 study. We decided to move forward with FOLFOX and during that, we did a global Phase II to expand Akeso's ongoing Phase II. So now there will be global data for Phase II, looking at the FOLFOX regimen with ivonescimab and that data, you might see sooner. Can we say like maybe this year?

Yes, probably this year.

And that will be very important data because Pfizer has released their FOLFOX combination data as well at the end of last year at SITC. So that will be a sort of a data point that can be compared. You should never compare single-arm studies to against each other, but everyone does.

Thanks for that, Allen. You guys -- so you earlier, Dave, you mentioned GORTEC, yes, ILLUMINE trial head and neck. So basically, same questions for head and neck. Why do head and neck, how is that program going to progress when we see data?

So that will -- we said early Q2 with respect to FPI there. And so look, there's a -- head and neck is another setting where you would biologically makes a lot of sense for ivonescimab. It probably wasn't one of our top 3 or 4 settings in terms of where to go next, however, we were approached by the GORTEC Cooperative Group. And anytime you're approached by an external party who has significant interest in running a study of unmet need with the compound. That becomes really important to take that seriously. And so that led to some pretty quick movement with respect to moving forward with the study. That's a multiregional study. And again, we'll take a look at bringing that into the United States as well. We'll consider that over the course of the next few quarters.

And what that really does is it continues to broaden the scope. In addition, as I said, if it's not one of our top 3 or 4 places where we intended to go, that means there are additional settings that we are looking at those -- looking at sponsored indications as well in those settings that we plan to continue to move forward later this year.

So what are your top 3 or 4 settings in terms of where to go next?

I love the question. We have them. But I think as an anecdote to that when we announced colorectal cancer in October of 2025 that we had planned to go first-line colorectal in Phase III by November of 2025. There were 2 other competitors, shall I say, who were going to go into colorectal cancer in the frontline setting. And so we're going to wait until we're basically ready to go forward with those indications as opposed to providing too much groundwork. We're in the background laying the foundations for those settings right now. And part of that is we're ready -- we'll announce that when we're basically ready to start enrolling.

Fair enough. We'll do my best to exercise some patience here. But in closing, since we're up on time, like to ask you both what aspect of the Summit story do you believe is most underappreciated by investors?

Yes. I think I alluded to this before. I mean everyone is asking us about HARMONi-3 and what indication we're going to next I think people think of this as operational execution, who can throw the more studies out there the fastest. But again, I think the format of the molecules is very underappreciated. I think ivonescimab is at that goldilocks or sweet spot in terms of design, binding affinity, daisy chaining that will make it competitively much more advantageous to use across some of these other formats. The other formats may work but they still have to prove themselves, right? So there's a lot of things to look at.

And I think on that point, not all PD-1 VEGFs are interchangeable. And we have now shown data in 4 Phase III clinical studies, 4 Phase III positive clinical studies. That's -- if you're going to make an adjustment, there's a lot more floor -- room to the floor than there is to improve upon that one. And two, there aren't a lot of compounds that have started with that track record that people are not excited about going forward and ultimately get proved out.

Wonderful. With that, Dave, Allen, thank you very much.

Thanks. Really appreciate it.

Good afternoon, and welcome to some Summit Therapeutics Q4 and year-end 2025 earnings call. [Operator Instructions]. Please refer to the company's website for updates. Please note that today's call is being recorded. [Operator Instructions]. At this time, I would like to turn the call over to Dave Gancarz at Summit Therapeutics, Chief Business and Strategy Officer. You may proceed.

Good afternoon, and thank you for joining us. On today's call, we will provide an update on our fourth quarter and year-end 2025 financial results and operational progress. This afternoon's press release is available on our website, www.smmttx.com. Our Form 10-K was also filed today and is available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will also be available later today on our website.

Joining me on the call today is Bob Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Maky Zanganeh, our President and Co-Chief Executive Officer, Manmeet Soni, our Chief Operating Officer and Chief Financial Officer, and Dr. Allen Yang, Chief of R&D Strategy. I'm Dave Gancarz, the Chief Business and Strategy Officer at Summit.

Before we get started with the rest of the call, I would like to note that some statements made by our management team and some responses to questions that we make today may be considered forward-looking statements based on our current expectations. Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information, including the Form 10-K issued today about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements, except as required by law.

One item to note, this presentation is being webcast with slides, so we'll be referring to the slides being displayed in the webcast link. I'd encourage you to use the webcast link to see the slides being presented this afternoon that will accompany our comments. Following comments from our team, we will take questions. And with that, I'd like to hand it over to Maky.

Thank you, Dave. Good afternoon, everyone, and thank you for joining us today. I'm very proud of team Summit's ongoing accomplishments and the growing positive data sets and support around ivonescimab, a PD-1 VEGF bispecific, our lead investigational assets. We are highly focused, mission-driven patient-first company with a mission to make a significant difference in improving the lives of patients suffering from cancer. Our team is growing rapidly as we expand our clinical development plan and prepare for commercialization in anticipation of a decision from the FDA on our BLA near the end of this year.

We have announced a few significant events today, starting with updates related to our HARMONi-3 study. Last quarter, we announced our HARMONi-3 Phase III trial evaluating ivonescimab plus chemo as first-line treatment for patients with squamous and non-small cell lung cancer was amended to have separate analysis by squamous and non-squamous histologies for primary endpoints of PFS and OS for each cohort. The squamous cohort was planned to complete enrollment in the first half of 2026, followed by the non-squamous cohort in the second half of this year. As announced today, we have now completed screening patients for the squamous cohort of the HARMONi-3 study, and the last patient will be randomized in the next couple of weeks. We have amended our statistical plan to now include an interim PFS analysis for our squamous cohort, and we are planning to conduct the interim PFS analysis during the second quarter of 2026. Overall survival will be immature at the time of this analysis. Therefore, we may not have overall survival results to communicate at that time.

As you recall, we initially included PFS as a primary endpoint in this study opened the readout of HARMONi-2 comparing ivonescimab to pembro in PD-L positive frontline lung cancer patients, which showed a highly statistical significant and clinically meaningful benefit in PFS with a hazard ratio of 0.51 and a median improvement in PFS of over 5 months. This point was later validated with HARMONi-6, showing that there was a substantial PFS benefit when comparing ivonescimab plus chemo versus a PD-1 inhibitor plus chemo with a hazard ratio of 0.60. 2 Phase III studies conducted by Akeso in China in frontline non-small cell lung cancer demonstrated a 40%-plus improvement in PFS for the ivonescimab or both the HARMONi-2 and HARMONi-6 PFS results were based on the planned interim PFS analysis of each study. By adding an interim PFS analysis, we opened the door to an earlier discussion with the health authorities for our multiregional Phase III study.

The final PFS analysis, if applicable, and an interim analysis for OS is planned to be conducted in the second half of this year, consistent with previous guidance.

For the non-squamous cohort of HARMONi-3. We continue to expect enrollment to complete in the second half of this year and to reach a prespecified number of events for the final PFS analysis by the first half 2027. There are several meaningful moments upcoming related to these 2 cohorts, each of which are independent from each other, like 2 separate studies in one protocol where 2026 will be pivotal to providing additional clarity to expand the reach of Ivo to a broader population of lung cancer patients.

Additionally, we announced today the first update to the IVO Phase III clinical trial program, which will continue to expand throughout 2026. ILLUMINE, a new Phase III study in PD-L1 positive frontline head and neck squamous cell carcinoma will be sponsored by GORTEC a French cooperative group dedicated to head and neck oncology with initial enrollment expected to begin early next quarter. The study intends to evaluate both ivonescimab monotherapy and in cognition with ligufalimab, Akeso's proprietary anti-CD47 monoclonal antibody against monotherapy pembro in this three-armed randomized study. Approximately 780 patients are intended to be enrolled across the 3 arms in multiple countries in Europe and in China. We may consider potentially expanding the study to include U.S. sites as well. Phase II data supporting the potential use of ivonescimab in this patient population was previously presented at ESMO 2024, where ivonescimab in combination with ligufalimab demonstrated an objective response rate of 60% in 20 patients with median PFS of 7.1 months after a median follow-up of 4.1 months.

At the time of this analysis, no patients receiving ivonescimab plus ligufalimab is continued treatment due to the treatment-related adverse events. The data generated in Phase II is encouraging in light of existing standard of care, and Akeso is also running a single [indiscernible] Phase III trial in this population in China.

Turning to our clinical collaboration with Revolution Medicines. Today, we announced the first patient has been dosed in the collaboration's initial clinical trial. As a reminder, ivonescimab is being evaluated in combination with 3 RAS(ON) inhibitors, including daraxonrasib, a multi-selective RAS inhibitor, zoldonrasib, a KRAS G12-D selective inhibitor, and elironrasib, a KRAS G12-C selective inhibitor across multiple solid tumor settings with RAS-mutations, including pancreatic cancer, colorectal cancer and non-small cell lung cancer.

Finally, as we announced last month, we entered into a clinical collaboration with GSK to evaluate ivonescimab in combination with GSK's novel B7-H3 antibody drug conjugate in multiple solid tumors. The initial study under this collaboration is expected to begin dosing patients in mid-2026.

Let's now take a step back and look at ivonescimab accomplishments today. There are many to list, we're just highlighting some of them. Ivonescimab has read out 4 Phase III clinical studies to date, all 4 of which have had positive data leading to 2 approvals in China so far. At this time, a total of 15 Phase III trials have been announced currently ongoing or have read out in multiple tumor types. 44 clinical trials have been initiated since 2019 between Summit and Akeso evaluating ivonescimab in a variety of solid tumors. When considering investigator-initiated and collaborative studies, a total of 142 clinical trials are now listed on clinicaltrials.gov, the enthusiast demonstrated by investigators around the world to generate data and see positive signals for patients facing high unmet medical needs really speaks to the opportunity and optimist surrounding ivonescimab.

Together with our partner, Akeso, we have enrolled over 4,000 patients in either Summit-sponsored or Akeso-sponsored clinical trials across the world. Commercially, in China, over 60,000 patients have received ivonescimab based on 2 approved indications by the NMPA in non-small cell lung cancer according to our partners at Akeso, a third indication based on the positive HARMONi-6 study in frontline squamous non-small cell lung cancer is currently under review by the NMPA in China. I wanted to make sure this point is not missed. 4 Phase III trials evaluating ivonescimab have read out to-date and all 4 with positive data readouts. This represents the only Phase III readout that we have seen in the PD-1 VEGF bispecific class today. These positive trials are supported by the -- by the differentiated mechanism of action of ivonescimab.

Here is the current ivonescimab development plan across Summit and Akeso. In total, there are 15 randomized Phase III trials 4 of which are global Summit-sponsored studies in non-small cell lung cancer and colorectal cancer, 1 of which is a multi regional cooperative group study announced today and 10 of which are being enrolled by Akeso in China in a variety of solid tumor types, including lung, breast, head and neck, BTC, pancreatic and colorectal cancers. Additionally, Akeso is also currently enrolling multiple Phase II trials evaluating ivonescimab in other tumor types: ovarian, gastric, HCC and others, including non-metastatic setting.

Through our partnership with Akeso, we continuously compile a substantial amount of data going us to make faster, more informed decisions fueling the rapid expansion of our global development plan. Focusing on our pipeline at Summit. We have 4 global Phase III trials completed or ongoing. HARMONi, which readout positively last year, HARMONi-3, HARMONi-7, HARMONi-GI3, all 3 of which are currently enrolling and progressing nicely. The HARMONi trial evaluated ivonescimab plus chemo against chemo alone and treatment for EGFR-mutant non-small cell lung cancer after TKI therapy, a population of significant unmet need with few available treatment options. We submitted a BLA filing last quarter, seking approval in this proposed indication and in January, we announced the U.S. FDA's acceptance of the filing and a PDUFA [indiscernible] action date of November 14, 2026. As previously disclosed, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. Considering safety and efficacy profile of the current FDA-approved options to patients in this setting, the positive regionally consistent results of this Phase III multiregional study as well as discussions with key opinion leaders and physicians who have administered ivonescimab to patients, we believe that ivonescimab is a potential treatment option with a favorable benefit risk profile.

In anticipation of potential approval in Q4 of this year, we continue to ramp up commercial capabilities in preparation for potential launch. HARMONi-3 is evaluating ivonescimab plus chemo against Pembro plus chemo in frontline metastatic non-small cell lung cancer. This patient population represents a significant unmet medical need with nearly 100,000 patients in the United States alone as this trial covers frontline non-small cell lung cancer patients, without genomic mutations, irrespective of histology or PD-L1 status. I spoke a minute ago about the recent changes to this pivotal study.

For HARMONi-7, this study is evaluating ivonescimab monotherapy against pembro monotherapy as frontline treatment for patients with non-small cell lung cancer that have high PD-L1 expression levels. HARMONi-7 continues to enroll well, and we look forward to providing additional updates in the future. And finally, last quarter, we initiated and began enrolling patients in HARMONi-GI3 evaluating ivonescimab plus chemo compared to bev plus chemo in first line therapy in patients with [indiscernible] colorectal cancer. Our decision to expand into colorectal cancer was driven by encouraging Phase II data published at ESMO 2024 and subsequent continuing enrollment in this Phase III studies in China and the United States with additional chemotherapy regimens. This data set allowed us to make an informed decision to move forward in CRC, specifically with a [indiscernible] chemo combination. We look forward to providing further updates on the Phase II data set later this year as well as the HARMONi-GI3 study as the trial progresses.

Looking beyond our own sponsored trials we are expanding into additional settings with multiple collaborations and other groups. We have the Phase III ILLUMINE study sponsored by GORTEC evaluating ivonescimab in head and neck cancer that I spoke to earlier, with respect to novel [indiscernible] combination. We announced that the first patient was dosed this quarter in our collaboration with Revolution medicine to evaluate ivonescimab in combination with 3 novel RAS-inhibitors across multiple solid tumor setting. We are excited to learn about the opportunity and potential to improve patient outcomes with ivonescimab combined with this novel-targeted therapies and promising molecule. This collaboration is intended to evaluate ivonescimab in combination with one or more of Rev Med RAS(ON) inhibitors in pancreatic cancer, colorectal cancer and non-small cell lung cancer. This collaboration has an opportunity to be mutually beneficial to both Summit and Rev Med by leveraging a combination of potential next-generation assets that individually have promised in each setting, and this may have high promise for patients with RAS-mutant cancers.

In our GSK collaboration evaluating ivonescimab in multiple solid tumor settings in combination with their B7-H3 ADC, we expect the trial to initiate in mid-2026. This is another example of promising targets seeking to significantly advance outcomes in settings where both Ivo and B7-H3 ADCs have shown promise. We have over 60 ISTs that we intend to support in various stages of development. Of these, 15 are currently enrolling 5 of this in collaboration with MD Anderson and ivonescimab has now been featured in over 45 publications, presentations and posters. Collectively, this trial enhance and inform our own clinical development activities as we learn more about new settings where neither we nor Akeso have had the opportunity to explore yet. Tremendous interest in ISTs is a testament to the enthusiast. We have heard from many investigators as they consider the potential opportunity that ivonescimab presents across multi tumor types.

Over the past 18 months, we have seen 4 positive randomized Phase III trials including the first and only Phase III trials to compare positively against anti-PD-1 therapies. Each of these studies represent a benefit either over a PD-1 inhibitor or in setting where PD-1 inhibitors have failed to achieve a benefit in either PFS or OS. Akeso's HARMONi-2 PFS results showed ivonescimab monotherapy as superior to KEYTRUDA in frontline non-small cell lung cancer. These results represent first time any therapy has achieved a clinically meaningful benefit over KEYTRUDA in randomized Phase III trial.

In April of 2025, Akeso announced that HARMONi-2 achieved a clinically meaningful overall survival hazard ratio below 0.8 at this early look. Moving to Akeso's HARMONi-6 frontline small cell lung cancer study in patients with squamous histology, results were announced at ESMO 2025, demonstrating ivonescimab with chemo was superior to PD-1 plus chemo in PFS. With this result, HARMONi-2 and HARMONi-6 represent the first and only known regimen to achieve a clinically meaningful benefit replacing an anti-PD-1 regimen. In EGFR-mutant non-small cell lung cancer, both Akeso's HARMONi-8 trial and our own global HARMONi trial achieved positive consistent results.

In HARMONi, a positive overall survival trend was observed with hazard ratio of 0.79, barely missing statistically significant. In a subsequent analysis in September 2025 with longer-term follow-up on western patients, ivonescimab plus chemo showed favorable trends in the overall survival with a hazard ratio of 0.78 and a corresponding nominal p-value of 0.032. In HARMONi-8 final overall survival analysis showed ivonescimab plus chemo achieved a statistically significant hazard ratio of 0.74 with a p-value of 0.019 supporting a treatment profile where OS does not degrade but rather improves over time in this setting.

Turning to our market opportunity. The value proposition is clear, ivonescimab on its own has the potential to be a platform blockbuster drug, additionally, novel-novel combinations with IVO could bring potential improvements over current standard of care which could expand market opportunity further. Ivonescimab is well positioned to make a significant impact across the solid tumor treatment landscape. Between JAK-point inhibitors and anti-VEGF therapies, TD Cowen and others estimate the total addressable market to be in excess of USD 100 billion globally, looking only at the JAK-point inhibitor market for non-small cell lung cancer market estimates for immunotherapy are expected to exceed USD 20 billion by 2028. And yet these estimates still do not include the full impact ivonescimab could have as it has already shown promising data in multiple tumor types where checkpoint inhibitors have not been effective including EGFR-mutant non-small cell lung cancer and PD-L1 low-triple negative breast cancer.

Ivonescimab differentiated profile supports its platform potential across multiple indications, many of which could be blockbuster opportunities on their own. We have a very exciting year ahead. Here are some of the upcoming milestones we expect to reach in 2026 and into the first half 2027.

Our global clinical studies pipeline will continue to expand, and we will provide further details in 2026 as we begin studies in new settings and indications. This will include additional novel-novel combinations as well as the new Phase III studies that we intend to launch in 2026. The first step with respect to this expansion came today with the announcement of the cooperative group led ILLUMINE Phase III clinical study in head and neck cancer. We will continue to expand often the details of our clinical development plan throughout 2026, including sponsored studies. With today's HARMONi-3 update. We anticipate an interim PFS analysis for the squamous cohort to occur next quarter, final PFS and interim OS data are expected in the second half of this year.

In the HARMONi-3 non-squamous cohort, we expect to complete enrollment this year. We anticipate final progression-free survival data in the first half of 2027. And as already discussed, we are looking forward to a potential first approval for ivonescimab in the U.S. around our November 14 PDUFA date based on our HARMONi BLA filings. Now I will turn the call over to Manmeet to provide a financial and operational update for the quarter. Manmeet?

Thank you, Maky, and good afternoon, everyone. On the financial front, let me start with our cash position. We ended the year 2025 with a strong cash position of approximately $713.4 million, and to remind everyone Currently, we have no debt. Turning to operating expenses. I will provide details on both GAAP and non-GAAP numbers. You can refer to our press release issued this afternoon for a reconciliation of GAAP to non-GAAP financial measures. As a reminder, non-GAAP expenses exclude stock-based compensation expenses.

Total GAAP operating expenses for the fourth quarter of 2025 were $225 million compared to $234.2 million for the third quarter of 2025. This decrease in GAAP-operating expenses was primarily due to the lower stock-based compensation expense of $19.1 million, and this was offset by an increase in our clinical trial-related spend of $8.8 million. Overall, our non-GAAP operating expenses during the fourth quarter of 2025 were $113.3 million compared to $103.4 million for the third quarter of 2025. This increase in non-GAAP operating expenses was primarily related to an increase in R&D expenses related to HARMONi-3 and HARMONi-7 trials. As you will note, we have been very efficient and disciplined in controlling our G&A spend. Our total G&A spend, excluding stock-based compensation expense has been approximately $43 million for the full year 2025 with a run rate of approximately $10 million to $11 million per quarter in 2025.

On the operations front, I'm extremely proud that Team Summit has been able to accelerate enrollment of 600 squamous patients ahead of our planned timelines, which will allow us to have interim readout by second quarter of 2026. With the acceptance of our BLA with FDA, we have accelerated our commercial readiness activities to prepare for our potential commercial launch of EGFR-mutant non-small cell lung cancer post TKI therapy. With respect to manufacturing and drug supply readiness, we have successfully transferred and validated the production process of ivonescimab to a U.S.-based manufacturer. And with that, I will hand it back over to Dave.

Thank you, team. And we will now see if there are any questions that our team can help answer. Operator, if you could please open the line for questions.

[Operator Instructions] We'll take our first question from Salveen Richter at Goldman Sachs.

This is Mark on for Salveen. Can you talk about what drove the decision to include the interim PFS analysis for HARMONi-3 for the squamous cohort and also frame expectations for both the initial data in the second quarter and also the potential final PFS analysis in [indiscernible] in the second half, will we see curves in addition to the top line data? And now given the split do you expect OS could reach that -- significance [indiscernible] that final analysis time?

Thanks, Mark. Appreciate the question. This is Dave. So we decided to amend the protocol for the HARMONi-3 study by including an interim analysis for the PFS primary endpoint. If you recall, we previously amended the HARMONi-3 study in order to add PFS as a primary end point in addition to overall survival. The reason for the addition of PFS as a primary endpoint was based on the results of HARMONi-2, which showed the large PFS delta that Maky spoke to a hazard ratio of 0.51, comparing IVO to monotherapy [indiscernible] lung cancer patients. And then this would allow for a -- so this was then seen again in the HARMONi-6 data. So this would allow for an earlier discussion with the agency based on the primary endpoint and now an interim PFS. So it's really about accelerating the timelines with respect to the data based on 2 interim readouts from our partners at Akeso in studies in lung cancer.

And so with both studies remaining -- or reading out positively, the overlap and the indication with respect to HARMONi-6, that gives a strong indication in terms of the opportunity that exists here with ivo plus chemo versus a PD-1 plus chemo here.

What I would say with respect to your question on survival, and I think Maky emphasized this point a minute ago as well. Overall survival will be a mature at the time of the interim PFS analysis. In terms of disclosure, with respect to when that will take place. That will -- so we plan to run the analysis in the second quarter. And then ultimately from there, what gets disclosed will be determined based on output results as well as traditional major medical conference guidance depending on how results are read out one way or the other.

And then with respect to your final question on final PFS interim OS. So that remains no real change in timing. That's the second half of this year again. We're not really guiding -- and we don't really comment historically on our expectations with respect to results. We don't -- we obviously are encouraged by ivonescimab's Phase II data, the Phase III data that took place in HARMONi-6, and so we really are looking to continue to follow in those trends, but don't necessarily guide specifically with respect to our expectations numerically, if you will.

We'll go next to Yigal Nochomovitz at Citi.

Thanks for the comprehensive update key and team. So just to kind of press further on this question around this interim PFS and second quarter now. So it sounds like what you're saying is that this is based on the optimism from HARMONi-2 and HARMONi-6, but I just want to check, was there anything specific that you saw in HARMONi-3 with respect to an event rate, it's faster or other new piece of information that increased your confidence in doing this interim now in the second quarter? Or is it really just a question of providing this update sooner to accelerate development based on, as you pointed out, what you saw with HARMONi-2 and HARMONi-6?

Yes. Thanks, Yigal, for the question. It's really a data-backed decision, as we mentioned, with respect to interim readouts for HARMONi-2 and 6. And then obviously, the significant overlap in setting with HARMONi-6. I would also reemphasize we are not changing the timing in terms of guiding towards final PFS expectations and then the internal [indiscernible] no change there from events. I'll let Allen provide more commentary as well.

Yes, Yigal. I think what you said, it's the latter. Remember, this study was designed way back in '23 right? And since then, we've had the HARMONi-2 and the HARMONi-6 readout. Our mission is always to bring this very important medicine, which we think is a game changer to patients as soon as possible, right? And I think the HARMONi-2 and now the HARMONi-6 data gives us growing confidence, granted both of those studies read out on an intra-PFS, which was very dramatic. And PFS is a surrogate endpoint. So there has to be some regulatory discussion, but we'll need to look at that data before we can make those decisions. But again, I think this is an opportunity to bring patients faster.

Okay. And at this point, are you providing any other details with respect to the office spend or the number of events that are triggering this interim in the second quarter?

No, nothing in terms of a statistical plan at this point has been provided neither for the interim PFS nor the final. But we have provided approximate sample sizes for both cohorts and then obviously, the primary endpoints of both PFS and OS.

Okay. And then a totally separate question. I just want to comment or ask about ILLUMINE. So is there -- you had the data in ESMO in 2024. What do you know about contribution of components with respect to Ivo and ligufalimab? Is there evidence to suggest synergy or not? Or is this just an additive effect. If you could just spend a little bit more time explaining the thinking scientifically to put those two together. I know the ESMO data was a little bit of a time ago and back in 2024.

Sure, Yigal. Thanks for the question. So if you recall from ESMO 2024, we showed data that was generated from our partners at Akeso both in monotherapy ivonescimab as well as ivonescimab in combination with ligufalimab that as Maky explained, was Akeso's proprietary CD47-antibody. And that data was encouraging in both cohorts, but it did show an additional uplift that we've seen with ivonescimab plus ligufalimab. We've seen our partners at Akeso launch a Phase III study with the combination in PD-L1-positive head and neck cancer. And so we've explored and have been encouraged by the data as it continues -- the Phase II data continues to mature. And part of the study being a three-armed study, with IVO in one arm, IVO plus ligufalimab in the second arm and then the control arm being monotherapy pembro. That will help answer definitively that question with respect to contribution of components. But the 2 cohorts within the Phase II each were encouraging. And there was encouragement from the cooperative group in GORTEC and I'd like to obviously thank GORTEC for their enthusiasm in terms of the study. And that's what's led to the progression here.

Yes. I would just add that, as Dave said Yigal, that the data from ESMO showed that the combination of ligufalimab and ivonescimab was -- had a higher overall response rate than ivonescimab alone. We're excited to work with GORTEC, which is a premier cooperative group in head and neck cancers. And they've designed a very rigid, clinically sound scientifically robust study to demonstrate that. And I think Maky's comments in the script showed that -- there are going to be ivonescimab as one group and ivonescimab plus ligufalimab. So you can demonstrate the contribution of components against the standard of care Pembrolizumab. So I think that's going to be very important.

Next, we'll move to Brad Canino at Guggenheim.

Congrats on the screening completion. For me, it's not quite clear yet why adding the interim provides a benefit with regulatory discussions because it seems like you'll reach final PFS before any OS data interim or final? And presumably, you would need the OS to file anyway. So can you help us square that for me I'm starting to beat the horse on this one.

Great. Thanks for the question, Brad. And so I think there's a couple of things in terms of what you said. So first of all, you can't really have a discussion with respect to data with the regulatory agencies without data, right? And so part of the interim analysis allows for the generation of primary endpoint based data. And then as we continue to mature that data, you'll see also no change in our guidance with respect to final PFS as well as interim OS timing in the second half of the year as well. And so when you kind of combine those two points, it allows for the acceleration of the conversation without much delay with respect to -- there's several months in between, obviously, second quarter versus the second half of the year, but it allows for progressing that conversation with the agency with data in hand to allow for next steps.

And I guess when I hear this and along with the regulatory strategy in EGFR-mutant, should we read this as like a company's evolving view that frontline lung could see approvals with just PFS benefits and only OS trends?

Yes. I mean I think there -- depending on -- it's a combination, right? It depends on the timing, right? The magnitude of the benefit is important. And then obviously, there'll be some contribution in terms of overall survival trends. And I think that's where we see dual primary endpoints in this study. And then across solid tumors, you see that in several places as well. the studies to be clear, is certainly powered for both primary endpoints, which is an important point as well.

So Brad, this is Manmeet. I think in other cohorts, right, depending upon this earlier interim PFS data and the magnitude of the PFS that will allow us a potential discussion with the FDA to accelerate our submission, as we submit right, OS may come and mature, and that is a path forward to accelerate, provide this drug to patients much earlier.

We'll go next to Cory Kasimov at Evercore ISI.

This is Josh on for Cory Kasimov. Our question is on the head and neck Phase III. Why opt to go through a co-op group here? And what signal will you want to see before committing to expanding into the U.S. here? And could it be used to leverage for a U.S. approval?

Josh, thanks for the question. So a couple of points there. I think one, we've talked a few times now in terms of expanding our Phase III program more broadly. So I think -- in some ways, there's an opportunity to work with some of the premier cooperative groups in terms of adding additional indications that we see promise in as well. And this is one of those indications. There's a highly competitive space in head and neck cancer, and we think there are multiple opportunities for patients in this setting. And we think ivonescimab presents a strong opportunity in particular, ivonescimab and then potentially ivonescimab in combination with ligufalimab, right? And so working with cooperative groups also expands a number of trials that are able to be performed ultimately. And so it's important that we are taking on as much opportunities as we can with respect to bringing ivonescimab to as broad of a set of patients who are impacted by cancer as we can.

So we think that, that is a strong approach overall. It's a strong cooperative group who's run multiple studies as well, and they were highly enthusiastic based on the data that's been presented and obviously working with them since. And so as Maky emphasized, earlier as well, it's important to note that we do plan to continue to expand that Phase III program in 2026, and I think we've been pretty clear that as we plan to launch additional studies, we would wait until we get to the readiness to launch, and we'd have FPI in sight. And so part of this will be over the course of '26, but this is an important concept that we had with respect to working with a highly enthusiastic cooperative group in a setting which they specialize and it was an opportunity to really explore on a multiregional setting, this -- these two regimens, really the monotherapy as well as the combination regimen.

I was just going to add, they approached us, right? So they came to us. Head and neck is an unmet need. It's not the largest unmet need in the PD-1 VEGF space. And so I think we are going to -- as Dave said, focus our resources on the largest unmet needs, and this one was convenient because they came to us wanting to do a study. Yes. Sorry, Josh, I interrupted you.

I was going to ask if there was anything specific you could give us on what may trigger like a U.S. expansion here?

Yes. Not -- I don't know that at this time, we want to start disclosing specific details, but obviously, we'll get enthusiasm with respect to enrollment with several countries in Europe who are enrolling in the study feedback from GORTEC as they operationalize the study, there's also additional data being generated by our partners at Akeso in Phase III in China with respect to the setting. I think there's a multitude of different is continuing maturity of the Phase II, obviously, as well. So there's multiple paths with respect to that, but nothing more specific there, just at this point.

We'll take our next question from Tyler Van Buren at TD Cowen.

Congrats on the squamous enrollment completion and the progress. So should we expect the HARMONi-6 OS data later this year? And how about HARMONi-2 OS data as well? And in general, given the upcoming HARMONi-3 OS data over the next year, can you just reiterate what gives you the most confidence that all the positive PFS data we have seen from the frontline lung cancer trials will ultimately translate to OS benefits in the frontline Western population or global studies?

Appreciate the question, Tyler. I think as we have said many time, so the HARMONi-2 and the HARMONi-6 studies are studies that are conducted by and sponsored by our partners in China and Akeso. So they have not necessarily guided in terms of looks on overall survival readout at this point. It's important to note again, HARMONi-2 is not necessarily powered for overall survival. And what -- was not powered for overall survival at all. That was a PFS primary-endpoint exclusively. HARMONi-6 was also a PFS primary endpoint but obviously a little bit larger in the sample size of over 500 patients. And so I think the protocol for HARMONi-6 was published, and so that would appear at some point to look like 2026 as an event, but they have not guided more specifically to that.

I think the second half of your question with respect to translation into HARMONi-3 and then obviously, the confidence that we have with the PFS data translating to OS. So I'd make a couple of points. I don't think there's a better analogy in terms of opportunity with respect to a randomized Phase III study. And in this case, in squamous non-small cell lung cancer, IVO plus chemo versus PD-1 plus chemo, then a randomized Phase III that was nearly identical just run in China, right? And so that was strongly positive. The PFS hazard ratio indicated a 40% improvement in terms of PFS reduction of risk and/or death, and so when we look at translation from China to the global setting, we're obviously very confident in HARMONi helped enforce that very consistent results with respect to OS, both from a media perspective as well as hazard ratio.

I think the other thing is we step back, we often talk about the question with respect to PFS and hey, what's the confidence level translating that into OS? And so at this point, 4 randomized Phase IIIs have read out, right? HARMONi-A was the first, and that was in China the EGFR-mutant non-small cell lung cancer after a TKI. And that final OS analysis was statistically significant, and that was displayed at [indiscernible]. The second was the HARMONi study, and we've talked at length there with a very strong showing with respect to overall survival, the final analysis was not statistically significant, but with longer follow-up time given the given the delays in initial enrollment in the follow-up time differences between China and the U.S., we saw a nominal p-value that was below any threshold with respect to what would be required for significance. We saw a p-value of 0.03.

When we look at HARMONi-2, the only readout we've seen thus far was the NMPA, the Chinese health authority requested, look. And that's sort of an OS hazard ratio of 0.777 comparing IV to pembro. So at this point, HARMONi-6 has not even hit that point, and it's still -- that application in review is our partners at Akeso have announced. And there hasn't been a look yet in overall survival. But of the 4 that have readout of those studies have shown some data towards OS. All of them have shown a hazard ratio of less than 0.8, which when we speak to KOLs, we speak to physicians globally. That's kind of the generally agreed upon threshold for clinical meaningfulness, if you will. And so the amount of encouragement that we've seen with respect to OS is about as high as you can get with respect to the time that we're at.

I appreciate everyone's focus on overall survival but overall survival takes time. in terms of the readout and all of the readouts that we've seen to date have pointed in one direction, which has been highly encouraging. So hopefully, Tyler, a comprehensive answer to your question, but one that answers it.

Tyler, this is Alan. I would just add from a clinical perspective, from the mechanics of the study, they're not a crossover design. The standard of care for both arms is the same, right? And the patients are blinded. So they don't even know whether -- which arm they were on. So they should get balanced standard of care. Now if you start that standard of care in the second line or later line, 5 months later because of the PFS benefit [indiscernible], that should translate to a benefit in OS, right? It's just such a large magnitude in delaying that next line of therapy.

And [indiscernible] your line is open.

More of a commercial question here. So as you're thinking about the commercial footprint you're going to need the EGFR-mutant non-small cell lung that you're building up right now, how much footprint could you -- would be usable for the broader [indiscernible] population. I'm assuming all of that. But then how much more would you have to add on top of that to address the broader squamous population? And then I have a follow-up.

Asthika is Manmeet, and I can take that question on commercial readiness, right? There are a lot of synergies, right? If you see our EGFR and squamous and non-squamous all are coming from the non-small cell lung cancer, right? And as you would note, right, most of them are treated by similar physicians over there -- so our footprint and synergies will come right pretty much. EGFR is a much smaller population base, squamous gets over like 2.5x to 3x bigger than EGFR and then non squamous comes, which is almost double of cues, right? So it keeps expanding, but it gets our foot into the door. We will have to do a lot of education, a lot of learning from our setting our basic infrastructure in next coming quarters, and that will be the backbone off as we expand into squamous and non-squamous because these are all similar physicians. Same indications.

How should we think about, I guess, the ramp-up in your expenditure for the SG&A line item?

Yes, we have been like pretty efficient over there. As I said, EGFR is the smallest one, right, to initiate. We don't have to put a lot of expenditure and most of the expenditure will come right when we hire our sales teams over there. We have been already doing a lot of activities on the medical affairs front, which we initiated right last quarter, and those all are happening. So I would say there will be expense, but that will come a quarter before the PDUFA right, as you get into that, you hire more sales people and other things. But other than that, we are already doing much of the activities and managing that right now very well.

Got it. And then as per -- I like that you guys are offsetting some of the development to these cooperative groups like GORTEC. But of course, these groups are going off the data that's generated in China also with novel agents that are not yet approved in the U.S. and Europe. So I guess, how are you thinking about when you think about these data [indiscernible] for U.S. submissions, how are you thinking about some of the regulatory requirements like Project Optimus that might be required perhaps to be done before a Phase III has started and how are you getting these cooperative groups to kind of play [indiscernible] with that and make sure that the data that they're generating is going to be applicable for a U.S. submission too?

Yes, it's a great question, Osaka. And so importantly, our partner at Akeso have started a Phase III in China in the setting. And so that also speaks to the additional data that exists with respect to some of the work that's been done in this setting. And also, there's optimism, there's contribution of components which we spoke to earlier as well. And obviously, with the novel-novel opportunity here with Ivo and Ligu, it's important to show Ivo as a monotherapy as well as Ivo and Ligu combined. And so I think a lot of the concepts that you're speaking to are something that's permeating both in the U.S. as well as Europe, the cooperative groups are very familiar with those thought processes of the health authorities. And so in general, that's not something -- that is a high concern in terms of pushback or anything like that with the cooperative groups, that's something that's pretty well understood at this point.

Asthika, this is Allen. I'll just add to what Dave said is that we've used Chinese data clearly to satisfy project optimism before. So that shouldn't be an issue.

We'll take our next question from David Dai at UBS.

Just on the HARMONi trial in second line EGFR and also small-cell lung cancer. Just could you provide some additional color on the FDA interactions leading to the BLA submission? And then more importantly, anything you can share on the FDA [indiscernible] on the OS, how has that changed your time?

Yes. This is Allen. So again, I think we've been very transparent that this study is positive with the PFS endpoint. We just missed OS because of delays in enrollment due to sort of post effects from the pandemic. The FDA was clear that they wanted to see the OS to make this a fileable package. And we said, look, we think the data are important. When we look at our data compared to other agents approved in the space, we think that this satisfies an important unmet need patients. And so we wanted them to review the full package of the data. We've submitted it and they've accepted that filing and they're reviewing the data now.

Got it. Okay. That's helpful. And then just on the most recent collaboration with GSK of the B7-H3 ADC in combination with Ivo. And so just maybe help us understand a little more on the initial indication you're exploring. We know that the GSK is currently exploring B7-H3 for small cell lung cancer. Is that an indication you think it will make sense for you explore in combination with Ivo?

Yes. We've specifically talked about in our press release announcing the collaboration in small cell lung cancer, right? And so that is a place -- we've also been clear also that there's multiple solid tumor settings where we believe both B7-H3 as well as Ivo have shown promise. And so -- but there's obviously a place where with the evolving landscape of small cell lung cancer, that's an important place for us to explore. And we think the B7-H3 ADC, that GSK has, is showing a lot of the -- we're not going to go into details with respect to the comparisons we've done against the B7-H3 across multiple companies. But it's important that we did look at that asset and feel that was a very appropriate partner for Ivo with respect to collaborating in small cell as well as a couple of other solid tumor settings.

We'll move next to Mitchell Kapoor at H.C. Wainright.

With HARMONi under consideration from the FDA, could you walk through your high-level thoughts on pricing strategy, given the competitive landscape in EGFR non-small cell lung cancer, but also the benefit of ivonescimab, what could provide in future expansion indications?

Mitchell, this is Manmeet, and it's very early to start talking about pricing. Pricing is dependent on as finally decided, right, based on the final label you have and the indication which we are launching in -- and obviously EGFR, is our first one, but we will not be commenting on the price. Obviously, as you see the other benchmarks, right, and you can easily look at, right, how other second-line EGFR drugs are priced, you could see that there is a big range, and we have the potential based on the benefit of ivonescimab to price it very well. But as you also stated, right, in the long run, we have multiple more indications to come. So we'll have to price it appropriately, but more to come. I think there is no decision or nothing to add over here right now.

Okay. Fair enough. And then on those potential expansion opportunities, obviously, ivonescimab is kind of this pipeline and a drug opportunity, which is rare these days, but what kind of gating items would be there to determine how fast you could initiate more trials? Is it additional partnerships? Or anything that could determine the next steps you take? Are you watching Akeso's next moves? Or what's helping you to decide how fast to initiate additional studies?

Yes, it's a great question, Mitchell. I think -- so I want to emphasize one of the points that Maky spoke to because I think sometimes there's a lot of really positive events that take place with Ivo and sometimes it's important to slow down on a couple. And so over 4,000 patients have been treated with ivonescimab just in clinical trial clinical trials sponsored by either Summit or Akeso, right? So it doesn't include the over 140 total clinical trials listed on clinicaltrial.gov at this point. This doesn't -- such as ISTs and whatnot. But so when we look at the amount of data generated by ivonescimab, there's a significant amount of information that can be really well understood in several different settings.

We've also -- it's important that our partners at Akeso have initiated 10 Phase III clinical studies. And so underneath that, you can do the amount of data that has been generated in terms of really understanding where ivonescimab can be successful. And then obviously, there's also a significant place where we can continue to explore where maybe the prevalence of a particular disease in China is not necessarily as high as it may be in the U.S. and vice versa, right? But there's a lot of overlaps with respect to the characteristics of those diseases, that's important for us to be able to kind of translate that inflation across. But because there's so much patient data with respect to how patients who have performed on ivonescimab, that really allows us to triangulate, if you will, the information.

So we're not running, hey, we've been able to dose 30, 40, 50 patients with Ivo and now it's very encouraging. So we are trying to figure out how to move forward. There's a plethora of information and data. So much of it truly highly encouraging in terms of what that opportunity can be. And that really gives us the opportunity to really think through the different places, the different standards of care. It's important to also consider what the standard of care is in some of these settings. How is that evolving? How is that evolving in the short term? How is that evolving by the end of what would be a Phase III clinical study. And so we can really look at the information we have internally, what's happening in the market to really, at the end of the day, -- what we're trying to do is provide a medicine that improves outcomes for patients, right? But that takes an ecosystem in order to do.

Physicians need to be able to access, understand and have clear answers from that data. Patients need to be able to see what opportunities exist based on data and outcomes from trials. And so when we look at the totality of the landscape across many of the tumor types that are sensitive either to immunotherapy, anti-angiogenic therapy, places where neither have been successful, but there's an opportunity with ivonescimab. We really can look at the totality of landscape, the data generated what physicians will need to see in a couple of years to really come up with the right answer. And that's why some of these even collaborative -- or collaboration opportunities, rather with Rev Med, with GSK, that's important. We'll have more of those coming as well. But when we look at totality of what's out there, it's really important to consider each of those points. And so that's why we really look to expand much further in 2026 as well.

Yes, Mitch, and I want to just address a couple of your comments. So at JPM, Maky announced we're going to be doing multiple new Phase III programs. We will, of course, continue to explore cooperative group studies and collaborations with external partners, and you should expect more of those to come. But our strategy is not dependent on that. We will have sponsored studies based on the Akeso data and moving forward. And so you should expect more of those studies to come as well.

Next, we'll go to Eric Schmidt at Cantor.

I wanted to go back to HARMONi-3 and beat the horse a little bit more. I'm wondering if you've had discussions with the FDA around what you think would be the maximum disclosable set of inflation, given you need to maintain the integrity of the trial? Do you think, for example, you might be able to give us specific ratios or any other meaningful data at that time?

And Eric, just to be clear, you're speaking about the interim PFS?

I am. Thank you, Dave. Yes.

No, I appreciate it, Eric. So I mean, look, I think -- and I think we kind of mutually addressed this across comments from Manmeet, Maky and myself a little bit earlier. But it's important that the analysis is run and then we see the analysis in terms of outcomes in terms of what the next logical steps are in that respect. And so -- and then obviously, positive data requires contemplation with respect to major metal conferences as well. And so it's -- we have several opportunities, if you will, in terms of the data and what that readout will look like. And as we get a little bit closer, we'll be providing a little bit more clarity on what that looks like.

But obviously, we thought it was very important now to provide effectively an immediate answer with respect to the analysis being run in the second quarter. And then the amount of that disclosure in some ways depends on what both the data shows and what the next steps are.

You just want to manage expectations here. Once we get the data, the most important thing is trying to provide this agent to patients as soon as possible. That requires a regulatory interaction, right? And as a courtesy to them, we need to demonstrate to them first, right? Then in collaboration with our investigators, we want to present this at a major medical meeting. So unfortunately, sort of a press release with curves for you guys as investors and analysts are not going to be a high priority for us.

Well, I guess my question was even just very specific to maintaining integrity of the final PFS readout from a regulatory standpoint? And whether -- even if you were able to get the interim PFS that would be [indiscernible] rated disclosure making regulators too uncomfortable. But do you have a view on that?

Sorry, Eric, I'm not sure we followed exactly what you're...

I think what he's saying is -- Eric, correct me if I'm wrong, but what you're saying is if we were to release top line interim PFS, would that impact the study scientifically in terms of unwinding it for the final PFS, right?

Exactly.

Yes, I understand what you're saying. And I guess I just don't want to disclose too much about what we're doing at this time. I understand your question. We're, of course, going to take that into consideration. But I just don't want to disclose how we're going to do this right now.

Yes, I would say a couple of key principles, right? We're never going to do anything that puts at risk the final analysis, if you will. And I think part of this becomes an outcomes-driven response as well in terms of what that data shows to be able to provide the clarity and transparency, but also be able to maintain the integrity of the study itself as well as the interactions with the health authorities.

And we'll take that question from [indiscernible] at Jefferies.

I wanted to ask on the FDA review for HARMONi. Have you guys had any interaction with the FDA since having the BLA submitted? And is there anything in the FDA's stance changing on excitability of PFS and read through that to HARMONi-3?

Yes. Thanks, Faisal. I think we addressed most of this a little bit earlier. But yes, we have interactions with the agency. We don't necessarily disclose mean by meeting discussions and whatnot. And so what we don't want to do is we're not looking to leverage external sources in terms of covering the agency or anything like that. We have confidence -- those discussions are intended to be confidential. So we're not necessarily giving step-by-step updates with respect to that. We have -- we do have interactions with the agency, both for this study as well as other current studies and then potential future studies. And so it's important in terms of the totality of what we're looking to accomplish with ivonescimab that -- we have the utmost respect for the FDA. I think that's just a level setting point. That becomes very important in terms of -- with the platform opportunity, if you will, for IVO, there's a lot of studies with a lot of potential settings where ivonescimab may benefit to patients, and we want to make sure that we have a strong relationship with the agency in order to do -- our mission is really to bring ivonescimab to be to as many patients facing an unmet need is possible in doing what's right for ultimately patients facing cancer diagnosis.

And that concludes our Q&A session. I will now turn the conference back over to Dave Gancarz for closing remarks.

This is Bob Duggan. Not only David is correct in saying that we have a tremendous respect for the FDA, is probably America's most respected agency around the world for its integrity the due diligence of its work for putting patients first, and we're really honored to be reporting into them. And lastly, we're also very [indiscernible] with our partner, Akeso. Akeso has almost a few hundred million dollars of investment value in their ownership along with you all, that are owners of Summit, and we're happy that they chose to do that. We're also quite pleased to see that time after time when they introduce new drugs, they get through their own agency, they get clearances. They're doing quite well. If there's any China look like Regeneron, it's Akeso, just a fabulous company with great engineers, great scientists, and we're pleased that they are the source of the bispecific [indiscernible] back in 2013, and we're proud to have that in licensed and we're making great progress with that. So thank you all. We look forward to updating you on our next call, unless there's great late breaking news in between.

This concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon. Thank you for joining us today, and thank you for JPMorgan for having us today to present at this conference. I'm Dr. Maky Zanganeh, President and Co-CEO at Summit Therapeutics; Bob Duggan, Chairman and CEO at Summit Therapeutics. I'm honored to go over the latest update for Summit, our lead asset, ivonescimab as well as reviewing our upcoming catalysts for what we believe will be a positive transformative year for Summit in 2026.

Summit and our partner, Akeso, have now completed 4 positive Phase III studies with ivonescimab, both in China with Akeso and globally with Summit, in setting either head-to-head against PD-1 inhibitors or in setting where PD-1 inhibitors have failed to show a benefit. The potential first mover status for ivonescimab in the frontline setting of multiple solid tumor and the positive results from the 4 Phase III studies of ivonescimab give us a clear leadership position in the PD-1 VEGF space, a market we believe could be over $100 billion annually. I want to take this opportunity to thank our current long-term investors for your continued support and looking forward to what we believe will be a transformative year in 2026. That is our forward-looking statement.

As guided during ESMO 2025 in October, we have submitted our BLA to FDA in Q4 2025. We did it based on the benefit-risk profile demonstrated by ivonescimab in the HARMONi study and considering the high unmet need and lack of options available for patients in the setting. This is a historic moment for Summit, and I would like to take the moment to pause and thank FDA for their continuing collaboration in support of global innovation.

At Summit, we are highly focused, mission-driven patient-first company. Our mission is to make a significant difference in improving the lives of patients suffering from cancer. I'm honored to lead the team at Summit alongside our Chairman and Co-CEO, Bob Duggan. Our team is currently over 275 employees, growing rapidly as we expand our clinical development plan and preparing for commercializations. At Summit, we have -- we are actively enrolling 3 Phase III global trials: HARMONi-3 and HARMONi-7, both in frontline non-small cell lung cancer, HARMONi-GI3 in frontline colorectal cancer. And additionally, last year, we announced positive results of our Phase III HARMONi study in second-line EGFR mutant non-small cell lung cancer, which was the first global Phase III trial completed for ivonescimab.

Let's look at ivonescimab accomplishment today. There are many to list. We are just highlighting some of them. As I mentioned earlier, we have a significant multiyear head start over in-class followers. Ivonescimab has produced 4 positive Phase III readout to date, leading to 2 approvals in China. At this time, 14 Phase III trials have been announced currently ongoing or have read out in multiple tumor types. 42 clinical trials have been initiated since 2019 between Summit and Akeso, evaluating ivonescimab in a number of solid tumors. When considering IST and other collaborative studies, a total of 116 clinical trials are now listed on clinicaltrials.gov. The enthusiast demonstrated by investigators around the world to seek positive signals for patients facing high unmet medical needs really speaks to the opportunity and optimism surrounding ivonescimab.

Together with our partner, Akeso, we have enrolled over 4,000 patients in clinical trials across the world. Commercially in China, over 60,000 patients have received ivonescimab based on 2 approved indications by the NMPA in non-small cell lung cancer. And the third indication based on the recently presented HARMONi-6 study is currently pending approval in China. I want to make sure this point is not missed. 4 trials evaluating ivonescimab have read out to date, and all 4 Phase III data were positive. This represents the only Phase III readouts that we have seen in PD-1 VEGF class to date. The positive trials are supported by ivonescimab unique differentiated mechanism of action.

Ivonescimab is potentially first-in-class, and we believe the best-in-class PD-1 VEGF bispecific antibody. It was intentionally designed and specifically engineered to improve upon existing safety and efficacy standard of other drugs targeting these 2 established targets in several solid tumor settings. Ivonescimab's cooperative binding properties drive potential synergistic antitumor activity in the tumor microenvironment by simultaneously blocking both PD-1 and VEGF. In vitro, we have seen the several fold increase in the binding rate to PD-1 in the presence of VEGF.

In addition, since VEGF is often expressed as dimer, multiple ivonescimab molecule may be able to link to VEGF, leading to a daisy chaining of ivonescimab molecule where PD-1 and VEGF are expressed the most in and around the tumor, avoiding healthy tissue and organs. We believe this is why we have seen such a differentiated, promising efficacy results and a consistently well-tolerated manageable safety profile in ivonescimab. Ivonescimab not only performs the function of both an anti-PD-1 agent and an anti-VEGF antibody, but it actually optimizes the activities of both. It is effectively a unique mechanism of action from anything developed historically. We believe binding to PD-1 is biologically important compared to other molecules.

The shortened half-life of ivonescimab, less than half of Avastin or bev, is critical to the safety profile we have observed. Finally, we believe the structure, format and placement of the binding domains of ivonescimab is an important factor in the human body biologically to allow for the cooperative binding properties to effectively take place.

Here is the current ivonescimab development plan across Summit and Akeso. In total, there are 14 randomized Phase III trials, 4 of which are global Summit-sponsored studies in non-small cell lung cancer and colorectal cancer and 10 of which are being enrolled by Akeso in a variety of tumor types, including lung, breast, head and neck, BTC, pancreatic and colorectal cancers. Additionally, Akeso is also currently enrolling multiple Phase II trials evaluating ivonescimab in other tumor types, ovarian, gastric, HCC and others, including non-metastatic settings. This strong pipeline has led to a tremendous level of patient experience with over 4,000 patients who have been treated in clinical trial globally and over 60,000 patients dosed commercially in China to date.

Through our highly collaborative partnership with Akeso, we are able to continuously compile a substantial amount of data, which allow us to make faster decisions and rapidly expand our global development plan. This gives us a major competitive advantage, helping us to stay well ahead of others in this space. While many competitors are just entering late-stage trials or are still in a very early development, we are already leading in Phase III across multiple tumor types. I would like to take a moment and thank our partner, Akeso, and Dr. Michelle Xia, their CEO and Chairwoman, for their collaboration and their efforts to bring ivonescimab to patients and physicians around the world. Thank you, Michelle.

But this is just the beginning. Turning to our pipeline at Summit. We have 4 global Phase III trials completed or ongoing. HARMONi, which read out positively last year; HARMONi-3, HARMONi-7 and HARMONi-GI3, all 3 of which are currently enrolling. Let's start with HARMONi. HARMONi evaluated ivonescimab plus chemo against chemo alone, a second-line treatment for EGFR mutant non-small cell lung cancer, a difficult-to-treat patient population with few available options. Positive results from this study were presented in the Presidential Symposium at the 2025 World Conference on Lung Cancer in Barcelona. HARMONi-3 is evaluating ivonescimab plus chemo against pembro plus chemo in frontline metastatic non-small cell lung cancer. This patient population represents a significant unmet medical need across over 100,000 patients in the United States alone as this trial covers frontline non-small cell lung cancer patients without genomic mutation irrespective of histology or PD-L1 status.

Last quarter, we announced a strategic trial amendment for HARMONi-3 that resulted in 2 separate patient population within the study, squamous and non-squamous. Both groups will be evaluated separately and have dual primary endpoints of progression-free survival and overall survival. Effectively, HARMONi-3 is now 2 global Phase III trials in one protocol with a significantly expanded market opportunity. In the squamous arm of HARMONi-3, we have enrolled over 90% of patients and expect to complete enrollment in the first half of this year. Progression-free survival and interim overall survival data are expected in the second half of this year. In the non-squamous arm of HARMONi-3, enrollment is expected to complete in the second half of this year and progression-free survival data is expected in the first half of 2027.

The HARMONi-7 study is evaluating ivonescimab monotherapy against pembro monotherapy as frontline treatment for patients with non-small cell lung cancer that have high PD-L1 expression levels. HARMONi-7 continues to enroll well, and we look forward to providing updates as the trial progress. And finally, last quarter, we initiated and began enrolling patients in HARMONi-GI3, evaluating ivonescimab plus chemo compared to bev plus chemo in first-line therapy in patients with unresectable metastatic colorectal cancer.

Our decision to expand into colorectal cancer was driven in large part by encouraging Phase II data published at ESMO 2024 and subsequent continuing enrollment in China and the United States with additional chemotherapy regimens. This data set allowed us to make an informed decision to move forward in CRC, specifically with the FOLFOX chemo combination. We look forward to providing further updates on HARMONi-GI3 as the trial progresses. To demonstrate our lead in-class competitors have announced studies in either first-line non-small cell lung cancer like HARMONi-3 or first-line...

To demonstrate our lead in-class competitors have announced studies in either first-line non-small cell lung cancer, like HARMONi-3 or first-line CRC like HARMONi-GI3. However, they either are still enrolling in the Phase II portion of the Phase II/III study or have otherwise not yet begun recruiting in their Phase III study. As mentioned earlier, we have a significant lead in lung cancer and colorectal cancer, which are potentially the 2 largest indication by market across solid tumors.

Looking beyond our own sponsored trials, we have innovative way to expand our reach into additional settings with novel combination. In June of last year, we announced our collaboration with Revolution Medicine to evaluate ivonescimab in combination with 3 novel RAS inhibitors across multiple solid tumor setting, prioritizing these 3 RAS mutant tumors type in non-small cell lung cancer, pancreatic cancer and colorectal cancer. We expect that study to begin dosing patients this quarter. Our second clinical collaboration was just announced this morning. In collaboration with GSK, we will be evaluating ivonescimab in multiple solid tumor settings in combination with their B7-H3 ADC. The study is expected to start mid-2026.

Turning to investigator-sponsored trials or ISTs. We have over 60 ISTs that we have agreed to support, 15 of which are currently enrolling. Of these 15, 5 are with our ongoing collaboration with MD Anderson. Collectively, these trials will enhance and inform our own sponsored clinical development activities and possibly show signals in settings where neither we nor Akeso have had the opportunity to explore. The large number of ISTs that are ongoing or are about to begin is a testament to the many investigators who are enthusiastic about the opportunity that ivonescimab presents across multiple tumor types.

We are also proud of the significant attention and praise that ivonescimab has received through top medical conferences and peer-reviewed medical journals around the world. Today, ivonescimab has been featured in 46 posters, publications, presentations, and that number only continues to grow. We look forward to seeing many of you at upcoming medical conferences in 2026 as additional ivonescimab data becomes available.

Speaking of the trial results, the past 18 months have been transformative for ivonescimab as we saw 4 positive randomized Phase III trials, a very promising indicator related to the opportunity ivonescimab presents. This includes the first and only Phase III trials to compare positively against anti-PD-1 therapies, including KEYTRUDA. Again, these 4 trials readout represent the only Phase III trial readouts to date in the PD-1, PD-L1 VEGF class. Starting with Akeso HARMONi-2, evaluating ivonescimab monotherapy compared to pembro monotherapy as a frontline treatment for patients with non-small cell lung cancer with positive PD-L1 expression. Results are announced at the World Lung 2024 showing ivonescimab monotherapy as superior to KEYTRUDA as measured in PFS.

The HARMONi-2 results represent the first time any therapy has received a clinically meaningful benefit over KEYTRUDA in a randomized Phase III clinical trial in non-small cell lung cancer. In April of 2025, Akeso announced that HARMONi-2 showed a clinically meaningful overall survival trend with an OS hazard ratio below 0.8 at this early look. As a reminder, this study was not powered for overall survival and this interim overall survival analysis was conducted at the request of the Chinese health authority corresponding with Chinese approval by the NMPA for ivonescimab used in frontline PD-L1 positive non-small cell lung cancer.

Moving to HARMONi-6, evaluating ivonescimab plus chemo compared to anti-PD-1 plus chemo as a frontline treatment for patients with non-small cell lung cancer with squamous histology. Results were announced at ESMO 2025, demonstrating that ivonescimab with chemo was superior to PD-1 plus chemo in PFS. The results from HARMONi-2 and HARMONi-6 represent the first and only known regimens to achieve a clinically meaningful benefit over an anti-PD-1 or PD-L1 monotherapy as we saw in HARMONi-2 or combined with chemotherapy as we saw in HARMONi-6 in a Phase III trial in frontline non-small cell lung cancer.

In EGFR mutant non-small cell lung cancer, both Akeso HARMONi-A trial and our own global HARMONi Phase III clinical trial achieved positive results. The Summit sponsored HARMONi trial results evaluating ivonescimab plus chemo compared to chemo alone as second-line treatment for patients with EGFR mutant non-small cell lung cancer that have progressed after receiving a third-generation EGFR TKI were presented at World Conference on Lung Cancer 2025 last September. Ivonescimab in combination with chemo, consistent with HARMONi-A from China demonstrated a statistically significant and clinically meaningful benefit in PFS.

A positive overall survival trend was observed with hazard ratio of 0.79, barely missing statistically significant. In the subsequent analysis in September 2025, which includes longer-term follow-up of Western patients and improving favorable trend in overall survival was shown with a hazard ratio of 0.78 and a corresponding nominal p-value of 0.0332. In both the May 2025 and September 2025 statistical analysis, consistent results were seen between Eastern and Western region across safety and efficacy.

In line with our prior guidance, we submitted our BLA filing to the FDA last quarter, seeking approval for ivonescimab based on the data for HARMONi trial, and we expect a regulatory decision around the end of this year. In preparation for potential approval, we continue to build our commercial resources and capabilities in support of successful launch of ivonescimab. We look forward to providing regulatory and commercial update as they become available. In addition, in November 2025 at SITC, it was announced that in the final overall survival analysis for the Akeso-sponsored HARMONi-A trial, ivonescimab plus chemo achieved a statistical significant hazard ratio of 0.74, supporting an efficacy profile where OS does not degrade, but rather improves over time in this setting.

Across all 4 of these Phase III positive readouts, ivonescimab was consistently well tolerated with a manageable safety profile. Ivonescimab has some immune-related and VEGF-related adverse event as would be expected with ivonescimab's mechanism of action. However, the low frequency of AEs leading to discontinuation or death demonstrated a manageable safety profile.

Here, we take another look at ivonescimab profile, specifically progression-free survival Kaplan-Meier curves for HARMONi, HARMONi-2 and HARMONi-6. We see a visual representation of ivonescimab's potential superiority over current standard of care in combination with chemo in second-line treatment for EGFR mutant non-small cell lung cancer as monotherapy frontline treatment for PD-L1 positive non-small cell lung cancer and in combination with chemotherapy in frontline treatment for squamous non-small cell lung cancer. Four Phase III studies across 3 non-small cell lung cancer setting have produced statistically significant clinically meaningful progression-free survival results for patients. Based on the results of Akeso HARMONi-A and HARMONi-2 studies in China, ivonescimab has received NPA approval in the second-line EGFR mutant non-small cell lung cancer setting as well as for use as monotherapy in frontline PD-L1 positive non-small cell lung cancer.

Additionally, Akeso submitted an sNDA to Chinese health authority last summer for potential approval in combination with chemo in frontline treatment for squamous non-small cell lung cancer based on the result of HARMONi-6, which is currently under review. These 3 Phase III graph shows consistent meaningful separation of progression-free survival curves, all favoring ivonescimab regimens over established standard of care. In particular, the graph on the left is in a setting whereby both KEYTRUDA and Opdivo leading PD-1 inhibitors failed to show a benefit in PFS or OS. The graph in the middle and on the right are direct head-to-head results against PD-1 inhibitor.

We appreciate the benefit these therapies were able to provide for patients in the past, but improvement is necessary, and we need to move forward. The safety profile observed was consistent with the previously established safety profile from Phase II studies and low rates of treatment-related discontinuation and death were observed.

Here are the milestones achieved with ivonescimab over the past 18 months. While much of this has been discussed already, I just want to highlight the continuous and growing flow of ivonescimab data readouts, approvals and new trial indications that we have seen since we first in-licensed ivonescimab just 3 years ago. This visual excludes the Phase III trials initiated by Akeso that you saw a few slides ago with a global pipeline. 2024 was a big year. 2025 was bigger. And with ivonescimab first global Phase III first-line non-small cell lung cancer trial readout expected in second half of this year, among other meaningful updates and catalysts, 2026 will be a pivotal year for ivonescimab.

Here are 3 questions, key questions that were asked at the beginning of 2025 that have been answered over the course of the last year. Number one, would Eastern results from Akeso China only trials translate to results from Western patients in Summit's global trials? The answer is yes. HARMONi results show clear consistently across region in both safety and efficacy and in both primary endpoints of PFS and OS. Number two, would progression-free survival results translate to overall survival? The answer is yes. In HARMONi-A, we have seen a statistically significant, clinically meaningful overall survival hazard ratio that improved with time counter to the theory that therapeutics blocking VEGF would only worsen survival outcomes over time.

In addition, HARMONi-2 showed a strong early look at OS and HARMONi on the global study had a nominal p-value that implied significance with more follow-up time, both HARMONi and HARMONi-2 had hazard ratio under 0.8. And finally, number three, would ivonescimab's positive monotherapy results be sustained with the addition of chemotherapy? The answer is yes. Progression-free survival results generated for ivonescimab monotherapy from HARMONi-2 and ivonescimab in combination with chemo for HARMONi-6, both demonstrated clinically meaningful improvement over current standard of cares.

Given the significance of the frontline non-small cell lung cancer study for PD-1 therapy plus chemo and the translation of PD-1 plus chemo as a backbone standard of care for many other solid tumor setting, this was a meaningful result, not just in this study, but in the potential of ivonescimab in a more than $100 billion addressable market.

Here are several upcoming meaningful inflection points for Summit. Our global clinical pipeline will continue to expand. We will provide further details in the next few months. This will include additional novel, novel combinations like we announced this morning with GSK and our existing collaboration with RevMed as well as the new Phase III studies that we intend to launch in 2026. We expect enrollment for the squamous cohort of HARMONi-3 to complete in the first half of this year with progression-free survival data and interim overall survival data coming in the second half of 2026.

For the non-squamous arm of HARMONi-3, we anticipate enrollment completing in the second half of 2026 with progression-free survival data coming in the first half of 2027. With regard to the potential for ivonescimab first U.S. approval, we expect the FDA to make a decision around our BLA submission in the second-line EGFR mutant non-small cell lung cancer setting before the end of this year.

Turning to our financials. Last October, we raised $0.5 billion over the course of about 48 hours, bringing our cash balance entering 2026 about $710 million, and we remain debt-free. I would like to take this opportunity to thank our long-term investors for believing in us as well as Bob Duggan and 10 other insiders who participate in the most recent round of investment. We remain well positioned to develop ivonescimab broadly and deeply, supporting our clinical development plan with an impressive market opportunity.

And my last slide, the value proposition is clear. Ivonescimab on its own has the potential to be a platform blockbuster drug. Additionally, novel, novel combinations with IVO could bring potential improvements over current standard of care, which could expand market opportunity further. Ivonescimab is well positioned to make a significant impact across the solid tumor treatment landscape.

Between checkpoint inhibitors and anti-VEGF therapies, TD Cowen and others estimate the total addressable market to be in excess than $100 billion globally. Just within the checkpoint inhibitor market for non-small cell lung cancer indication alone, the market estimate to top $20 billion by 2028. And yet these estimate still exclude the full impact ivonescimab could have as it has already shown promising data in multiple tumor types where checkpoint inhibitors have not been effective, including EGFR mutant non-small cell lung cancer and PD-L1 low triple-negative breast cancer.

Ivonescimab differentiated profile from data generated to date support its platform potential across multiple indications. Many of these setting individually may be blockbuster opportunities on their own. 2026 is a transformational year for IVO and its potential to make a meaningful difference in the lives of patients with cancer.

In closing and on behalf of the entire Summit team, I want to thank our incredible partners at Akeso, our clinical trial investigators, our collaboration partners and especially the patient and patient family that have all played an instrumental role in getting ivonescimab to where it is today. Thank you for your time today, and I would like to open the question. 8 minutes, record time.

Any questions?

[indiscernible].

Dave, do you want to answer? Can you repeat the question?

[indiscernible].

So thank you for the question. I think the question related to -- with respect to Maky's comments regarding a platform, does that involve ivonescimab as a platform? Or does that involve bringing in other molecules? And so I think, by and large, we think there's a significant opportunity that exists with ivonescimab. In doing so, as we progress within the development plan for ivonescimab, novel, novel combinations will be exceptionally important as well. And so while we're not excluding the possibility of bringing in another asset, what we think is very important is actually following the data. right?

And so as opposed to locking down our pipeline with an additional asset that will effectively force pipeline optimization and additional combinations that favor those 2 assets together, we think it's important to follow the data with respect to ivonescimab. Look at, for example, what we did this morning with GSK, what will be started in a month or so with RevMed and really develop the right opportunities for the right combinations in the right tumor settings as opposed to trying to artificially expand those combinations into different settings where it may not be the best fit. So we'll continue to follow the data. It was nonexclusive as we announced this morning. So it doesn't force that to be the B7-H3, for example, that we will use going forward. But what we want to do is really leverage the data that's able to be generated to allow ivonescimab to have the most beneficial impact to patients with the right combination in different settings.

Any other questions? So everything is clear.

If I may make a comment. Thank you, Maky, for the presentation, and thank you, Michelle, for attending our presentation. We basically have the #1 biotech company in Asia, China. in joint relationship partnership with the #1 biotech company based on historical experience of delivering what we promised in America and a $100 billion revenue opportunity, which is about a $400 billion to $500 billion wealth-creating opportunity. We're pleased with our shareholder base. Everyone else that has yet to make up their mind, you're always welcome. All these opportunities are something we focus our full attention on day in and day out. We're optimistic and pleased with everything we've seen. We've yet to see an indicator that this isn't anything other than an outstanding drug.

One of the indicators is how many others have come along. I'd just remind you that the source of bispecific tetravalent for oncology and solid tumors is sitting in the front row with a group of people numbering close to 3,000 that really engineered this specifically with all the white space in the world and no barriers to the freedom to operate back in 2013. Everyone that followed has to do something different than what this group decided to do. And if you look at what the Akeso group has done away from this, it's all worked. So these are quintessential drug developers. Our relationship with Akeso goes all the way back to the Pharmacyclics days when Michelle was working at Celera, we picked up IMBRUVICA. So she watched what we did then and somewhere in her mind thought I should have partnered with them at that time. And so this is her opportunity. She hasn't missed it.

So with the compliment of the people on the dais here, Dr. West here in the background, we're really pleased with what we see. It's great for patients. It's great for the industry. It's great for our 2 countries, by the way. We're bringing country together, not separating them apart. And we think that's one of the real features of health care. When a person is sick and they're in need of care, they don't ask what's the nationality of the inventor. They go, give me that medicine. I need to be cured. I need to be mitigated. So it's been an honor. We thank you, and we thank JPMorgan for handling conferences like this, be almost impossible otherwise to be in front of a group such as yourself.

Thank you so much.

All right. Good afternoon, everyone. My name is Cory Kasimov, one of the senior biotech analysts here at Evercore. It's my pleasure to host this next discussion with Summit Therapeutics. So Dave and Allen on stage now. We might have Bob and McKee jumping in here in the midst of this. And so in case that happens, don't be surprised. We fortunately have a little bit more time for this discussion. I'm sure you guys are excited about that. It's obviously been a very, very busy year for the company.

So I mean, Dave, maybe I'll turn it over to you to kick things off by reviewing kind of the company's accomplishments thus far in 2025 and kind of act as a level set for our conversation.

Sure. Thanks, Corey, and I appreciate you hosting us and appreciate the invitation to the event. So we have accomplished quite a bit in 2025, and I think I would level set with speaking a little bit on the background of ivonescimab. So importantly, there are 14 Phase III clinical trials that have been launched either by our partners at Akeso or by Summit on the global stage. So 4 global Phase IIIs in addition to 10 that are being currently run in China. That results in about 3,000 patients who -- over 3,000 patients who have been administered ivonescimab in a clinical setting.

And I believe our partners at Akeso have also noted that over 40,000 patients have been administered ivonescimab when you consider the commercial market in China. And so a lot has been accomplished over the course of the last 2 years and in particular, over the last year. And so as we came into 2025, there were some critical points that we were looking to prove over the course of the year based on the expected readouts.

And that started with HARMONi-2 had a tremendous result in monotherapy in 2024. And now the question as we got into 2025 would result in with the backbone standard of care for solid tumors largely being PD-1 plus chemotherapy, would the addition of chemotherapy to both arms effectively water down that benefit? Or would the benefit hold? And we saw a pretty definitive answer in the HARMONi-6 study at ESMO about 6 weeks ago where there was a very strong PFS signal in HARMONi-6. And so congratulations to our partners at Akeso on the tremendous results there. And that really showed that the benefit of ivonescimab really goes beyond niche settings and is really applicable in a broad stage.

We looked at as well the difference between PFS and OS, and we looked at would the benefit we're seeing in PFS look to be translated and ultimately result in OS benefits. We saw with longer follow-up. The HARMONi-8 study conducted by our partners in China was statistically significant and was the first study that was opened with ivonescimab and also achieved a statistically significant benefit.

In addition there, too, we saw the HARMONi study where with longer-term follow-up, a nominal p-value that showed the benefit of ivonescimab in an overall survival setting there as well. And finally, earlier this year, we saw the HARMONi-2 study, the ad hoc administrative request for the NMPA to look at overall survival prior to approval of HARMONi-3, and that showed a clinically meaningful early ad hoc look with a hazard ratio of 0.777. So under that clinically meaningful threshold, if you will, that's generally accepted of around 0.8. And so that's the second point.

Third point then becomes as we look at the translation of that data from China studies that were conducted by Akeso into a more global broader population. We saw the HARMONi data readout at the World [indiscernible] in September. And that showed remarkable consistency regionally across both PFS and OS. From overlaying the curves from a PFS perspective, we saw remarkable consistency. Overall survival, the gold standard in oncology, especially on the global setting, showed high consistency across the regions.

We saw medians that were nearly identical between the East, the West and the ITT population. And what we also saw, when you look at the same follow-up time, HARMONi sequential enrollment first in Asia, then globally. But when you look at the same follow-up time, remarkable consistency even from a hazard ratio. And that really extended beyond what we see in other PD-1 trials, other frontline lung cancer studies in terms of that consistency. You see the shapes of the curves as well with maturing data from the West really being very consistent with what we saw from an Asia-only population.

So we came in looking to show PFS to OS, [indiscernible] translating to West and monotherapy into a chemo combination. And throughout 2025, that was really accomplished, accomplished, accomplished. In addition there, too, beyond the studies that have been run in non-small cell lung cancer, our partners at Akeso have opened up several studies outside of lung cancer. And now in a global setting, we have opened up a frontline and are now enrolling in the frontline colorectal cancer study as well.

So that is now showing as we look beyond just the lung cancer setting into more of the solid tumors landscape as a whole, we're also pursuing those settings as well.

Okay. Like I said, it's been a busy year.

It's been a busy year.

So there's a lot to dig into clearly. I want to start, though, bigger picture. And we've all seen the competitive intensity really get ratcheted up this year in the PD-1 VEGF bispecific space. How much does it ultimately matter being first to market in some of these larger indications like lung cancer?

I mean I think we've seen historical data would tell you that it's incredibly important, right? I think when we look back at the PD-1 race in particular, pembro not necessarily was the first mover in the PD-1 space as a whole, but became really the first mover in terms of non-small cell lung cancer, and that proved to be pivotal in terms of the trajectory of pembro from both acceptance perspective amongst physicians as well as commercial uptake.

And so I think -- and there are many other analogies as we go into other drugs. But by and large, there is a significant advantage for first mover because then at that point, you get experience and comfort with actually using the drug, and that really then puts the onus on second and third movers to then become better or differentiated in some ways. So it's incredibly important.

We believe we have both first-in-class and best-in-class with ivonescimab, which is also the other critical difference, which effectively prevents that second and third mover from having differentiated or better profiles because we really believe 4 Phase III clinical trials have read out, 4 Phase IIIs have been successful, right? And that's a pretty high bar to set when you think about drug development. There aren't a lot of drugs that have produced 4 Phase III studies that have all read out positively that aren't pretty successful ultimately at the end of the day.

And it speaks to the broad -- the breadth of the potential program, but also the potential of the compound as a whole. And so the way we look at the competition now, there's really 2 approaches, one of which is to be as close to ivonescimab as you can to try to replicate those results, at which point, second and third movers don't have the ability to differentiate if they're intending to be the same or you have to make a meaningful change with the intent to modify the molecule, if you will. at this point, again, being 4 for 4 in Phase III studies, when you look to modify, you also run the risk of not necessarily being able to show those same results. And so it becomes more of a risk at this point than it does a benefit to make those modifications given the proof that has been shown across 4 Phase III studies with ivonescimab.

Right. Okay. So then speaking to the breadth component of this, we've noticed a large number of investigator trials popping up in various indications. You also mentioned the work being done by your partner, [indiscernible] across indications. How much do those go together to kind of maintain this competitive advantage as well?

Yes, great question. And so if you think about the breadth of the program, part of why we complement so much our partners at Akeso is the breadth, speed and depth at which they've studied the program, including the 10 Phase IIIs, but that's backed up by a substantial data set in Phase II. In addition there, too, there are also a number of settings where those tumors aren't as prevalent in China. And so as you mentioned, the IST program, we also have clinical trial collaboration set up at MD Anderson.

And in addition there, too, we have the clinical trial collaboration that we plan to begin in terms of dosing patients shortly in 2026 with Revolution Medicines. We have -- we take all of that and are able to compile a substantial amount of data, which provides that comfort and data-driven decisions, if you will, in terms of the ways we can expand that pipeline. And so as we looked at colorectal cancer, for example, we had extremely encouraging data that was published in 2024 at ESMO.

In addition there, too, we opened that study, that Phase II study in the U.S. and expanded it as well in China and ultimately looked at 3 different chemotherapy backbones to really understand ivonescimab's performance across a number of historical comparators in [indiscernible] plus different chemotherapy combinations. And that data set really allowed us to make an informed decision in terms of moving forward with the [indiscernible] combination, and now that's open and enrolling. So there -- some of the competitors need to run the Phase II/III in order to catch up from an [indiscernible] perspective on that. And so that data that's being generated both in China as well as by the IST programs, the clinical trial collaborations are incredibly important.

Okay. So taking this notion of combination treatments a step further, obviously, combinations are sort of are crucial to developing oncology drugs. What kind of novel combinations do you believe are best suited for ivonescimab? And can you discuss kind of your plans to accelerate these efforts?

Absolutely. That's a meaty question. And so short term, we have a clinical trial collaboration with Revolution Medicines that will look to start early in 2026, right? And so that takes multiple RAS inhibitors, pan-RAS inhibitor and a couple of specific inhibitors, RAS inhibitors and look to explore multiple tumor settings. So that becomes critically important. If you think about opportunity there, you take a subset of patients, but on target mutation targeted therapy has shown extension of both progression-free and ultimately, the hope for overall survival.

When we look at adding the benefits of [indiscernible] on top of that, that's extremely exciting. So that's one place that we're very excited about. It also opens up opportunities that aren't necessarily as applicable to PD-1 and VEGF like pancreatic cancer, right? And so there's a significant amount of opportunities that that we've talked about, and I think we released in our initial press release some of the details behind that. In addition there, too, ADCs become really important within the landscape of where the [indiscernible] is going, if you will. Novel, novel combinations will become very important.

And there are places where we have the opportunity. So part of where we believe we have a strategic advantage really becomes the ability to make data-driven decisions here, right? And so there are a number of different ADCs. We see in EV, the [indiscernible] in bladder cancer that's standard of care and just read out very positively in the earlier stage setting. We see a couple of TROP2 ADCs showing very promising data ultimately looking for approval in triple-negative breast cancer. We're seeing multiple lung cancer ADCs going. But a lot of those are -- even the TROP2 ADCs from the Nectin-4 are different platforms, right?

And so what we don't believe is that there is a single platform that will overtake become essentially backbone therapy across solid tumors. So what the competitive advantage we have is we can look at each of these, look where the [indiscernible] is going, if you will, the future standards of care and look to combine with multiple of those across multiple different ADC platforms, right?

And that's one of our goals in 2026 is really to expand the novel, novel combinations that are able to be done, but without looking to optimize our own pipeline and really looking to optimize ivonescimab, follow the data and make the biggest difference that we can for patients. So it's a very broad opportunity, but it's something -- because we are -- to your earlier question with respect to the lead, those companies are coming to us and looking to combine with us as well. So that gives a strategic advantage as well there in terms of the ability to move quickly.

Yes. Those are some good points. All right. So let's dig into some of those specific studies, and I'll apologize in advance do you want to...

Yes, Cory, I was going to add something just to go commercial and get into trouble. So this ADC question in combinations is terrific, right? But to be honest with you, from a scientific perspective, the way I look at it, it's these companies that have huge investments in ADCs justifying those investments. There's this whole adage of being prepared to fight the last war, right? And so the strategy was pembro was unbeatable. Let's buy something to add on to pembro, right?

I think what people don't appreciate is ivonescimab is something new, it's not just a better PD-1. If you look at the largest opportunity for PD-1s, it's non-small cell lung cancer. That's the largest unmet need. That's the largest commercial opportunity. The one thing that IVO is doing that can exceed that is colorectal cancer. That's something that doesn't -- wasn't on the radar, right? That's a huge opportunity. It's the one indication, one unmet need that could potentially be larger than non-small cell lung cancer. We saw that very early with the Phase II data. We were the first ones in that space, right? That doesn't need anything else. That doesn't need an ADC, doesn't need a RAS inhibitor. That's just IVO. There's a lot of those opportunities that are very large that these other guys don't realize yet. And with Akeso's Phase II data, with our own internal data, those, I think, are the unmet opportunities, not the sort of let's combine with the drug I just paid several billion dollars for, right? So I just wanted to add that out.

No, that's a good point. I'm glad you did. All right. So as we get into these, as I was about to apologize in advance before, I know some of these questions get annoying. I still have to ask them, deflect where you need to deflect. But we'll start with.

That's a great lead-in, by the way.

All right. We'll start with HARMONi-2 and given the pending interim update on overall survival. Is there anything more you can say on the anticipated timing of this disclosure? And I think more importantly, at the end of the day, how much does it really matter as an underpowered secondary endpoint as if it's stat, if it's 0.77 or 0.79 or whatever?

It's also a great lead-in. So yes, I would say in terms of timing, just to take that off the top, I think we defer to our partners at Akeso in terms of the specific timing. Part of that because it's an underpowered study, that's a secondary endpoint. I just want to -- as I think we talked about early, but haven't as much lately.

When we entered into the transaction with Akeso and that went effective in January 2023, Akeso was running the study, right? And with the attempt of a stand-alone company in China that was looking to achieve approval in China with a PFS endpoint, we do the deal a couple of months later past they complete enrollment. And then everybody wants to go, well, let's talk about overall survival in a study that was never designed for that and its purpose.

And so I think more specifically, when we looked at the interim -- or not even interim, actually, the ad hoc data cut that read out in the spring of this year, what we saw was a 0.777 hazard ratio. This is -- I just want to like take a step back and just make sure we're all acknowledging what we're talking about here. There are approximately 0 drugs that have gone head-to-head, not on top of, but replacing pembrolizumab and have shown benefits here. There are 2 studies that have now done that. It's HARMONi-2 and it's HARMONi-6, right? And so monotherapy and chemo combination. Then at an early look because, again, this is underpowered and it's immature at this point, we're now seeing a clinically meaningful hazard ratio in overall survival. That's incredible.

Like I just want to make sure like we're taking a step back and thinking about what the implications of that are. Now one of the potential criticisms that came off of that was, well, hey, there's a VEGF component. This will degrade over time. The OS will raise up. Well, that was also -- as we looked at more follow-up time in HARMONi-A, we saw an improving hazard ratio in terms of overall survival and ultimately, a statistically significant benefit.

What we're not seeing in these studies are high discontinuation rates. What we're not seeing are high death rates due to adverse events. What we're not seeing are these complications that are coming up that are requiring large interruptions in therapy. Ultimately, what we saw in some of these earlier studies of PD-1 plus VEGF, VEGF [indiscernible], where a lot of those showed PFS benefits, but the interruptions that were being seen in treatment was causing ultimately the lack of benefit because the patients weren't receiving the drug, right?

And so what we're seeing is the ability to continuously administer ivonescimab. And that's a differentiated approach as well within this -- it's a novel mechanism, but within this combination itself is novel, right? And so when we look at HARMONi-A, we're seeing improving overall survival hazard ratios over time. And so for us, HARMONi-2 showed exactly the scientific point of what we were looking for, obviously, very successful for Akeso with respect to commercialization opportunities in China. We've designed HARMONi-7 powered now for overall survival in addition to PFS. But we're continuing to see very positive momentum here that we're less focused on studies for that are not powered for OS that are not designed for U.S. approval, we're now focused on the HARMONi-3 study looking to complete enrollment shortly, which will then have readouts in 2026, right? Like that's much more where the opportunity ultimately lies for us.

We've seen the good news come from HARMONi-2 already. And HARMONi-A really with the OS benefit alleviates any of those concerns with respect to VEGF toxicities and OS.

So then let me maybe ask this OS question from HARMONi-2 in another way. When you get that readout, does it impact your powering assumptions for either HARMONi-3 and/or HARMONi-7? Like maybe asked another way, are there patient expansion levers that are built in? Or do you already have the answer you need for those trials?

Of course, we're going to look at the data when it comes in. But what we've powered for HARMONi-3 and HARMONi-7,we're pretty confident and comfortable with where we're at.

And to be clear, is the pending HARMONi-2 OS update, is that still -- is that an interim look? Or is that the final look?

I mean I think the protocol was -- there's some reactions, but it was published at the [indiscernible]. So that's still -- the interim has not taken place.

Right. Okay. Okay. All right. So moving on, let's talk about HARMONi, which is exploring IVO in EGFR mutant patients. So the final overall survival results from Akeso HARMONi-A study in China demonstrated the emergence of this tail, right, for the IVO arm. Have you been able to -- or has Akeso been able to look into that data? I can offer my seat if I need to, to identify trends within -- with these responders to give that encouraging tail that you're seeing?

Yes. There are not that many patients in the tail yet. I mean it will take some time. I'm trying to remember like which data I saw and where I saw it. So there's a treasure trove of data that Akeso has created across multiple randomized studies. So we are developing an understanding of which patients we think that benefits, not necessarily just coming from the EGFR study, if that's fair.

Okay. And then given the smaller sample size and the unique tumor type here, how much can you read from the data you're seeing in HARMONi over to the much bigger and broader frontline non-small cell lung cancer indication?

Yes. I mean I think there's a couple of critical components, right? We talk about a very tolerable and manageable safety profile that's clearly differentiated from historical combinations of PD-1 and VEGF, VEGF-A, VEGFR TKIs, any combination of VEGF inhibition. And so when we look at that, a lot -- one of the major components that people had was, hey, we're seeing very good safety in China, will that translate into a global setting. I think kind of irrespective of setting, the randomized Phase III that includes a very representative portion of [indiscernible] patients and seeing very comparable safety between the 2 is extremely important, right?

And so this is something that I think for us is not -- was not something that we were particularly concerned about given the diligence and the work that we had done and the data that we had seen. But I think this was reassuring for external folks, physicians, investors and any -- depending on wherever you take that in the sense of from a safety perspective, what was seen in the single region studies was replicated in the global studies. I think we can -- that's one.

I think, two, in general, that you take away the translatability from East to West was very consistent. And so when you look at these additional studies like HARMONi-6 and how does that translate into HARMONi-3, you feel very confident that both from the efficacy and the safety perspective, the HARMONi-6, which is IO plus chemo versus PD-1 plus chemo in frontline squamous non-small cell lung cancer as compared to HARMONi-3, the squamous arm, which is IO plus chemo, PD-1 plus chemo, frontline squamous lung, there's no better representation of a proof of concept than running a randomized Phase III study with your drug in the right -- in that setting to then show the translation there. So by seeing the safety and the efficacy, translate directly, seeing the overall survival in HARMONi-A, the nominal p-value that showed the survival in HARMONi. I mean, those are very important in terms of the applicability across studies.

Got it. Got it. So I want to go back on this translatability question and go back to the HARMONi update you provided at World Lung this year, this fall. A question or if people wanted to take issue with and we kind of got pushed back on was this how the European patients did in that study relative to patients in North America. Do you see the European patients underperforming this? Is it small numbers, timing of coming on the study? Is there anything to it?

Let me give you an analogy for that one, right? So one of the strongest drugs currently in lung cancer today is actually in the frontline setting of EGFR mutant, which is [indiscernible], right? It's an exceptionally strong drug. It's wonderful for patients. It's very well positioned. both in the FLAURA study and the FLAURA-2 study, so FLURA frontline [indiscernible] monotherapy, FLURA2 [indiscernible] plus chemotherapy, both of those had subgroups regionally that showed a hazard ratio of 1.00.

I don't think anybody should read into that. I think that's a subgroup that is not intended to be looked at statistically. It shows nothing meaningful in terms of what that means for the ability of the drug. And so now we're looking at a much tighter look in terms of Western patients versus Eastern patients, which is much more in line with the ITT overall. So our hazard ratios in overall survival, in particular, are a couple of basis points off of each other. I think trying to look at subs and subs, I mean, at one point, you can just keep going down and down and down. I don't think in any way that there's anything more than trials that aren't powered to look at that level of detail. All patients -- I think we're very clear on this, all patients had a -- in the long-term follow-up analysis, we -- you had the [indiscernible] there all showed a benefit. I think over analyzing those levels of details is not really what the trial is powered for or designed for.

Okay. That's a very good point. All right. So I have a couple of questions for you on the plans to file for approval for this EGFR mutant indication. And I guess one question that comes up is why even pursue the indication given the IRA implications here of getting that clock started like 18-plus months earlier. I guess this goes back to one of the first things we talked about, like how strategically important is it to get onto the market ASAP. Is that the reason you do this?

Yes. I'd say 2 things there. One, I don't know that it's 18-plus months before, right? We talked about reading out frontline squamous in the second half of 2026, right? So that readout can come before a BLA decision. And so I don't know that I would put quite as long of an arc on that. I would also say you're now talking 11, 12 years out that the entire U.S. health care landscape doesn't change in that period of time.

Maybe, right?

Maybe not. And so I don't know that a decision to look quite that far out on ivonescimab makes a lot of sense in terms of assuming nothing will change with the IRA over the course of multiple administrations, multiple congresses coming through. I think the other thing that's really important, too, is when we in-licensed ivonescimab, one of the -- we had a couple of things.

One, we saw the frontline squamous data. It was clearly differentiated. It was -- we needed to go very quickly into that space. But the other piece was we saw an unmet need in relapsed EGFR mutant patients. And part of the reason we looked, one, there was an ability to get on to market more expeditiously and provide a broader set of physicians with the opportunity to use the drug. But I don't want to lose sight of the fact that what we also did was we saw an unmet need where patients needed improved therapies.

And so we ran a clinical trial. We asked patients to trust us and to trust their physicians and the physicians to trust us with a drug that has now shown clinically meaningful benefits, right? And now to say we're going to not put that, we're not going to make that drug available to patients who need it. And we still believe there's a real unmet need in that space. We can go into that in more detail. But we have a very tolerable regimen that showed clear benefits from an efficacy perspective.

The idea of withholding that for maybe in 12 years, the way in which we approach economics with drugs doesn't change. I don't think that's ethically the right thing to do. We have something that can benefit patients. We should take that opportunity to provide that benefit to those patients should the agency agree.

Yes. I think that's a very fair point. So in terms of the agency agreeing, how much risk do you see to the filing given the dialogue you've had with the FDA in the past about needing a statistically significant improvement in overall survival?

Yes, you want me to take that?

Sure.

So I think we've been pretty transparent that we've had discussions with them. They said we need OS. But if you look at it from a physician's point of view, this is an important therapy for patients. And I think Dave touched on that. I don't think Bob and McKee would allow us for a business reason to deny patients this drug, right?

If you look at the clinical data and you look at the efficacy, it seems comparable to [indiscernible], right, with a much better AE profile, any way you look at it, number of AEs, number of discontinuations or dose reductions, right? So we're comparable to that. And that's the one of the 2 drugs that is approved in that space. fully approved drug. Fully approved drug.

The other approved drug was approved on overall response rate and duration of response in a pooled data set, right? And that was conditional approval. We're a lot closer to the other drug and probably a little bit better from a tox profile. The physicians say they want this drug. And this is the drug that they would want to give to their patients, right? In addition, if you look at it, amivantamab with [indiscernible] in combination is now approved in the first-line setting, right, with an OS benefit over a third-generation TKI, right? So many patients will move on to that therapy. And what do those patients have available to them second line, right? So here's another unmet opportunity. So given all that, sort of an arbitrary agreement based on OS, which no other drug has hit, doesn't seem fair to us or the patients, right? And so let the FDA say that. Let them look at the data and see what we see and then make their decision.

Right. Okay. All right. So moving on to HARMONi-6, where we saw the really strong PFS data at ESMO. I guess similar to HARMONi-2, when could we expect to get an overall survival update from that study? And again, much like HARMONi-2, how do you think about this in the context of it again being a relatively underpowered secondary endpoint?

Sure. Yes. So again, that study was run by our partner, Akesa. So I won't -- I'll defer in terms of specific timing. I think we saw the protocol again in the Lancet publications are strong. And so we have multiple of them now. So in the Lancet publication, we saw the protocol. We can kind of surmise that it's -- there's an interim somewhere in '26, somewhere, but that's up to -- in terms of more specifics, I won't shed light there. But I think when we look at what does that mean, right?

And so this is -- the other thing to consider is we'll see HARMONi-3 data in 2026 as well, right? So we said we'll complete enrollment in the squamous patient population in the first half of 2026 with a data readout in the second half of 2026, right? And so depending on timing, which comes first will have an impact there. But I think we saw incredibly encouraging signs from the HARMONi-6 data. If you look at the curves, the curves continue to separate beyond chemotherapy induction, and those curves grow over time basically through the median follow-up time. You have a higher numerical overall response rate, duration of response is longer. And those curves again stay separated until the median follow-up time.

And so it's important to consider how long patients have been on therapy when looking at those curves. We see an AE profile that's pristine. We see low and comparable discontinuations and death. So with all that -- if you look at what's a prognostic factor in terms of looking at what are ways in which you ultimately shed light early on what potential survival can look like, it's a pretty good start.

And so part of this is time in terms of the actual analysis. I think that's important. It's important to remember that the HARMONi-6 study hit on an interim PFS look, right? And so typically, you have interim overall survival linked more to the final PFS look, which would have been much later, but the interim PFS hit, which is where it's just simply too immature for OS at that point.

So then to piggyback on that, the global Phase III equivalent of HARMONi-6 is HARMONi-3. And this is where you've now -- and it's great to see if you did is split it up into the squam and non-squam -- and we'll get that first update from HARMONi-3 in the squamous population in the second half of next year is what's anticipated. Big difference here versus HARMONi-6 is that PFS and OS are co-primary endpoints. So should we expect an overall survival look when you get to that data readout in the second half of next year, assuming that's the time it hits on?

Yes. And so -- and I think that's where, again, I'd differentiate HARMONi-3 and 6, which is we won't have an interim PFS look. We'll have a single PFS look. And so with that coming in the second half of 2026, we would also expect in the second half of '26, an interim OS look as well.

Okay. Do you plan to disclose the powering assumptions for HARMONi-3, HARMONi-7? Any journals we should be looking into?

We likely will not publish the results of the study before we disclose them now. I think there's no imminent plan in terms of powering. What I would just say a similar comment we've made before, it's powered for a clinically meaningful benefit. We're very much -- we feel very confident in terms of where we sit today, and that's where the study is designed to show that success.

Okay. I did want to spend some time talking about opportunities beyond lung cancer and just kind of the strategy around ivonescimab overall. As you alluded to upfront, you committed -- you've started now the Phase III in colorectal. You talked about how large of an opportunity that could be, and we totally concur with that. I guess one question is, when do you expect to be in a position to announce additional indications? And then the follow-on specifically of colorectal, will we see additional data there that kind of helped inform the move into that Phase III trial?

Yes. So I think -- the second one first, which is the more data to help inform that. Probably. In terms of timing, not yet in terms of where and when. I think importantly, though, if you look at the data that was used in -- or presented rather at ESMO 2024, you saw a FOLFOXIRI IO combination that showed about an 82% overall response rate. And so that obviously is significantly encouraging to us, if you will, in terms of what that looks like compared to historical results of [indiscernible] plus FOLFOXIRI.

So we ran, again, those multiple chemo settings in addition there, too, and ultimately landed based on physician preference, standard of care in the Western markets with FOLFOX. That data -- we have that Phase II data. So we will likely make that more available in the future. In terms of additional indications, there are obviously a number, whether you look at the Phase IIIs that Akeso has opted to run outside of outside of lung cancer in addition to some of the Phase II data that's been generated. Even if it hasn't been published, you can see where some of that data is being generated in terms of the Phase IIs in addition to what's being done with clinical trials at MD Anderson, other IST programs and so forth.

So we said at ESMO, we plan to run additional Phase III studies. We -- because of -- we have multiple companies out there with PD-1 VEGFs, we have no intention of taking the treasure trove of data that we have access to and kind of giving any more insight in terms of where we plan to go and where we think we should go next because we can make those informed decisions. If you look at -- we announced CRC mid- to late October and are now in the beginning of December here enrolling patients. And so we have no need to foreshadow multiple places to allow others to be at the same track.

No, that makes a lot of sense. All right. So this is where I want to bring the discussion full circle and bring it back to strategy. And Bob, I'm thrilled you're sitting up here with us. to be here. Do you believe you need a large pharma partner to maximize the potential of ivonescimab? And maybe another way of asking this is how big can you feasibly go without a partner?

Yes. Two very good questions. Let me interject another one. Should we have had one already. And I can assure everybody in the audience here that had we had a big partner, we would not be where we are today. If we had a partner, we on maybe half the revenue or we could have sold the company. We looked and examined the partners, and we would not have gone into the IST program we've gone into. We have over 50 IST programs, and they're flourishing. -- we would not have gone outside of NSCLC. We've gone outside of CLC, and we do have plans of at least 3 more, and those look really, really appetizing. And we've not refiled for the -- we would never have done the EFG study. EFRG study for patients was a nominal p-value success. And it took courage to do it, but there was an opportunity to do it, page back. This is our second-generation team, by the way, was a wonderful drug in their hands.

The [indiscernible] team was the first generation. And some people followed me even over from robotics, which is the early beginning where the outsiders when that's not going to happen. And we'd love to hear that because if we win, we win big. So the EGFR, there's a need there. And we have a solution to the need. And so let's go ahead and do it. And we did it.

What we misestimated was the angst and the concern about the transfer of China data to the U.S.A. data. I have a key to the city of Shanghai. I'm proud of that. I love the Chinese. I love their innovation. I was there in 1987, and I saw things then that I've now seen and I don't look back with amazement, I look back with admiration for what they've really accomplished, the best and the brightest that are out there.

So we took that trial on, and we're glad that we did. But in the first 4 months, we enrolled 2 patients the American doctors -- you want me to go be a getting pick for Chinese data. It's not going to happen. Bispecifics is a new word to me. I don't really know it. And what are the class of doctors do? They do what they read that others have done that have worked. There's nothing to read to show that it worked.

So by the way, there's bleeders in the study, and we're going to show them. And then nothing that, there will be complication of brain mets, none of which have occurred. -- the translatability there, the brain mets didn't occur, bleeders didn't occur. The bispecifics are out. There's 40 of them and everybody is in them, except there's not one that looks like we look like. If they're exactly like us, then with the lowest royalties.

So we're an aggressive courageous company that goes for what we see is true, not what we can go to others and say, it looks true to us, does it look true to you? And if we get 10 out of 10, then we go ahead and do it. And oftentimes, they're wrong. If it's good for us, it's good. But we've got these 2 on the table like this, how many of you would not hire them immediately if we let them go tomorrow to be on your research team. There's no 2 people better than this. And the third one is better sitting in the front row, which is the [indiscernible]. We got a pack of winners here. Yes, the brilliant -- I was telling [indiscernible], you took a weight loss drug and you made it cure everything, and now you've got a $1 trillion company. Congratulations because he deserves -- he really did a hell of a job there. That's a big drug.

Then you've got pembro, another big drug and add [indiscernible] to another big drug. We go beyond. We could have the biggest of those 3 sitting right here in this room today at a $12 billion market cap. And that's why I got $1 billion. I listen to these guys chat back and forth every day of the week, 7 days a week because we're on phone or working with them one way or another and just get validation for the courage that I had to put the money in here and to do business when others were doing it.

So this is a victory for patients first, for having the courage to go with what you see is true, not what other people see is true, and this is a follower in the industry. So I don't mean that, that doesn't work. It does. There's a lot of me-toos and a lot of followers, but this is not what this company is about. It's an aggressive company and a partnered with Akeso.

There is not a company that I've seen or found in my 25 years in this business that has more new products doing better than Akeso. There isn't one. They don't have 5 losers and 2 winners. They don't have 25 losers and 3 winners. They're all frequent winners. I mean they are unbelievable people that work in their [indiscernible] and they're incredibly bright.

And by the way, the leaders have American citizenship. And by the way, we borrow -- we took that technology from China and brought it to America and the rest of the world and are going to generate a lot of revenues of it. Thank you very much, boys and girls in China. So -- and we're going to get paid for it. And that's why we haven't partnered yet.

Now to your 2 questions, when is the right time? Well, when it's recognized, when there's enough written data to show you that you can follow the written data. So when you follow the written data and if it doesn't work, you don't get fired because say, look, that's what the freaking told me that that's going to come as we're sitting here. And it's in the next 12 months that's coming. And then we'll see what the enthusiasm is and what the price is. If we do anything, it won't be partner because in a partner, you've got to give up control, control equals income, you've all made money, you know that. You turn control over and you may go to Las Vegas to be the [indiscernible] of somebody else's rolling the dice. So that's not going to happen.

So if you don't give up control, then they need to control. But we can still own it and control if we pick the right partner and we get equity and not cash. So that's what, in my opinion, you should expect. So we're -- first place, we're in wealth -- the health business, health. You're born, you die because nobody gets through without needing [indiscernible] to cure the disease. We all need that.

And aside from that, we're in the wealth business. And we're going to create wealth doing that, and that's what makes the world go around. So if you like that kind of a game and you own it, hold on. If you don't like it, buy it, if you're short, you should go. At the end of the day, nothing beats big pharma when you've got the machine. But you've got to load the gas tank and it's got to have the right bullets in it. And we're a loaded gas tank. We've got the right bullets. And we just rest assured, we will pick the group that can really take this to market and shares our enthusiasm for patient-first therapy. And I'll be a shareholder.

I love it. I was going to ask for a sneak peek into '26. I think we all know what's coming in '26. That's too good not to end right there. Bob and the rest of the team, thank you guys very much.

I mean who doesn't love [indiscernible]? If you followed [indiscernible], not made money, go and do another business.

Thank you very much. I appreciate it. Thank you, guys, and good luck.

Thank you.

So welcome to the session of Citi's Global Healthcare Conference. Yigal Nochomovitz, biotech analyst. I've been covering Summit for a number of years now and following them for longer. I think it started in -- when I first saw the ASCO data in June 2020. But anyway, I welcome, everyone. Thank you so much for joining.

Bob, do you want to start out and just sort of set the scene and tell us...

It's been a great journey to get here and, Yigal, you're at the top of the list of the way you dig in, your diversification and flexibility. This guy can do anything from play the piano to race cars to evaluate companies quite accurately.

So Summit has been in existence for quite a while. I bought a 25% interest in the company when it was in the anti-infective business, antibiotics. And we did some work there. I like the evaluation that we did, but it was not an area where you got compensated correctly for the amount of breakthroughs that occurred. And we pivoted over to oncology. And then Maky and the team that had been working at Pharmacyclics joined in. So we're really a second-generation team.

We spent 10, 15, some of us 20 years together. We've got -- and then we took a good hard look at what we wanted to do, but we had a couple of hundred million in cash ready to do something. That sounds like a small amount of money, but it's something to start with.

And David joined us -- joined us, and we got him busy looking at opportunities and we came upon Akeso. Akeso cofounders were Americans. Michelle Shao had vested interest in a company called Celera, she worked at Celera, and that is where the IMBRUVICA really came from. So she knew that drug, and she knew us.

And over spending 6 months together, we were really the only one standing up when she said, I need $0.5 billion and $5 billion, $4 billion partnerships. And within 24 hours, we raised the additional money, put it up. And 3 months later, we had a Phase III going. We've now got 4 Phase IIIs going, really to step into an opportunity, and I've been an investor since I was in my 20s to see a blueprint like KEYTRUDA has put forth.

And behind that, another nominal product, OPDIVO, with a good reputation, but you're really dealing in $30 billion to $40 billion of revenue. And then to see a customer come in and go head-to-head with KEYTRUDA and score victories and wins and know the people and know their science and feel good and comfortable about it.

We did the right thing at the right time by putting that partnership together. It's now validated and clear to everyone that if you want good drugs, go to China, and we were there first, [ ivonescimab ] in city of Shanghai introduced robotics to China. So we have a long-standing relationship and high appreciation for who the people are.

So we've got a good team here. We really like the position that we're in. I believe you've got weight loss in Mounjaro, and you've got NSCLC and other solid tumors with pembro and you got ivo. And we just wanted to show people what ivo could do. But I don't know anyone that would have gotten off to the kind of start that we've gotten off to. And we've yet to see an iota of data that says, hey, you should slow down, you should be cautious. Pristine safety profile.

In June, Akeso had dosed 50,000 patients. They're dosing at the rate of 1,000 a week. So you can imagine how many that they've got. Now no one else has that condition of proven safety. They went head-to-head with pembro and won. We stepped up into EGFR. And we misestimated the inertia that occurs when you bring a brand-new product from China to America and the transitioning from 2022 to 2023. And in the first 4 months, we enrolled all of 2 patients.

Others, if you're a VC-backed, you have been fired. If you're a big pharma-backed, you have been lowered to the sandlot and discarded. We stayed right with it. And 16 months later, we actually had a p-value of 0.0323 and a great hazard ratio and demonstrated a great drug. But for the 12-month trial that we've been assigned and you don't go to the FDA and get assigned that kind of a trial and change it midstream. We had a p-value of 0.5 and change. And so we did not cut the line. But if you look at it very carefully, if you're patient, you're taking this drug if you have EGFR. There's anything that really compares to it in my opinion.

So we've got a lot more than that going on, and I'll let the team and Yigal who knows us deeply express that. But I think we're in a primary position and we can talk if you might have questions on partnership and other transactions.

I think we'll finish the year with close to $700 million in the bank. We have access to money. We were at ATM. We raised $0.5 billion in 48 hours 1.5 months ago. When we needed the $0.5 billion for Akeso, we raised that in 48 hours also. So in our view, there's no scarcity of money, there's a scarcity of confidence. People like what we're doing. We're doing good. And I think we've got an incredibly bright future.

Okay. Well, that was a great way to start the conversation. So that's a great point as far as the scarcity of confidence. And I think -- and if you could help us sort of identify the key data points this year. There have been a number of them that really everyone should look at and say, there should be a lot of confidence in this molecule and the data that you've generated at ESMO earlier in the year, updates from your partner, you pointed out Akeso a few times.

So maybe Dave or Allen and Bob, Maky, talk us through what are the key gate points that show us that you're seeing the evidence that this drug is producing the kind of strong data that Bob and Maky had identified back in whenever it was summer, when you looked at it in December 2022, you did the transaction, right?

So just what are the proof points that you're seeing this year? And then we'll talk about, of course, HARMONi-3 and everything else.

A couple of factors. I'll let David and Allen handle it, but evidence that it is, any evidence that it isn't and any evidence that anybody else is better or even in the same ballpark and we will have to cover all 3.

Yes, absolutely.

So are we not -- so thanks, Yigal, for the question. I think -- so if we look at where we started in -- coming into this year, into 2025, the announcement of the HARMONi-2 results have been published, right? So there was a strong PFS benefit between ivo versus pembro in the monotherapy setting. And as we came into 2025, basically the questions that people wanted to have answered were monotherapy showed improvement over PD-1.

The overwhelming standard of care in non-small cell lung cancer in many solid tumors is in combination with chemotherapy. And so does that benefit hold when we look at chemotherapy combinations?

Two, it was the data that has been produced in China is a single-region trial. When you get into a global study, does that data hold?

And the third piece became strong data with respect to progression-free survival. And as we get into the gold standard of overall survival in many oncology trials, does a drug that contains a VEGF component like ivonescimab, does that lead from a PFS benefit into an OS benefit.

And I think we pretty demonstratively and convincingly showed in 2025 that all 3 of those major points were very much proven and shown in favor of ivonescimab. So if we take PFS to OS, we saw the data that was generated in 2024, both in HARMONi-A as well as the HARMONi-2 study. We saw a statistically significant OS benefit in the HARMONi-A study, the single-region EGFR mutant trial. Bob spoke to with longer follow-up of patients in the global study, both very consistent data as well as a nominal p-value of 0.03, so showing the OS improvement there as well.

When we look at the East versus West, again, same concept, we look at HARMONi-A to HARMONi, we now show in a global setting, very consistent results between the single-region study and the global study as well as within the individual cohorts of HARMONi, the consistency between the data that was shown in the Asian cohort versus that of the Western cohort.

And the final piece, when we look at the data in combination with chemotherapy, we saw HARMONi-2 in a monotherapy setting looked very good in 2024. We saw the OS trend in the administrative cut for the CDE upon approval. So that was below the clinically meaningful threshold of 0.8, so 0.777 in at the ad hoc administrative look there. But also, we saw the HARMONi-6 data then readout in combination with chemotherapy, and that was strongly positive against the PD-1 plus chemo.

So you take now 4 clinical trials have read out in the Phase III setting, 4 positive Phase III trials. So as we look at I think Bob was alluding to as well, the competitive landscape that exists, other PD-1 VEGFs, we've got 4 Phase III clinical trials that have read out positively. And it's the only PD-1 VEGF that's read out in a Phase III setting. Four for four is a pretty good start.

And then when we look at each of the key questions coming into the year, in terms of how ivonescimab will perform East to West, PFS to OS, monotherapy to combination with chemo, all of those questions were pretty clearly answered in 2025.

So as we look forward now with the opportunity to bring in the global setting in frontline non-small cell lung cancer, that's in combination with chemotherapy. So effectively, the KEYNOTE-407 in squamous and the KEYNOTE-189 settings in frontline non-small cell lung cancer.

We have that data that we'll talk about in the short term from a catalyst perspective as well as expanding now with that confidence beyond non-small cell lung cancer. We've talked about the frontline colorectal trial that is open and enrolling. And then we also implied in the Q3 earnings call that we will be expanding our Phase III program beyond that.

So in terms of setting that stage for the confidence and the meaningfulness, we're seeing all of that continue to come to fruition.

Okay. So you've answered a lot of very key questions, ones that we've explored in detail as you know. So when you think about what's coming up and obviously looking at HARMONi-6 partner, I assume we'll tell us about OS, which we don't know.

You have a big readout, obviously, with HARMONi-3, which we can discuss in greater detail. But is it sort of augmenting the strength of those points you've already made and for example, with HARMONi-3, I mean you would kind of remake the point again on chemo combo, you remake the point on East versus West again. Allen, it looks like you want to...

Yes. Is this working? Okay. So yes, so maybe take a second here, and I want to take a victory lap for the team, right? We're approaching our third anniversary as an oncology company, right? And what has the team accomplished?

So less than 3 years ago, there was Phase II data that looked very intriguing, right? But at the time, people looked at it and said, well, it's from China, there's no good biotech in China, right? Can you trust that stuff? And then -- so what's happened, HARMONi-A read out, randomized against placebo, second-line EGFR where PD-1s don't traditionally work, right? PFS endpoint, right?

That's now been confirmed at SITC as hitting an OS endpoint in a very tough space, right? When I saw that data, I said, oh, wow, that's really tough. I get placebo. And then the next readout was HARMONi-2, right? I think it might, wow, that's going to be really tough because that against pembro. And there you go, you won against pembro. It was a definitive win on an interim PFS look. And what you're talking about this year is an interim OS look, right? This drug keeps exceeding expectations, right?

What was really cool about looking at HARMONi-A and HARMONi-2 was that you -- not only was the efficacy phenomenal, the safety data was pristine, right? Then the natives, well, once you add chemo, you're going to wash out that frantically. HARMONi-6, we hit it out of the park, right, again, hindering on interim PFS, right?

So what you're really going to see is confirmation of the OS. They want to see the OS, and that's what they are saying. Those voices have gone down because HARMONi-A, the first one, which is the toughest one, I think, has hit, right, and it's mature, right?

There were selling [indiscernible] when you looked at 30% versus 50%, you see some deterioration. But you see a tail for them, right? That's what you wanted to see.

So I think HARMONi-3, HARMONi-6 with chemotherapy in the same setting is going to sort of reiterate that. And then of course, HARMONi where you have Western data, and you see the same benefit there. So I think you're seeing all the naysayers go away, and I think those voices are going down. And this has all been accomplished in less than 3 years.

So in the time when most studies can't even enroll in that period, we've already had 4 readouts, right? And they have 10 other Phase IIIs that have been publicly disclosed. So yes, I think there's a lot that's going to come out next year, but it's more confirmatory of what we think is a great molecule. And that's our victory over the last 3 years.

Would you agree though the HARMONi-3 sort of encapsulates everything into one place in terms of chemo combo, doing it in U.S. and Europe and front line. I know we can talk in more detail about the mechanics of the squamous and the non, we can get to that. But just at a high level, that sort of -- that is sort of the most definitive experiment or just adding to the overall trend set?

Yes, I was going to say like, we've already done the most definitive experiment 4 times, right? So they're placebo-controlled or PD-1 controlled, double-blind studies, right? I think the importance for HARMONi-3 is that it's going to be the linchpin of the franchise, right? So with that one study, you will capture 80% of the non-small cell advanced -- non-small cell market, right?

And so that was the linchpin that pembro used to control the whole market, right, because that was probably the most important consideration. So with HARMONi-3 and HARMONi-7, you will pretty much dominate the advanced non-small cell lung cancer market 2 years ahead of everybody else, right?

And I know that there's a lot of competition, Pfizer has jumped in, BMS has jumped in, BioNTech, right? Merck has even jumped in even after sort of entry data point, well, you have to think it's just Chinese. Well, they don't have OS yet, right? Then secretly, they were sort of jumping into the market themselves, right? So I think the 3 and 7 will be the linchpin for the rest of the franchises, right? And I think that's how you win the whole market, right?

So if you go back, let's say, a decade to when Merck, BMS, Roche, were in sort of a foot race for PD-1, they were all going at it at the same time, right, because ipilimumab was approved about 3 years before. So they all knew that checkpoint inhibitors were going to be important, right? And if anything, Roche and BMS probably have a little bit of a head start, but Merck through a little bit of luck and a little bit of good science, won lung cancer and even indications where they were laid into, let's say, like kidney cancer, where BMS with nivo, ipi had a few year head start, they still not control 70% of the market. So I think if we stay focused in on HARMONi-3 and 7, we'll win.

So just for those less familiar since the last trial, just tell everyone what -- we know what it is, tell us everyone what HARMONi-7 is?

HARMONi-3 is sort of squamous, non-squamous, in combination with standard chemotherapy. That study is running against pembrolizumab, replacing classical KEYNOTE-407 and 189.

HARMONi-7 is a repeat of HARMONi-2, with a slightly different population, the higher PD-1 population for Western audience, and that will replace KEYNOTE-024 and 042. So it's monotherapy. Monotherapy pembro versus monotherapy ivo.

So again, sort of derisked by HARMONi-2, which is the Chinese data, but now a global population. But remember, 1/3 of those patients will probably come from Asia.

Okay. And then just kind of a little bit more mechanical questions on HARMONi-3 because originally, it was -- well, the original thesis [Technical Difficulty] I mentioned at the beginning, the ASCO data where you looked at the better OS and the squamous, remember that. And that set up the whole thesis for doing squamous first.

Then you saw HARMONi-2 in May of '24 and we expanded. And now -- but now you kind of start to separate probably. So kind of just walk through the overall thought process there. And I mean, it makes sense why you did it in order to have Phase III data sooner. So just walk us through the thinking on that.

Yes, I think you actually did a really nice job of setting that up. And so yes, so from a Phase II perspective, we did the deal with Akeso in December, January. December '22, January '23, right, we immediately go into the EGFR mutant setting and then immediately set up the frontline chemo combination. And that, at that time, more mature data with respect to the squamous population. So immediately moved into the comparison trial against KEYNOTE-407 with HARMONi-3.

So to your point, we see in May 2024 the results of the HARMONi-2 study, which showed benefit in both the squamous and non-squamous populations. And at that same time, the Phase II data in combination with chemo and the non-squamous is also very compelling. And so we make the amendment to include non-squamous patients single ICT, 1,080 patients.

As we are now coming into 2025 and continuing through, we're rapidly enrolling the squamous population, which is, in some ways, a little bit more difficult to treat. You've got some different characteristics between squamous and non-squamous patients. And we're also, at the same time, rapidly enrolling the non-squamous patients, so a little bit of a broader market.

And so when we take a look, 2 things in particular, become clear. One is there's a bit more regulatory scrutiny with respect to individual histology have sufficiently positive data for approvals. And then there's also looking at North American patients, in particular, becoming more of a focus.

So as we look from a regulatory probability of success, we want to make sure that the histologies are fully powered for the 2 primary endpoints, PFS and OS, to ensure effectively no questions that come into play on, hey, did one perform a little better and drag the other one across the line, if you will?

So full confidence in both, but instead of running a potential risk of having one just -- if you run a study, one may look better than the other by -- in some ways, chance, you want to make sure that you're fully powered both so that there's no question with respect to statistical significance.

And then we can look at the North American patients in each of those and it's one kind of subpopulation as opposed to trying to do that across histologies as well.

But the other piece that becomes very important as well is the accelerated time lines, right? And so with the opportunity to complete enrollment in the squamous cohort in the first half of 2026, that also lets that ITT now, a separated analysis read out in the second half of '26 and ultimately allow for potentially an earlier submission and approval in that setting based on the data, right?

And so we're able to increase probability of technical and regulatory success and in particular, regulatory success and accelerate the time lines by which we can read out the squamous, which is a significant population in front line. We don't delay in that same point, the non-squamous population because we're able to enroll so rapidly in that population as well. So we're really either holding or accelerating time line in access to the market in frontline non-small cell lung cancer and improving probability of technical and regulatory success in the same way.

And then HARMONi-7 [Technical Difficulty] specific time line yet. Is that correct?

That's right. Not yet. We began enrollment earlier this year. Haven't laid out quite the time lines like HARMONi-3 just yet.

And then Bob started talking the work in EGFR and the improving OS results there. What is the latest from the filing perspective? What can you tell us about the discussion from the FDA around getting that from any of the agencies to get a label in that setting?

Sure. Yes. So I think we announced about a month ago that we -- so in May, we said that we intended to file, but the timing would be determined. And part of that, we said at the time, we wanted to continue to follow patients from the Western markets. We did that, and we announced that data in September. And then in October, we intended to submit the application in the fourth quarter of 2025. And so that still holds. We intend to submit the application in the fourth quarter of 2025. So no change in terms of guidance from that perspective.

And so with respect to individual conversations, what we don't tend to get into is individual discussions with the agency, but those are intended to be collaborative conversations between the agency and the sponsor. So we won't necessarily give step-by-step updates there, but we'll provide further updates as appropriate as we go through the process.

Okay. And then the work to expand beyond lung cancer. So you mentioned colorectal and there are others too. How are you setting priorities there as far as where you want to go beyond lung cancer?

Yes, I'll start and then Allen can jump in. But I think -- so colorectal cancer is another one significant population of patients, right? It's also a place where PD-1 inhibitors in the non-MSI-high population, in particular, have not been effective, right? So this will be a trial that's designed ivo plus chemo compared to bevacizumab or Avastin plus chemo. So it's a significant opportunity. It's one that goes beyond the existing PD-1 markets.

When we look beyond that in terms of where do we go, well, we've talked quite a bit about that, that there would be additional Phase III programs that go -- that are intended to be in the short term for initiation. And in reality, that will be judged off of a couple of points. One, there's a bit of Phase II data that's been generated by our partners at Akeso, some published, some not.

There are 10 Phase III studies running in China with our partners that's either based on Phase II data or other supporting data that's been published.

And then there's additional work that's been done in a combination with our collaboration with MD Anderson through Phase II data like the colorectal trial that we also opened Phase II sites in the U.S. and biological rationale, right? And so when we look across the landscape of the opportunity, in terms of prioritization, we're not going to necessarily give too much -- there are other competitors that are in play, and so we don't want to necessarily provide a direct road map in terms of where we're going, but we've been very clear that we intend to expand that Phase III program.

And the confidence, I think going back to what we were talking about earlier, both the question that you asked, Bob laid out, I spoke a little bit too and Allen reiterated, the confidence that we have with respect to the data being generated by ivonescimab is not only narrow in terms of where we've gone, but it's quite broad in terms of what we're seeing across solid tumors, right?

And so we see Phase II data. 4 Phase IIIs have now read out and have fully supported that Phase II data. I mean you take a look at even the frontline squamous, right? I think the medians for -- the median PFS for ivonescimab in China in Phase II was 11.1 months, and in China in Phase III, it was 11.1 months.

So we're seeing consistent validation of that Phase II data as well. And so as we look across, we have a number of different opportunities that we can continue to expand and do so pretty quickly.

And Yigal, I want to add as well, for sure, we started our IC program about 2 years ago. So we are very well advanced in our IC program. And at a minimum, is around 60 of them and some of them up and running, and we are enrolling patients, which is totally different than some of the indication of Akeso's -- sorry, the expansion above other indication of Akeso.

For sure, as the data is maturing and we are presenting, a lot of big pharma as well, they would like to combine with us because ivo will become the backbone of many, many indications, combinations with the ADC of the world or the combination of the KRAS of the world or other molecule.

So that as well put us in the situation that is we have a lot of opportunity to expand with other big pharma.

Did you have a collaboration with Pfizer yet with the ADC portfolio or...

We started, but then at this moment of time, we decided to not continue with Pfizer as soon as they got their own molecule.

Okay. So I guess that's part of the larger question, which I always get is and you pointed out, big pharmas are interesting combinations. You've got lots of competitors, Bob listed all of them, I think.

Everyone is asking me, and you're very successful raising capital very quickly. Is there a need for or do you want to have the imprimatur of a large pharma partnership to help you accelerate even further and infuse more capital so you can run the kind of KEYTRUDA-like scale of Phase III trials that can keep you in the lead with everyone competing?

Bob, do you want to answer or? You know what, at this moment of time, I can say that we are going with the speed of light, the team doing an outstanding job. We are really ahead of our competitors, I can say. Akeso is doing an outstanding job to provide us information and all of the latest data.

When everybody thinks that we are a small company, but perhaps we are, but we are a big company in the small division. We -- what we did in the past 2 years, nobody could do it in such a short period of time with such a short team, smart team.

So to answer your question, the speed that we have in the company right now is huge. So when and as is appropriate, we are going to partner. But we are not accelerating to just go for a partnership. We have enough cash. We have a great team. We have a great partner. And at the same time, at this moment of time, we are moving and when is appropriate, we will discuss the partnership.

Okay. So you feel comfortable about your position and your lead relative to the competitors and the pace of your continuing to generate data?

It's a critical time in the company when you want to make the decisions, and these decisions sometimes with all respect to the big pharma. They have their own way of strategy. We have our own way of strategy. We take more -- I'm not saying risk, but different way of doing ourselves and in a very fast space. So therefore, I believe in this regard, we are in a good position. Allen, Rob?

I think today, had we partnered with anyone, we would not be close to where we are today in terms of penetration to the market and access to patient bases.

So now moving forward, as it becomes more clear that the pristine safety profile is there and the efficacy is, without question, there at that point in time, if big pharma decided to go all in, then it would have to be with us because there isn't another drug or another molecule at this point in time that is within 2 years of where we are.

So then from our decision, how do we create wealth for our owners and maintain control. So my view of it as being a significant shareholder is I look at patients first. And if they can get to more patients more quickly, but we remain owners of the asset, even if it's embedded within a bigger pharma, then the right big pharma would be acceptable. There's no question about that.

So it's just they would need to feel that, hey, look, this is pedal to the metal all in right now. I don't think they would have done the IST programs. I don't think they would have pivoted to outside of NSCLC. I don't think they would have gone forward with EGFR.

There's a lot of things that be a little patient. And if it's a big money, we just spent $5 billion to get in and we need to spend another $3 billion or $4 billion to carry this out. They're going to go at a major pace. You're not dealing with the owners of the company. You're dealing with employees of the company, and they report to the Board members, and they elect, they decide really how the game is going to be played.

So at Summit level, the Board all owns shares, the company owns shares, just take my share count out, we still have more shareholder ownership inside Summit than any of these other companies combined. They don't own 2%, 3%, 4%, 5% of the company.

So we are, I believe, the best people at this time to be doing what we're doing. We've got significant money to carry out everything that is on our plate right now. We've got the ATM, and we always have access to money through people like yourself and others. People are attracted to winning situations.

In all of pharma in the years I've been in it, close to 20 now, there have never been 3 more prominent molecules of magnitude. We have weight loss, you have the NSCLC pembro and you have ivo. And I don't see a fourth one that is sitting there. So this is -- if you want to make -- have a big impact and a pristine profile and a group that has moved molecules, our second-year commerciality at Pharmacyclics, we did $1 billion in revenue. We hadn't been in the business 5 years earlier. But we were good businesspeople.

So that's the way I look at it. This is, to me, I haven't seen a riper apple sitting on a tree that is going to bear fruit than this ever. This is amazing.

Yes. And I can add to what Bob is saying is like, I can say that the development program hasn't been slowed because of number of people, right? So if you look at the indications like Dave and Maky pointed out, Akeso is a great partner. They're running 10 Phase IIIs and you can say, well, why aren't you running those Phase IIIs?

I mean we were very clear like TNBC is a good example of that was obvious, right? Avastin is approved in Europe. Pembro is approved in triple-negative breast cancer. There was another company that went full in into TNBC. But we said early on that the landscape is important, like the study that they're running in China is where the puck was, right, because that's the control against chemotherapy.

We now know ADCs are very important in TNBC. And so we were very strategic in waiting for the right data to understand the field, right? You don't want to jump into a study that's going to be out of date before it's done, right?

Pancreatic cancer, another Phase III that Akeso is running. China is a different market. They see the signal. That's very unique, right, to understand the biology of why ivo works in pancreatic cancer, whereas other drugs like both VEGF and PD-1 were not that effective.

But we didn't jump into that Phase III, right, because the control arm of chemotherapy. We knew that RAS inhibitors were going to be important and then the RevMed deal. So I think we are sort of being very strategic about our development program, and it's not just fast, like fast with colorectal cancer. We saw that 80% overall response rate, yes, we have to jump in there, right? Because that's where BMS and Pfizer have both jumped in. Interestingly, we still beat them, right? So I think we're not missing out by the size of what we have.

So -- and then just getting -- so with lung cancer, I mean, you've covered -- we've had this question before, but just -- so for the benefit of new listeners, you've covered all your bases in lung cancer in terms of -- I mean, you haven't looked at Stage 3, like extensive states, those are things you haven't looked at yet, right. Tell a bit more about that.

Yes. So from a metastatic perspective, and Allen alluded to this, right, between HARMONi-3, HARMONi-7, the non-driver mutations is largely covered in front line. EGFR mutant, the largest single driver mutation and then we'll continue to explore RAS mutant lung cancer through our collaboration with RevMed.

That doesn't preclude where you get into the 1C to 3A, the resectable population. We've seen significant advancements from the PD-1s there. So that's -- we had data in 2024 that was released that was very promising in that particular setting.

You talked about the unresectable in the Stage 3, right? So there's still additional opportunities even beyond the significant places that we've been in lung cancer at this point and in small cell as well.

And in fairness. It's not that we haven't looked at it. We look at it every day. We just haven't publicly disclosed our strategy there yet.

I remember at the event you had at ASCO, when Bob, you asked, when could ivo be on the market? I remember you asked that question. And that was a very good question. And then you remember that. And so if HARMONi-3 hits in squamous and like, let's just make up a time, October 2026, when -- and it goes fast and we had Marty Makary this morning talking about accelerating novel therapies and therapies that have transformative and benefit for human health, when could -- and I know you're going to have the EGFR approval. So that's -- but that's a much smaller market. So for the frontline market, the expectation should be what as far as getting onto the market in frontline, assuming you hit in HARMONi-3 in squamous.

You put that up pretty descriptively. In terms of -- absolutely, we have a readout in frontline squamous with PFS and an interim OS look in the second half of '26, right, as you mentioned. And so part of the component will depend on both the package there as well as the EGFR -- the HARMONi submission, right? Because with the HARMONi submission, if that continues to progress positively that is approved in sBLA for the frontline study.

And if not, there's opportunities in the frontline setting as well to accelerate that time line. I think you've talked about this morning with Dr. Makary talking about accelerating novel therapies through. So there's certainly ample approaches we can take in terms of accelerating that process for the frontline.

2027.

Okay. I've got to tell my team to check the Excel model. All right. Well, I think we're wrapping up. So -- but thank you both, and thank you all so much. Great, great conversation. Appreciate it.

It's always a pleasure to be in your company. Appreciate your insights, your hard work. It's tremendous.

All right. We'll see you later for the dinner, I think, later tonight.

All right. Good afternoon. Thanks, everybody, for joining Jefferies Healthcare Conference in London. My name is Clara Dong. I'm one of the biotech analysts here at Jefferies. So sitting next to me, we have Chief Business and Strategy Officer, Dave Gancarz; and Manmeet Soni, Chief Operating Officer and Chief Financial Officer of Summit Therapeutics. Welcome.

Thank you for having us.

Thanks.

So Summit is definitely a very well recognized name in the industry. But just to set the stage for our discussion and for our audience here, can you share a little -- a brief overview of the company, what's your mission, what's the current development of your bispecific ivonescimab and your just broader strategic vision?

Sure, happy to. So Summit Therapeutics is a mission-driven organization. Our mission is simply put to make a significant difference for patients who are suffering from cancer. And so our co-CEOs, Bob Duggan and Maky Zanganeh have a storied history with their experience in not only biotechnology, but the health care sector as a whole. And in our current state, we are focused as I mentioned, on cancer and the way in which we are seeking to execute on that mission is through the development of ivonescimab, our PD-1 VEGF bispecific antibody.

So ivonescimab is a specifically engineered bispecific antibody, and its intent is really to improve upon the previously established efficacy and safety standards of those 2 targets. And so that intent is what we look to carry out our mission on.

Very importantly, there are -- this is not a concept anymore at this point. And so there are over 3,000 patients who have been dosed in a clinical setting with ivonescimab. And when you expand that into and incorporate the commercial setting in China where the drug is approved, that number expands to over 40,000 patients who have received ivonescimab.

Currently, there are 14 Phase III clinical trials. There are 4 global studies that Summit is sponsoring in addition to 10 additional trials that are being sponsored by our partners, Akeso in China. So you can see the vast breadth and depth of the program from that point. And so with that, that becomes our mission -- the execution path for our mission.

Great. And you did have a lot of data events this year, and we will definitely touch on all of that. But maybe before we talk about the efficacy of ivonescimab in broad indications and I also -- I just want to take a step back and talk about the safety profile of ivonescimab, as you mentioned, a lot of patients have been treated. And how is the patient experience, especially on the safety so far compared to single-agent anti-VEGF and PD-1?

No, thank you for that question, Clara. And I think it's a really important point because as we speak about -- I talked about the molecule was designed by our partners at Akeso to improve upon both the safety and the efficacy standards that were established in those 2 targets and specifically with respect to safety.

Nothing illustrates the tolerability of ivonescimab better than the recently disclosed HARMONi-6 data by our partners at Akeso. So this is a single region Phase III study conducted in China, that met its primary endpoint in progression-free survival.

And importantly, is in a space where anti-VEGF monoclonal antibodies really haven't been able to be developed. If we go all the way back to 2004 in the JCO paper that spoke to the difficulties of bevacizumab in the history of hemorrhage and significant hemorrhage, fatal hemorrhage events that took place for squamous non-small cell lung cancer patients.

What we've been able to show with -- through our partners at Akeso is the tolerability of ivonescimab in squamous patients. And so that was very important. That was also demonstrated as a part of the HARMONi-2 study as well in the monotherapy setting that included both non-squamous and squamous patients.

And then we take that forward in the HARMONi study, the global study that Summit sponsored, we saw very consistent results with the safety profile that was demonstrated in the HARMONi-A study in China, in the same setting in that second-line EGFR mutant population. And so we saw consistency of that data between the East and the West.

And then we saw 2 particular Phase III trials, whereby historically, anti-VEGF has not been tolerated. And this is a place where we think there's a clear distinguishment when we talk about, hey, is it the VEGF contributing more? Is it the PD-1 contributing more? This is really where we speak to the novel mechanism of ivonescimab, that's really different than the 2 administered individually.

Yes. And I would add, right? This is distinguished, right, because we had engineered, right, our partner, Akeso, had engineered it so smartly, right, so that because of the cooperative binding, we see this impact, right? And another thing to note is the half-life right? Half-life for ivo is approximately 7 days -- 7 to 8 days, which is much less the other comparable drugs and whether it's VEGF or PD-1 alone. And that cooperative binding and the half-life makes it right, much -- having much better efficacy and reducing toxicity. So that helps us a lot.

And then since you already mentioned the ESMO data HARMONi-6, so maybe we start talking about that first. So you reported hazard ratio of PFS 0.6. So maybe just help us contextualize that number? What does that really mean to patients? And then squamous non-small cell lung cancer, I think historically, it has been really difficult to treat but just anti-VEGF single agent because of the hemorrhage risk you just mentioned. So like data from HARMONi-6 change people's perception on that?

I think the best way to change perception is through data and through a randomized clinical trial, right? And so when we step back contextualizing the results as a whole, 0.60 hazard ratio effectively is intended to represent a 40% improvement over existing standard of care. And so when we started this journey, the first trials that read out were HARMONi-A, which was in the second-line EGFR ivo plus chemo versus chemo alone. And that was a place where the PD-1 antibodies had historically been unsuccessful, both from a PFS and an OS perspective.

And so the next question became good. You were successful in a place where PD-1s weren't, how about going head-to-head? HARMONi-2 monotherapy, ivo versus pembro and head-to-head against the PD-1. That was successful. And the next question became, but the standard of care is largely dominated by chemo combinations, and some of these questions might have been asked by a lady to my left.

And the -- well, can you carry that forward? That's really what will be the dominant standard of care in frontline lung cancer is and can you show a result there? And so this 0.60 hazard ratio in HARMONi-6 answers the third question of frontline the overwhelming standard of care across many solid tumors is immunotherapy plus chemotherapy.

And so this was really the groundbreaking piece of rising tides raise all ships was the concern, and this was a clear difference the curve separate and continue to separate really through the median follow-up time for HARMONi-6. And so we see a median PFS difference of 11.1 versus 6.8 months. So there's about a 4-month difference there in terms of just the median difference, and then the hazard ratio represents about a 40% difference in the single region study that was conducted by our partners at Akeso.

And so that then reads into the global study that we're conducting with HARMONi-3, which looks at both squamous and non-squamous patients, and that will be the most direct answer to your question, Clara, with respect to changing care. But the feedback has been extremely positive from physicians, both KOLs and in the community with respect to the data at this point.

Yes. So Clara, one thing to add, right? If you remember, 18 months ago, right, there were -- in early 2024, right? There were a lot of questions whether this China data will translate into Western patients? Whether the PFS will translate to OS and the early OS will be sustained? And now we have answered all those 3 questions through these 4 positive 3 trials, right? And that's how -- it's a combination of the data and the safety, as we -- as Dave mentioned earlier, right, that we have now the safety pool of that. Over 3,000 patients, we don't upgrade it on a monthly basis, but it is much higher now, and it's increasing as we are enrolling. And we already mentioned, right, HARMONi-3 study, which is the squamous study is now over 80% enrolled, right? So those tells you right that the safety efficacy is all there, and it's a combination of the data sets altogether.

Great. And then you just mentioned HARMONi-3 trial, the global trial. So I mean recently, you also shared an update of the patient number for the trial and then you say you will conduct separate analysis for squamous and non-squamous population. So maybe just walk us through the rationale here?

Yes. So I think on HARMONi-3, right, we wanted to make sure that we have enough probability of success on both arms, right? Squamous and non-squamous, they are 2 distinct populations. And you know there is different even the treatment right over there, durations over there. And non-squamous is twice as big as squamous and it's growing. So it was very important for us to make sure we have enough that we even wanted that in the future when we read out the data that 1 data set is more stronger than others, so now we have powered them individually in the same protocol, and that will allow us to have the squamous results much sooner.

As I said earlier, a few minutes ago, that squamous study, even with 600 patients, we are saying it's over 80% enrolled, right? So the data set we said we expect to complete the enrollment in the first half of 2026. I can say that we are enrolling pretty good on that metric. And non-squamous is expected to complete enrollment by second half of 2026.

So you will see the data sets for squamous, right, the results should come out in the second half of '26. And in first half of '27, you will see non-squamous. So we are accelerating the time line because the enrollment is going so strong on both sides and making sure the probability has increased.

And then how should we think about the time line for pivotal readout? And are you going to conduct both PFS and OS analysis?

That's correct.

Yes, that's right. So for the squamous population, we've been clear that we plan to -- the data that Manmeet just spoke to in terms of second half of 2026. The intent there is that, that would be a primary PFS readout, and then there would be an interim look at overall survival at that point in time.

Great. And then also, very recently, at CITIC, your partner, Akeso also reported an updated data for HARMONi-A with an updated hazard ratio for overall survival at 0.74. So maybe just tell us a little bit more about the data, like what's the key takeaway from that updated data, especially in the context of long-term overall survival benefit?

Yes, great question. And so part of what Manmeet just spoke to in terms of when we look at PFS translating into OS, and then there's also been a notion where anti-VEGF has been combined 2 monoclonal antibodies or a monoclonal antibody and a TKI. But there's been a lot of combinations of PD-1 and VEGF. And there's been good data with respect to progression-free survival, but does that always translate into overall survival.

Anti-VEGF tends to compound adverse events over time. And so the longer you administer anti-VEGF, the more the toxicities tend to arise has been the notion, and that ultimately leads either discontinuation of therapy, which is harmful in terms of achieving your OS standard, or frankly, those adverse events can become life threatening at times.

And so what this showed was that, that notion that the anti-VEGF portion of the antibodies is going to be a PFS driver and not an OS driver. It basically kind of broke that notion. It was direct evidence against the idea that this compound is going to be mainly PFS without OS. The first study that was conducted that was a randomized Phase III is a randomized Phase III that showed an overall survival benefit over standard of care.

And so what we didn't see were discontinuation rates that were high. What we didn't see were compounding toxicities. What we saw was a tolerable regimen that over time showed an overall survival benefit that was statistically significant. And that's the single region study conducted in China. But it's the first Phase III study that was run with ivonescimab, and it's very important that, that now has a statistically significant overall survival benefit as well.

And then as you mentioned in the beginning, the novel mechanism, so do you think the sustained overall survival benefit actually offers any new insights into the contribution of PD-1 and VEGF components? And we are seeing what appears to be a long tail effect with ivo and a point that many physicians we've spoken with have frequently discussed and agreed upon. So do you agree with that as well?

Yes. I mean I think the IO tail or that long tail is generally associated with immunotherapy, right? And so the HARMONi-A data as well as -- and I would say the HARMONi-A overall survival curve and the HARMONi overall survival curves were generally a consistent shape, the hazard ratios were generally consistent as well. The long-term follow-up analysis was 0.78 with HARMONi and 0.74 on HARMONi-A. And so you can see that very consistent results, consistent shape of the curves.

And so with that, you see what appears to be the IO tail there. And that further speaks to 2 things. One, PD-1 monoclonal antibodies themselves weren't successful in showing PFS or OS benefits. This showed both the PFS and an OS benefit. It appears to have that IO tail. And there's been a lot of discussion with respect to anti-angiogenic therapy for EGFR mutant patients.

And so the contribution of targets is clear. I think the one thing I would go further, though, is I often want to break apart from the idea of how much was PD-1, and how much was VEGF. I think what Manmeet spoke about in terms of this is a novel mechanism, this is different. It is through its cooperative binding capabilities, a new approach to treating cancer. And I think that's something that was demonstrated. Even when we look historically at PD-1 plus VEGF in monoclonal antibodies in EGFR mutant, we have not seen an overall survival benefit.

I think another thing to note is the sustained OS benefit, right, and HARMONi-A has already demonstrated, right? When we did earlier maturity, data cuts, right, at 50% maturity, right, it was around 0.79, 0.80, it was ranging at different times. Now it's 0.74 when it has matured. Same thing we have demonstrated on the Western patients data and HARMONi, right? Even after waiting like with the September data cut, which we did, it was coming into a significant number. So it is showing that as you sustain, right, because you have to wait for the maturity of the data, and that has been pretty encouraging.

And then before we move to HARMONi trial. I also want to ask, this is a second-line EGFR mutation. So do you think this long-term overall survival benefit have any readthrough to frontline trial as well?

Yes. I mean it's certainly a fair question. I would say it's difficult to make that assertion without the data. That's why we're running the studies. What I would point to, though, is the consistency of the results of the Phase II and III data. And we saw that again, even with HARMONi-6, the Phase II data showed 11.1 months of median PFS. The Phase III data showed 11.1 months of median PFS, right? So we saw that consistency in translating through.

I think when we look at the frontline data, some of that -- there was a longer-term follow-up in some of the Phase II data that we saw there. This was presented at ELCC in 2024 with about 22 months of median follow-up time. And we're seeing that tail that you talked about, it's a single-arm study. It's a Phase II, but you see that tail. You're seeing the consistent results when Akeso ran the Phase III study.

And so I think when you take the totality of all of this data, that's really what encourages most -- again, 4 Phase IIIs have read out, 4 positive Phase IIIs, different settings within lung cancer and now the 10 Phase III trials that Akeso is running that are now well beyond just non-small cell lung cancer. We have that trial this now up in microsatellite stable colorectal cancer.

And so when we look at all of the -- it's really the totality as opposed to kind of saying this one piece is this directly read through. It's really the totality of the evidence across all of the studies.

And then for HARMONi trial in second-line EGFR mutated non-small cell lung cancer. Maybe tell us what's the significance of this trial and what are the key takeaway from the data and especially in the context of BLA submission as well?

Yes. So I mean, I think this is the first global study, right? And so this was a place where people were looking at the comparability of what we've seen in the readouts from China and how that translates in. I think when we look at the gold standard of overall survival, we saw extraordinarily consistent results, both looking at hazard ratios and medians.

And so when we look at medians, basically 16.8 to 14 months, 17 months to 14 months when we compare the East and the West. When we look at hazard ratios at the same follow-up time. So Manmeet spoke about is we continue to follow the drug. And again, contrary to what people have assumed that you'll continue to get worse, we saw an improvement in overall survival with longer follow-up time.

And so when we look at now consistent follow-up time, as we know, HARMONi was enrolled sequentially. And so the follow-up times between the East and the West were different. But when we look at that, about 50% data maturity, if you will, number of events over total patients enrolled. We saw in China, about 0.8 to 0.82 at that point in time, we see in the West 0.84.

So remarkably consistent results at the same follow-up time, which is incredibly important when we look to -- as we continue to expand our development plan, looking at the results that are coming from our partners at Akeso, looking around at the standards of care. This becomes really important to show that. So I mean that's -- first and foremost, an incredibly important data point. And then secondly, this is an area of high unmet medical need, right?

There's one fully approved regimen in the space in post-TKI EGFR mutant patients. And so this is a place where we believe ivonescimab plus chemotherapy has a significant place to make a difference for patients. And hence, that's the reason for when we see the results moving forward with an application. There is no regimen in this space that is demonstrated an overall survival benefit that's been approved by the FDA. And so that's an important point as we think about the risk-benefit profile, which we -- in our review of the data is there in this space.

And I guess based on your interactions with the FDA, like how should we think about the balance of importance of primary overall survival analysis as well as long-term follow-up data because, obviously, the changes in long-term data will likely be driven by ex-China patients?

Yes. I think I understand where you're going with that question. The -- so as we said, announced, we intended to submit our BLA in this quarter. And part of that was really taking into account all of those factors, right? The consistency of the data, the East to West, the long-term follow-up analysis that was performed.

Understanding, to your point, the FDA had asked for a statistically significant overall survival benefit. And so when we take all of those factors together, that's really where we come to the conclusion that we believe that this is meaningful in this space for patients, and it's in the best interest of patients to move forward, and this is our perspective.

And we've also noted, right, none of the approved therapies have seen any OS, which got recently got approval, right? So yes, we understand the bar is high, but I think if you look the combination of all the data, including HARMONi, which has shown OS significant, HARMONi-A, right, there. So all those things will be combined. And now we have much more data sets, which will be coming in the next 6 to 9 months.

Great. And also, you recently opened new trial in colorectal cancer. So maybe talk about your -- the opportunity there and your development path.

Absolutely. So we've been clear from the beginning of this year that there's a significant opportunity in non-small cell lung cancer for ivonescimab, but this is not a lung cancer drug. It happened to be the place where we started. And that's evidenced as well by the pipeline demonstrated by our partners at Akeso with so many trials outside of lung cancer.

But obviously, ESMO 2024, there was data that was provided with FOLFOXIRI chemotherapy backbone that was highly encouraging. And we continued to run that Phase II study with multiple chemotherapy backbones. We also enrolled patients in the United States in that setting.

And so when we looked at the totality, we were able to compare several data points, different chemotherapy backbones, different follow-up times. We had multiple endpoints that we're able to assess both safety and efficacy. And so that gave us the confidence with which to move forward in this space.

And it was -- another example of a place where PD-1s have not been historically as active. There has been a VEGF component. But we think that the novel mechanism that exists here is explaining that increase that we're seeing in the efficacy profile in -- to Manmeet's point, with the half-life maintaining that tolerable safety regimen profile as well in the regimen.

And can you also talk about your collaboration with Revolution Medicine about the RAS(ON) inhibitors combination?

Absolutely. We're extremely excited about this, and we're looking to begin dosing patients early next year. And so what that really does is the next step becomes -- as we move forward as an industry at oncology, novel, novel combinations are exceptionally important. And this is really the first step for ivonescimab in that -- from that perspective.

And so in walking through the tolerability of ivonescimab, that gives us confidence with which to combine with several different targets. So the multi-RAS and the targeted KRAS inhibitors from Rev Med are extremely exciting and are something that we watch closely, and it became very much a clear pathway by which we could look to combine and do what's best for patients.

That is step one for us also in terms of potential combinations. We've been very clear that we believe we have a strategic advantage by not looking to combine with those molecules in our pipeline, but to follow the data to collaborate in a clinical trial collaboration setting with multiple other targets that exist.

We can follow the data, and then we can find where the data points to -- I think we've talked about this historically, but we don't believe there's a single platform of ADCs that will become the standard of care across all solid tumors. And we've seen this with chemotherapy as well, there's not a single chemotherapy backbone that is the standard of care for all solid tumors. And so it's very important for us to -- instead of looking to synergize within our own pipeline, really to follow the data to do what's best for patients.

Great. And lastly, what are the key milestones in the next 6 to 12 months that investors should watch for?

A lot of them, right? I already mentioned about, obviously, BLA filing this quarter, right, which we plan to submit for HARMONi or EGFR second-line, completing enrollment for squamous arm for HARMONi-3 in first half of 2026, completing enrollment for non-squamous arm in the second half of 2026, and then finally, pivotal data for squamous arm in the second half of 2026. So those are a lot of milestones in near term, and that's why -- that was the reason, right, we make sure our balance sheet is strong enough, right, to carry on for the next 12 to 18 months. And now we are -- we can say we had $0.75 billion in the bank, right, after doing this latest $500 million financing.

And that allows us to look to expand the lead that we currently have in this space.

Yes. And our success has been, right, the mantra for our success has been right, focused retention and massive action. And by putting focus, we think we can achieve much faster than what anybody can do. And that is pretty much visible that we have already a lead in lung for over 2 years, right, based on other people who are following in lung and similar in CRC, right, other companies are going to start their Phase II, III, we are starting Phase III. So that will be a distinguished -- you are ahead in the game.

Great. Very much looking forward to all those milestones. And thank you so much, Dave and Manmeet for this session. Thank you for all the audience here joining us. Enjoy the rest of the day.

Thank you. Thank you for having us.

Thank you for your time, Clara.

All right, everyone. Thank you for joining us. Our fireside chat with the Summit Therapeutics. It's a great pleasure to welcome Manmeet Soni, Chief Financial Officer; and Dave Gancarz, Chief business and Strategy Officer.

And before I start, I just want to do a quick -- kind of just check -- for anybody who wants to ask a question here, please feel free to scan the QR code and we can ask a question on your phone, then they will transfer over to my iPad here, and then I'll ask a question. So feel free to ask away any questions that you might have.

All right. With that out of the way, Manmeet, Dave, really pleasure to have you. Welcome to the UBS Healthcare Conference.

Thank you. Appreciate you having us.

Thanks, David. Thanks for having us.

Excellent. So maybe just to start from a high-level perspective. Of course, Summit is a very topical name everybody cares about now. But could you just provide a kind of high-level overview of Summit your lead molecule, ivonescimab and the overall strategy for the company.

Yes. Yes. So thank you for the question. I think the -- overall, our lead molecule is ivinezumab, but it's a PD-1 VEGF bispecific antibody. This is our lead and primary focus of Summit Therapeutics. So from a background perspective, Bob Duggan and Maky Zanganeh our co-Chief Executive Officers, as well as the rest of our management team, Manmeet and I are here, [indiscernible], when we look at the opportunity of what someone is looking to do, it is focused primarily on bringing the mechanism of a PD-1, the mechanism of an anti-VEGF together into a single molecule and creating a novel mechanism through it.

So we target both PD-1 and VEGF, but the molecule itself was specifically engineered to really exceed what both previously established targets do into a new mechanism that's primarily driven by a couple of factors. One, ivonescimab being a tetravalent bispecific antibody has a shorter half-life. And so what that does is really emphasize the safety of the compound. So when we look at some historical considerations for anti-VEGF therapy that have had higher risks of bleeding proteinuria and hypertension that have ultimately been results of accumulating toxicity that maybe have reduced some of the opportunities for overall survival. Ivanesmab was designed to, with a shorter half-life, reduce that risk. And then finally, cooperative binding is a key component of this.

So in the presence of VEGF ligands, the affinity or the binding of ivonesemab to PD-1 is about -- is tenfold stronger than in and of itself, a traditional PD-1, if you will, without the presence of the VEGF and the VEGF finding. So what that allows for is really the hypothesis being that, that is most effective in the tumor microenvironment where both PD-1 and VEGF exist. And so that really attracts the molecule to be on target at the tumor to help ultimately slow disease and ultimately kill the tumor cells and then the ultimate goal being to increase survival for patients. And if we move earlier and outside the metastatic phase, increased cure rates would be the intent.

Got it. That's really helpful here. Great. We can move on to some of the key trials. You do have multiple trials, including HARMONi, HARMONi-6, HARMONi-2 and others, right? So let me start maybe talking about the Harmony I and then the most recent update from [indiscernible], which is HARMONi-H trial where you guys provided some updated data in overall survival that should have a ratio of 0.74, which is static. It's 0.019, right? So maybe help us contextualize that data here, Dave, what does it mean for you? And also at the same time, how do you think this data kind of translates into HARMONi-I, which was recently presented at WCLC?

Yes. So there are 4 Phase IIIs that have read out with respect to ivonescimab. So the first trial -- and all 4 of those were positive readouts. So 4 Phase IIIs that have read out 4 positive Phase IIIs. When we look at the opportunity in HARMONi-A, that was the first trial that was initiated from a Phase III perspective, right? So that ultimately, on Friday, you mentioned, resulted in a statistically significant OS benefit.

So contextualizing that, if we think about -- and this was part of what we spoke about at the beginning, what was ivenesimab designed to do. It was really to increase the potential of duration and quality of life of patients. In doing so, the half-life of ivanesemab is intended to make a more safe molecule as opposed to the individual compounds. And so what we hear historically, the notion is that if you -- anti-VEGF when you accumulate duration of therapy, you ultimately accumulate toxicity and that prevents survival. This really was intended -- this shows that that's not the case for ivonescimab.

This was the first Phase III study. It was a statistically significant OS benefit, though. And so this is a place where PD-1s have failed historically. PD-1 plus VEGF has not shown an overall survival benefit. And so this really puts on the -- or puts to rest the notion that a PD-1 VEGF bispecific will not show an overall survival benefit full stop. In addition, you asked about the translation to HARMONi, the global study. And so what we saw there as well was the data that we presented at the World Conference on Lung Cancer, World Lung in September, we showed a longer-term follow-up of overall survival as well for the global patient population, right?

So HARMONi-A is specific to China, HARMONi global population. And that had a nominal p-value of 0.03. And so again -- and which would have been below the statistical cutoff for survival in that study. So what we show is the mechanism is very much bringing an additional enhanced benefit to those patients. And we think the benefit risk profile is reflected in both of these studies now. It also shows the consistency of the data. When we overlay the curves from HARMONi-A and HARMONi extraordinarily consistent in terms of the overlap. We showed at World Lung as well the consistency of those curves from a PFS perspective as well when we added in additional patients from the West. So I think in total, I think that kind of covers the translatability and the opportunity.

If you go back like 18 months, 2 years, there were a lot of open cushions, right, which all investors had -- and all of them have been mostly answered, right? The first one was, guys, can Chinese data replicate into Western. We have shown that, right, through HARMONi, right? Will BFS translate into OS. We have shown that also, right? And the OS will be consistent, right, like on maturity is not Detroit. And we have shown that through HARMONi-A, right, which it used to be 0.80 and after further follow-up, it's now 0.74. So all those questions which were there have been answered, right? Best in versus Eastern, BFS to OS and OS to further mature OS.

Yes. Do you attribute that difference in terms of OS, where we saw a benefit and start static statistically significant OS in the HARMONi-A trial whereas the HARMONi-I, although the nominal p-value is less than 0.05, do you first analysis that the primary analysis was not, right? The attributes to the statistical plan powering? Or how do we think about this? Timing of enrollment, right? The Western patient was data was not mature enough. Once we did the mature data for Weston, it was significant. It can't be called fat significant because now we have used that, done that, but it's a statistic issue.

But the drug is working as it was engineered, right, as you were saying, the drug demonstrated but you'll have to wait for the appropriate follow-up of the patients, right? You can't have 8, 9 months material data to show an OS benefit. And once we reach 13, 14 months of follow-up, that was converted into showing a significant.

I think there was an understatement on the expectations when we started this trial in terms of what it takes to bring a trial directly into Phase III in the U.S. and Europe where it hadn't been previously exposed. So if you think about the factors here, right, we took a -- we had -- obviously, we did the deal in end of 2022, beginning of 2023. I had a lot of confidence in the opportunity, and that's why we started immediately. But for physicians, they had not been previously working with the drug. So this was we're effectively asking trust the data that we had been generated.

Now today, over 40,000 patients have been administered ivonescimab, either 3,000 or so in a clinical trial setting. And when you include those in the commercial setting in China, over 40,000. But at the time, we had several hundred patients, but all from China. And so we're asking physicians to trust the data from China. There were, as we talked about concerns with respect to VEGF tolerability. Is this something that leads to bleeding risk? Are there additional risks for patients. And we were able to demonstrate through putting a few analyses together and then ultimately further data readouts that the risk was much lower.

When you look at the specific factors for EGFR-mutated lung cancer, brain metastases is a common location of metastasis. TKI is effective in slowing down progression of brain mets. There was -- we didn't have data that has been published at that time with respect to control of brain mets. We've now -- you see the published curves, PFS and OS with those patients with brain metastases entering the trial. And we see that, that has been something that ivenesumab has shown an improved hazard ratio for those patients with existing baseline brain metastases.

And finally, we're still working through a lot of sites. We're still working through some of the ramifications of COVID in early 2023 in terms of fully gearing up their staff back and whatnot. That led to as Manmeet talked about that 4-month delay or so. When we did that ad hoc analysis at the -- it were lung -- at 4 months later on follow-up, and then you saw the p-value that was attributed to that study. The nominal p-value.

I think another thing to add and might be in different words is when you generally are doing a Phase III, you had some experience in the United States, right? Because we had got this drug from China. There was 0 experience, right, with the drug. We had to open up the sites. The company was just starting up, right, to open up the site, get the operational delays in getting the CTAs up and sites up, it takes time, right? So that was the few months delay, right? And now it's like now we have announced that we are enrolling so fast on [indiscernible] how many. It's different now after 18 months, 2 years.

It's ironic when you look back, I think people talk a lot about the PD-1 VEGF class. We talk about the other big pharma who are very interested. Only a short period of time ago, all of that was a bit different in terms of the climate, the experience and the perceived opportunity at the time.

Yes. That's really helpful. And then regarding the HARMONi and BLA submission, which I think called many investors back surprise here, and then you're saying that you're actually planning to submit in 4Q. So I was curious around the decision to do that. Have you met with the FDA? Have you got buy-in from them regarding the submission how confident are you that overall package of the FDA will lead to an approval.

Yes. So we don't -- we have a ton of respect for the agency. And we've -- across -- we have announced or started 4 Phase III clinical trials that obviously comes with a lot of meetings with the agency across a bunch of divisions as well. What we don't do is get into meeting-by-meeting discussions in terms of what we have. But what we made the conclusion on was really the benefit risk profile that we saw with ivinezimab, considering what's the historical precedent, what's been approved historically.

There are no regimens within statistically significant OS benefit that have been approved in the U.S. in this setting. We look at the tolerability of the ivonescimab plus chemo in the setting and we see a very manageable safety profile. So that risk-benefit profile in consultation with many folks in many different areas, physicians and so on and so forth, this became the path forward that we wanted to pick.

Got it. And then for the BLA submission, do you expect the FDA to have a later data cut of the OS for the submission?

Similar to what I said. I think we don't -- we're not going to presuppose what the agency will do. We ultimately -- we have an extreme amount of respect for the agency as well as the process to go through that, whether it's the pre-BLA, the BLA process and whatnot. So we'll have multiple engagements throughout, but we're not going to give kind of step by step through that, but we'll certainly work with the agency.

But to answer your question in different words, right, if they will ask, right, yes, we want to and provide them, right? We generally have to do that and follow their advice and their questions.

Yes. That's fair. Great. Let's switch gears and talk about HARMONi-6 data here. So HARMONi-6 is the China trial for ivonescimab plus chemo versus tislelizumab plus chemo in frontline non-squamous lung cancer...

Squamous...

I'm sorry, yes, squamous -- my apologies, squamous non-small cell lung cancer. So just help us understand concentrate the meaningful efficacy there. And what does it mean for, let's say, readthrough ability to the global HARMONi-3 trial there.

Yes. I think you know that [indiscernible] right, there's a pretty comparable to pembro, right? It's in China. And that trial, like if you're comparing with PD-1 showing 0.60 hazard ratio, 40% improvement in PFS is huge. And that gives us confidence and read out on HARMONi-3, which we said, right, we will be completing enrollment for that in first half that it's looking pretty stronger in our view.

I think the other -- so continuing on that thought, right? I think we saw HARMONi-A reads out, and it's against placebo and albeit in an indication that PD-1s have been ineffective. And it was, okay, well, you need to go in to PD-1. And then HARMONi-2 reads out in PD-1 versus ivo head-to-head and that being pembrolizumab, beat it head-to-head. Then -- well, but when you add chemo that rising tides raise all ships. And so that will dilute the effect decisive statistically significant and clinically meaningful PFS benefit over PD-1 plus chemo.

Frontline -- now this is the frontline undisputed standard of care in terms of both squamous and non-squamous patients, right? Squamous, this is very much comparable in terms of the results of pembro, tisle, so on and so forth, cemiplimab, they've all shown reasonably consistent results here in terms of the PD-1 category. So now then you take the next step with respect to the safety profile, right? Anti-VEGF, again, accumulating toxicities and in particular, in squamous patients, where it's effectively contraindicated because of the very high risk of hemorrhagic events, grade 3 to 5 leading risks, so on and so forth.

We not only show a victory in terms of the trial from an efficacy perspective, but also the safety was incredibly important here. This is a randomized Phase III study against PD-1 plus chemo in squamous lung cancer patients. And so these are patients who are not necessarily highly preselected either in terms of risk criteria, so central lesions, capitated lesions, surrounding major blood vessels, right? So this isn't a cherry picked profile as well. And what we saw was a very manageable safety profile, oftentimes between the 2 Ivo plus chemo or tisle plus chemo, it was difficult to tell which was which.

And so that's also extraordinarily reassuring in terms of going back a couple of years and people are saying, "Hey, VEGF, there's a risk, how do we mitigate some of those safety risks. This is a great example of the tolerability and the manageability of Ivo.

And how should we think about the PFS benefit will translate to OS benefit there going forward? Dave, you mentioned about the short half-life, improved tolerability there. just help us understand then the other flip side of the argument is there may not be contribution to the PD-1 arm. I'm just curious in terms of your thoughts around the PFS to OS translation ultimately.

Yes. I think the HARMONi-A study for 1 showed directly that PFS benefit leads to an overall -- a statistically significant overall survival benefit. So I think now that argument becomes a little bit tougher with [indiscernible] benefit. I think the other piece becomes what's the rationale why it won't right? Because in some ways, I want to turn that question around. We say, "Hey, why do we think it will. But if we look at the -- what are the concerns?

Again, VEGF, toxicity accumulates shorter duration of treatment, ultimately, those toxicities can lead to earlier death. We didn't see either of those. We saw a duration of response that was longer. We saw higher overall response, and we saw an increased PFS benefit. We also saw an increase in a PFS curve that continue to separate further, right. And with that, you ultimately -- you see the first trial run lead to a statistically significant benefit. We talked about HARMONi, the global study. And with the -- what we believed would be the follow-up time for when that analysis would take place, nominal p-value under the threshold.

We're seeing HARMONi-2 in an early ad hoc data cut that was requested from the Chinese health authorities, already showing an OS hazard ratio under 0.8, but generally accepted clinically meaningful threshold. And now we're seeing very positive, albeit early results in terms of the HARMONi-6 study without the toxicity and with and with a growing benefit across all of the major early end points here, if you will. And so it becomes, in some ways, difficult to believe that, that is not something that translates into OS instead of the other way around in terms of why not.

Got it. And then in terms of the other debt, which is thinking about the China to floorage inflation, a lot of skeptics around how likely will a China trial translate in terms of global trials. So I'm curious in your thoughts around any updated data or anything you've seen so far that would give us some confidence around the translation from China trial to global trials. How many was that, right? How many was from how many or how many are replicated. If you see in North America, the OS was exactly similar, right? PFS was exactly right. So that's how -- if you look at those graphs right there totally so much overlapping over there to translate. And now you'll have to wait for the next 1 is HARMONi-3, which will read out next year to do that right?

Yes. So in addition to what Manmeet said, if you look at median overall survival, 17 months versus 14 months in the West, 16.8 months versus 14 months in the East right? I mean, effectively, incredibly consistent median overall survival. You look at -- so let's look at, for example, on this one, it's the same follow-up time. Right. And so in HARMONi-A at ASCO 2024, at about 50% data maturity, 52% of events that took place, hazard ratio of 0.80. That included those who didn't receive a third-gen TKI.

We've seen about a $0.02 difference when you exclude those patients, right? So if you pull those patients out of HARMONi-A, it's about 0.82 at that point in time. Pretty much exact same follow-up in the long-term Western follow-up that we presented a world long 0.84. So you're talking 0.82, 0.84, that same about 50% of events time period, incredibly consistent. The PFS curves as Manmeet talked about as soon as you add in more longer-term follow-up on those western patients, the curve doesn't move same with OS.

You can overlay the HARMONi and the HARMONi-A curves. If there were a difference in terms of the way patients reacted, you would see fundamentally different shapes. 38% of patients from the HARMONi trial are from the West, 38% of patients acting differently will absolutely change the curve.

Got it. Okay. Great. And then in terms of the next steps for HARMONi-6, could you maybe just share some of the thoughts around what should we expect next data on OS data or PFS data?

Yes. I think importantly, that trial is sponsored by and conducted by [indiscernible]. So that is mainly for them. I think the -- there's been some -- the publication in terms of the land it had a little bit more indication with respect to statistics. So that looks like something that comes at some point next year, but that's really for the team at [indiscernible] to give specifics in terms of that guidance.

Great. And then moving on to your global trial HARMONi-3. So you recently amended the protocol to increase sample size for both the squamous and non-squamous non-small cell lung cancer where each cohort now is powered separately. Could you provide some color in terms of what you saw in terms of enrollment rates, physician feedback and end of the clinical data that made you decide to amend the protocol there?

Enrollment has been going pretty fast. That's why we guided in October only that we will be able to finish squamous enrollment by first half of 20 and non-squamous, which is now 1,000 patients, it's double the size, right? Because squamous patients is 1/3 of the frontline and nonsquamous is 2/3 of the population. So that's why they are powered separately to see that 600 versus 1,000 patients.

But non-squamous is also -- we started only this year, and we are saying we'll be finishing the enrollment right in the second half of 2026. So enrollment is going pretty fast. That gives us the confidence. And that's why the readout for squamous could happen in the second half of '26 for squamous and nonsquamous readout would be in 2027.

Any kind of physician feedback you'd be hearing so far on the enrollment on the receptor.

Yes, we had a lot of calls with all our sites. We have now so many sites up and activated, all positive feedback. They were all surprised with the outcome of the data and ivonescimab has always right work. So we are not seeing anything all positive feedback from physicians. Their enrollment is going pretty fast. So I think...

Yes, I think the only thing I would add to that is I agree with everything that Manmeet said, I would also add a decrease in regulatory risk here. So it increases the probability of regulatory success here by splitting it out the 2 individual cohorts, right? You never want 1 to look a little bit better than the other, then you asked the question, did 1 drag, the other 1 across the line. We started squamous a little bit earlier. And so I think part of this becomes -- let's have clean IT for squamous and nonsquamous power them both individually. In that way, when we look at the analysis, they are very clean.

You can look at the we've had a lot of topics of conversation in terms of -- and this is -- this being a more general comment, but the FDA really wanted to make sure that U.S. patients reflect the overall global patients results that we see in the trial, we've seen that across a couple of ADCOM meetings or ODAC, the FDA has held in the past year. And so this what's out the populations between the squamous and the non-squamous and that will make everything a bit cleaner in terms of review and not have any implied questions that can come. So these are very important settings for ivanesamab and for Summit as a whole. And so this becomes important to be as clean as possible.

So just to clarify, so by separating them out, you're actually able to derisking the regulatory side of things, right? You're able to separately submit BLA submission. We respect of other success of [indiscernible] trials.

That's exactly right. And so think of it as 2 clinical trials within 1 protocol, if you will.

And it accelerates the opportunity for squamous to come faster, almost a year faster because otherwise, you have to wait until end of '27, if you do combined analysis.

Anything to share on the powering assumptions for the trials there.

I don't think so we have discussed any public assumption.

Other than to say that they're both squamous and non-squamous are adequately powered for both PFS and primary endpoints.

Yes. It's interesting. You also mentioned that you're able to get PFS data for squamous and at the same time, you're able to get in terms of the OS. So could you help us understand what's next steps from here? Are you able to file for approve if you are to show data in the second half, 26-year to approve or are you to submit data right away? Submitted for approval right away.

Assuming positive data, right, that would be the intent to submit it for the BLA.

Yes, it's a total package question exactly as Manmeet said, it's -- we have to review the data and if that data supports, then that would be the decision to make at that time.

But our confidence increased, right, because of the HARMONi-6, right? HARMONi-6 squamous PD-1 plus chemo, right? That tells you that guys. The drug is working in squamous patients and our mechanism of action which was engineered denier, right, for that half-life and the cooperative mining, it's working exactly how it was planned and engineered.

Got it. Great. And then moving to HARMONi-2, the China trial for [indiscernible] monotherapy versus pembro, we've seen the PFS data. We also saw the interim OS 39% maturity. Anything you can guide on in terms of when should we expect the OS data for the final analysis?

So again, that's in Akeso sponsored study. So at that point, I'll let the team at Akeso updates with respect to that guidance. But obviously -- and it was really an administrative ad hoc look at that OS look when the CDE was looking to approve and the NMPA ultimately approve that indication, but we'll leave it for the team at Akeso in terms of updated guidance there.

Great. Okay. And then you moved recently into a CRC, which it's great to see that. And the indication expansion. Maybe you can just tell us a little more about the clinical trial design, any powering assumptions and potential time lines for enrollment and readout.

So we're just getting ready to start at this point. So I appreciate the readout in the next steps question there. But look, we're very excited. And I think -- so we gave a little bit of detail in our press release and 10-Q, but currently structured at 600 patients with a PFS primary endpoint. I think the place where I would focus that really, though, is if you take a step back, right, because I think you're -- I'm anticipating your question, but with this, how do you how you think about where this goes and how you're going beyond lung cancer, right?

So if I step back a little bit, this becomes -- and just look at ivonescimab, right, there's 14 Phase III clinical trials right now. being conducted globally now including the CRC and then 10 being conducted by our partners at Akeso in China. 4 of them have read out, 4 of them are positive studies. So great backbone. But what that 10 implies is really that there's multiple additional places we can go. So CRC is 1 of the places where Akeso was also running a Phase III study. But then you get into head and neck, you get into pancreatic cancer, you get into triple-negative breast cancer, additional spaces within lung cancer, so on biliary tract cancer, so on and so forth.

And so there is a multitude of different places where this drug can go. Another piece that might have been slightly overlooked with respect to HARMONi-6 is the consistency by which ivonescimab performed in that trial compared to the Phase II trial, so that AK112201 study, 11.1 months of median PFS 11.1 months of median PFS in the Phase III study. So you typically have that drop off from Phase II to Phase III and whatnot. And look, that's not something that I expect will have in every single time by any stretch.

But when I mentioned at the beginning, 3,000 patients have been administered ivonescimab in a clinical trial setting. Obviously, a lot of that data has not yet been published. But what it shows us is the consistency of the impact of ivonescimab, the different settings in which ivonescimab can be impactful in all of the places that ivonescimab has the opportunity to go in addition to where even those 14 Phase III clinical trial starts.

So we have an opportunity. And we mentioned this during the earnings call, we have the opportunity to expand into a multitude of places, and we plan to do so in the shorter term as well here. This is not done with CRC and then we're going to take a break, and we're going to prepare to continue to expand that plan because this is what the drug deserves.

Yes. I mean this thing on which I know we're 3 minutes left. I do want to ask some questions around the competitive landscape as you can imagine as an is picking up is getting really fierce with Pfizer jumping on and beyond Tacos has a competitive PD-L1 VEGF program as well, and they're all going after different indications, right? And there potentially adding different combination strategies with ADCs and others. So curious your thoughts around how are you -- how are you viewing the compete landscape and how you're staying ahead of the curve in terms of developing ivonescimab?

Yes, it's a great question. So I think we need to continue to expand the places that we look, and that's what I was just speaking to in terms of all of the trials that are being run in lung cancer, the opportunity to go into colorectal cancer and now expanding -- continuing further within the solid tumor space. In addition, combinations are and will continue to be important with respect to treating solid tumors.

I think we have a competitive advantage in the sense of -- and we're evidencing this with our collaboration with Rev Med. So we're taking ivonescimab and combining it with multiple RAN inhibitors from Rev Med. And that -- those patients will begin to receive that combination in early 2026, right? But that's not the only time we'll do that. I think we've been very clear, we'll continue to expand the number of clinical trial collaborations that we have by following the data. There's no chemotherapy backbone that's the standard of care across all solid tumors. And we don't believe that there'll be a single ADC platform with a single payload that will be the standard of care across solid tumors.

We've seen many places where Platform A has worked in 1 type of tumor, but not necessarily another and then platform B is worked there, but not in the third place, right? And so solid tumors biologically are very different. I appreciate that we put solid tumors around all of them, but they're biologically extraordinarily difficult. We see PD-1 work in some and not all, right? And so what we can do is really follow the data and continue to expand the number of different novel combinations that we do with ivonesumab, and that positions us extraordinarily favorably in terms of where we can go quickest without being encumbered by our own pipeline, if you will, in terms of looking to find synergies within our own portfolio.

And obviously, there are other companies who see where the puck is going. We see this now read out with HARMONi-6 that gives a lot of confidence in terms of HARMONi-3. And so as we look at non-small cell lung cancer going forward, could ivonescimab be part of that standard of care backbone. Well, now other companies are -- can reach out and say, "Hey, is we're looking to get into that space as well, this might make sense for combinations.

And you know the right checkpoint anime market is expected by 2030 to be over $90 billion, right? So that is -- there will be competition, and you should expect that. And lung cancer is there, right, non-small cell and cancer, colorectal, they are big markets, right, to play. And I think we are not saying it's the -- we are taking the 100% market share also, right? So it's -- it's good to have competition, and it's good for patients, right?

Absolutely. Yes. Great. All right. Great. One last question. Just over the next 12 to 18 months, what should be -- what is scale we should watch for.

HARMONi-3, is a big one, right? Squamous, you'll get the readout, right? The first global trial, which people have been waiting. Again, all the questions, which we have answered is how many will be again answered through HARMONi-3, and BLA filing, right, for EGFR. So those all will come in 12 months and 18 months, you get HARMONi-3 non-squamous. And then further updates on colorectal and few expansion opportunities in the pipeline.

We're not stopping anytime soon.

That's great.

[indiscernible]

Yes, don't stop. Just keep going.

We have to love it. We have an obligation. We have taken responsibility to bring this medicine to patients who are in need.

Excellent. Okay. Great. I think with that, we can wrap it up here. Manmeet, Dave thank you for joining us here.

Thank you for having us.

Appreciate it.

Thank you, everyone.

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the Summit Therapeutics Q3 2025 Earnings and ESMO Data Update Call. [Operator Instructions]

I would now like to turn the call over to Dave Gancarz. Please go ahead.

Good day, and thank you for joining us. We issued a press release on Friday morning regarding the expansion of our Phase III clinical development programs, unveiling the global Phase III study in first-line colorectal cancer. Yesterday, we issued a press release relating to the Phase III HARMONi-6 data featuring ivonescimab presented as a part of the Presidential Symposium at the European Society for Medical Oncology's 2025 Congress, otherwise known as ESMO 2025. The HARMONi-6 study was conducted in China, sponsored by our partners at Akeso. All relevant data was exclusively generated, managed and analyzed by Akeso. And finally, this morning, we announced our intention to submit a BLA this quarter for ivonescimab based on the results of the HARMONi study as well as expand our Phase III study plan with additional color to be provided in the first quarter.

Additionally, on today's call, we will provide an update on our third quarter financial results and operational progress. Press releases are available on our website, www.smmttx.com. Our Form 8-K and Form 10-Q were also filed today and are available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will be made available later today on our website.

Joining me on the call today is Bob Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Maky Zanganeh, our Co-Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; Dr. Urte Gayko, our Chief Regulatory, Quality and Safety Officer; Dr. Allen Yang, our Head of R&D Strategy; Dr. Jack West, our VP of Clinical Development; and Dr. Fong Clow, our Chief Biometrics Officer.

Before we get started with the rest of the call, I would like to note that some statements made by our management team and some responses to questions that we make today may be considered forward-looking statements based on our current expectations. Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties.

Summit undertakes no obligation to update these forward-looking statements, except as required by law. One item of note, this presentation is being webcast with slides, so we'll be referring to information on these slides being displayed in the webcast link. I'd encourage you to use the webcast link to see these slides being presented this morning that will accompany our comments, and these slides are also available on our website.

Following comments from our team, we will take questions. With that, I would like to hand it over to Jack to walk through the beginning of the presentation.

Thank you, Dave. Yesterday, as you're aware, ivonescimab data was featured in the presentation at ESMO 2025 as part of the Presidential Symposium. The presentation titled Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer, HARMONi-6 was given by Dr. Shun Lu, MD, PhD, Chief of Shanghai Lung Cancer Center at Shanghai Chest Hospital, Professor of Medicine at Shanghai Jiaotong University, and associate editor for the Journal of Thoracic Oncology. Revisiting the schema for the HARMONi-6 trial, this study evaluated ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, a PD-1 inhibitor in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous non-small cell lung cancer irrespective of PD-L1 expression. HARMONi-6 is a single region, multi-center Phase III study conducted in China sponsored by Akeso, with all relevant data exclusively generated, managed and analyzed by Akeso.

Key eligibility criteria are shown here. Patients were randomized 1:1 stratified by stage of cancer and PD-L1 tumor expression at baseline. Patients received either ivonescimab at 20 milligrams per kilogram plus carboplatin paclitaxel or tislelizumab-plus carboplatin paclitaxel for up to 4 cycles and then received either ivonescimab or tislelizumab as maintenance therapy for up to 24 months. Treatment was to be discontinued for intolerability, progressive disease or initiation of new antitumor therapy. The study's single primary endpoint was progression-free survival by independent Radiologic Review Committee. Secondary endpoints included response rate, duration of response, safety and overall survival.

The trial included a total of 532 patients. Baseline characteristics show that this was a predominantly male population nearly all with Stage IV disease, and it's important to underscore that these patients with advanced squamous non-small cell lung cancer, included those with characteristics that we have traditionally considered as potentially associated with bleeding on anti-angiogenic therapies. Specifically, approximately 2/3 had a central tumor, 17% had encasement of major blood vessels in the chest, 9% had tumor cavitation and nearly 1 in 3 had a history of some hemoptysis. The breakdown of PD-L1 expression showed approximately 40% had a PD-L1 negative cancer with the remaining 60% of PD-L1 positive cancers showing 40% in the low range of 1% to 49% and about 20% with high PD-L1 expression of 50% or greater.

The figure for progression-free survival by independent Radiologic Review Committee [indiscernible] analysis shows the trial was positive for the primary endpoint with the hazard ratio of 0.60 and a corresponding p value of less than 0.0001. Median progression-free survival was 11.14 months for the ivonescimab plus chemotherapy arm compared to 6.90 months for those patients receiving tislelizumab plus chemotherapy, a difference of 4.24 months favoring the ivonescimab plus chemotherapy arm. PFS by investigator assessment showed a consistent hazard ratio of 0.64. When we look at various subgroups, it's important to highlight that the size of the subgroups are smaller by definition and not designed to show statistically significant on their own, but they can be informative. The subgroup analysis for progression-free survival confirms benefit in all preplanned subgroups as indicated by point estimates for each subgroup landing on the left side of the dividing line favoring ivonescimab, overall showing that the study results were observed broad and not driven by a specific subset or subsets of patients.

These progression-free survival curves show the benefit in patients with negative, low and high PD-L1 expression, representing PD-L1 TPS scores less than 1%, 1% to 49% and 50% or more respectively at baseline. Patients with negative PD-L1 tumor expression had a hazard ratio of 0.55. Those with low tumor PD-L1 expression had a hazard ratio of 0.63 and those with high tumor PD-L1 expression had a hazard ratio of 0.71. In other words, ivonescimab demonstrated benefit relative to tislelizumab across the entire spectrum of tumor PD-L1 expression. Objective response rate irrespective of PD-L1 expression was improved for ivonescimab by an absolute difference of 9.4%. In patients with PD-L1 expression less than 1% and those with PD-L1 expression of 1% or greater, objective response rates were improved for ivonescimab by an absolute difference of 8.5% and 9.9%, respectively.

The median duration of response was also improved from 8.4 months for tislelizumab plus chemotherapy to 11.2 months for ivonescimab plus chemotherapy. Treatment-related adverse events showed only a small increase in the ivonescimab group. Any grade events were 99.2% versus 98.5% and serious treatment-related adverse events were 32.3% versus 30.2% in the ivonescimab and tislelizumab arms, respectively. Treatment-related adverse events leading to discontinuation of ivonescimab plus chemotherapy or tislelizumab plus chemotherapy occurred in 3.4% versus 4.2%, respectively. Based on the dual targeting of ivonescimab against PD-1 and VEGF, we analyzed adverse events that were thought to be immune related or possibly VEGF related.

For the ivonescimab plus chemotherapy arm, compared to the tislelizumab plus chemotherapy arm, Grade 3+ potentially immune-related events were 10.2% versus 9% and potentially VEGF-related events increased from 2.3% to 7.5%. These events will be characterized further in the next slide.

On the right, events are split out by the specific terms for adverse events. The most common events for ivonescimab treatment in combination with chemotherapy were common chemotherapy-related adverse events, including alopecia, anemia and various laboratory abnormalities, including neutrophil, white blood cell and platelet count decreases. As such, these rates were similar and manageable between the 2 arms.

Focusing further on immune and VEGF-related events, we see that most events were low grade with approximately 9% to 10% of immune-related adverse events reaching Grade 3 or higher in either arm. Of interest, Grade 3 or higher irAEs, serious irAEs and irAEs leading to discontinuation of ivonescimab or tislelizumab were all numerically lower in the ivonescimab. Among the possibly VEGF-related events, proteinuria was seen in 27.1%, hemorrhage in 21.4% and hypertension in 10.2% of patients. The vast majority being generally low grade with the rate of Grade 3 hemorrhage under 2%. Venous and arterial thrombotic events were 0 in the control arm compared to 1% for each in the ivonescimab.

I want to pause here for a moment and speak to the validating and convincing safety profile seen yet again with ivonescimab in the results of this study now in combination with myelosuppressive platinum doublet chemotherapy in a population of patients with advanced squamous non-small cell lung cancer that was a real-world experience that included patients with central, potentially cavitary tumors, encasing vessels in some cases and a history of hemoptysis in a significant fraction. This clearly differentiates ivonescimab from what is feasible with a combination of routinely used PD-1 or PD-L1 directed immune checkpoint inhibitor plus VEGF monoclonal antibody therapies administered together.

In summary, ivonescimab provided a significant and clinically meaningful progression-free survival benefit for advanced squamous non-small cell lung cancer as first-line treatment of patients in HARMONi-6 with a hazard ratio of 0.60 that was consistent across all key subgroups, including those with negative, low or high tumor PD-L1 expression, and those with liver or brain metastases. Hazard ratios in patients with negative low and high tumor PD-L1 expression were 0.55, 0.63 and 0.71, respectively. Ivonescimab's strong performance across all levels, tumor PD-L1 expression is important as ivonescimab appears to provide clinically meaningful improvements to patients regardless of the degree of PD-L1 expression.

Response rate and duration of response were also increased. Ivonescimab was well tolerated with less than 2% Grade 3 or higher bleeding events and low rates of adverse events leading to discontinuation or death, both comparable to the tislelizumab plus chemotherapy arm. The incidences of any grade treatment-related adverse events were similar between the 2 arms.

Prior to HARMONi-6, there were no known Phase III clinical trials in non-small cell lung cancer that have shown a statistically significant improvement compared to PD-1 or PDL1 inhibitor therapy in combination with chemotherapy in a head-to-head setting.

Following the success of Akeso's HARMONi-2 study in China, where the PFS benefit was observed in a monotherapy setting for patients who had squamous or non-squamous tumors that were positive for PD-L1 expression, this is now the second time in which we see ivonescimab-based regimens becoming the first known investigational therapy to demonstrate a statistically significant benefit compared to standard of care PD-1 or L1 inhibitor-based regimen. This underscores the specific value that ivonescimab and the HARMONi-6 regimen could bring to patients in this setting.

With the opportunity to include a differentiated mechanism of action for physicians and patients to choose, ivonescimab has the potential to become a new standard of care for advanced squamous non-small cell lung cancer. And we look forward to HARMONi-3, a global Phase III study reading out in the coming months and years.

Importantly, we want to thank the patients and their families, the clinical site personnel and the Akeso team for carrying out the HARMONi-6 trial. And now I'd like to turn it over to Maky.

Thanks, Jack. I would like to echo Jack's comments around our gratitude for the patients who enrolled on HARMONi-6 family members, trial site personnel, investigators and, of course, the Akeso team. We are slightly encouraged by the readout of this study to our other ongoing Phase III study in frontline non-small cell lung cancer, HARMONi-3, HARMONi-7, PD-1 therapy with or without chemotherapy depending on the PD-L1 status is the more overwhelming standard of care in frontline driver mutation negative lung cancer. Ivonescimab both as monotherapy and in combination with chemotherapy compares favorably to the result of the PD-1 monoclonal antibody previous studies.

While additional overall survival data will be important to see in the future, consistent, clinically meaningful, statistically significant resource in progression-free survival in HARMONi-6 and progression-free survival and interim overall survival data of HARMONi-2 announced previously are very encouraging when we look to global studies HARMONi-3, HARMONi-7 and beyond. Yesterday's HARMONi-6 results presented at ESMO and subsequently published in the Lancet are highly encouraging in showing the consistent performance of ivonescimab and its ability to break into a setting where existing anti-VEGF therapy is not an option due to historically observed tolerability concerns from early phase clinical trials. HARMONi-6 continues to validate the opportunity presented by ivonescimab to make a significant difference across a vast number of patients facing solid tumor diagnosis. I would also like to highlight several important updates to our Phase III clinical development program that we have announced over the past few days.

As we announced Friday, our clinical development plan has expanded beyond lung with the addition of our global Phase III HARMONi-GI3 trial, a brand new study evaluating ivonescimab as first line therapy in first-line unresectable colorectal cancer, including studies sponsored by our partner, Akeso. This brings a number of planned or ongoing Phase III clinical trials to 14 in total, evaluating ivonescimab in multiple solid tumors, including lung, colorectal, breast, head and neck, biliary tract and pancreatic cancer. This is the fourth global Phase III study and the first global Phase III study to be conducted with ivonescimab beyond lung cancer. I will review the HARMONi-GI3 study design and what drove our conviction to initiate this study shortly, but I wanted to take a moment to remind everyone of the impressive development efforts behind the growing collective pipeline of ivonescimab.

Turning to our ongoing Phase III trials. I will provide a regulatory update on HARMONi and as well as updates relating to a HARMONi-3 protocol amendment, including expectations for data readouts. I would like to take a moment to express our gratitude in working thus far with the FDA regarding our clinical development of ivonescimab. With 4 Phase III clinical studies, we have had a number of interactions with the agency and their feedback and advice are invaluable.

When we plan to move forward with the HARMONi study upon signing the collaboration agreement to acquire the rights to ivonescimab, we have multiple interactions with the agency regarding how to proceed. The collaboration demonstrated our ability to move forward with a clinical study based on early phase clinical trial data that had been generated in China prior to our acquisition of all rights given the strong potential of ivonescimab and opportunity to make a meaningful difference to patients in a setting that has very limited therapy options in something that really reflects the agency's commitment to patients facing difficult diagnosis with limited options.

We are incredibly proud to work with the agency and appreciate the endless hours that members of the agency spent with the best interest of patients always in mind. Based on the result of the HARMONi study, today we announced that we will submit a biologics license application, or BLA, with the FDA in order to seek approval for ivonescimab plus chemotherapy for this proposed indication in the United States. We intend to submit the BLA during the fourth quarter of 2025.

As previously disclosed, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. After a careful consideration of the safety and efficacy profile of the current FDA-approved options to patients in this setting, the positive regional consistent results of this Phase III multi-regional study as well as discussions with key opinion leaders and physicians, who have administered ivonescimab to patients, we believe that the safety and efficacy data generated in the HARMONi study demonstrate that patients suffering for EGFR-mutant non-small cell lung cancer in this setting can benefit from the ivonescimab regimen. This is a monumental moment in the development of ivonescimab, and we are excited for the opportunity to work with the U.S. FDA in order to discuss our application.

Yesterday, we also announced updates to our global Phase III HARMONi-3 study, which is intended to evaluate ivonescimab combined with chemotherapy compared to Pembro and anti-PD-1 antibody combined with chemotherapy in patients with first-line metastatic squamous and non-squamous non-small cell lung cancer.

This study is currently enrolling patients globally and is conducted with registrational intent for the United States and other regions within Summit licensed territories. The primary endpoints for this study are progression-free survival and overall survival. Summit has amended the protocol for the HARMONi-3 study in order to separate the statistical analysis of data of the primary endpoint by histology. Therefore, there will be separate analysis conducted to evaluate ivonescimab plus chemotherapy compared to Pembro plus chemo in patients with squamous non-small cell lung cancer and in patients with non-squamous non-small cell lung cancer. As a result of having 2 separate intention to treat analysis within the HARMONi-3 study, the analysis for squamous tumors and non-squamous tumors may be conducted at separate time as each analysis will be conducted upon reaching pre-specified numbers of events in each cohort. Ultimately, it will allow us to read out data earlier for squamous non-small cell lung cancer and ultimately potentially move forward more quickly in frontline lung cancer for patients seeking improved options over the existing standards of care.

Currently, we expect to complete enrollment in the squamous cohort of HARMONi-3 in the first half of 2026 and expect to reach the prespecified number of events for the progression-free survival dual primary endpoint analysis for the squamous cohort in the second half of 2026. An interim analysis for overall survival may be conducted at a similar time.

Turning to non-squamous. At present time, Summit expects to complete enrollment in the non-squamous cohort of HARMONi-3 in the second half of 2026 and expect to reach the prespecified number of events for the progression-free survival endpoint analysis for this non-squamous cohort in the first half of 2027. An interim analysis for overall survival is planned to be conducted based upon reaching a prespecified number of events.

In order to sufficiently power each of the dual primary endpoints in both cohorts of the study, Summit plans to enroll approximately 600 patients with squamous non-small cell lung cancer and approximately 1,000 patients with non-squamous non-small cell lung cancer for a total of approximately 1,600 patients enrolled in HARMONi-3, which is reflected in this updated HARMONi-3 study design slide. While we are increasing the sample size, we are over 80% enrolled in the squamous cohort. And as I mentioned, we believe we will complete enrollment in the first half of next year, and the non-squamous cohort is enrolling fast and with complete enrollment short time thereafter, currently projected to be the second half of next year. This ultimately will allow us to have this analysis fully powered by cohort in order to allow for us to have a clear regulatory path forward for frontline lung cancer around the world.

As mentioned earlier, our Phase III clinical development program has expanded beyond the lung with the intention of HARMONi-GI3, a global Phase III trial evaluating ivonescimab plus chemo compared to beva plus chemo as first-line therapy in patients with unresectable metastatic colorectal cancer. Here, we see the study for HARMONi-GI3, which has a primary endpoint of progression-free survival. Clinical trial sites in the United States are planned to begin activating by the end of this year, and we currently expect to enroll a total of 600 patients in HARMONi-GI3.

Each year, 48,000 patients are estimated to be diagnosed with or have recurrent metastatic microsatellite stable metastatic colorectal cancer, also known as mismatch repair proficient colorectal cancer or pMMR CRC. There have been limited options approved in the United States in the last 20 years for those first-line patients whose tumors are not positive for certain biomarkers or other activating mutations. Microsatellite stable metastatic colorectal cancer is a setting where monocolonal PD-1 inhibitors, such as pembro and nivo have failed to show a clinically meaningful benefit. Anti-VEGF therapy like bevacizumab plus chemotherapy is the standard of care for many patients with first-line metastatic microsatellite stable metastatic colorectal cancer.

Based on extensive feedback with KOLs and treating physicians in this space, we have opted to evaluate ivonescimab with FOLFOX in this study. I will take a moment to walk through the data we have previously shared in first-line CRC as a brief reminder as to the potential of ivonescimab in this setting. While the data is with FOLFOXIRI, a more intense chemotherapy regimen, we also noted in our release that we enrolled patients in both the U.S. and China with FOLFOX as well to test ivonescimab with multiple chemotherapy options. FOLFOX in combination with a monoclonal antibody such as beva represents a preferred treatment regimen for physicians treating MSS CRC patients in the United States and other Western territories.

Last year, at the 2024 Annual Congress of the European Society of Medical Oncology or ESMO 2024, Akeso presented encouraging AK112-206 Phase II data of ivonescimab in combination with FOLFOXIRI chemotherapy in patients with microsatellite stable metastatic colorectal cancer. Here, we see the figure for Akeso AK112-206 study. In this Phase II study, ivonescimab, in combination with chemotherapy demonstrated an overall response rate of 81.8% and a DCR of 100% in 22 patients. This cohort of AK112-206 was conducted in China sponsored by Akeso with all relevant data exclusively generated, managed and analyzed by Akeso.

In the ivonescimab-plus FOLFOXIRI chemotherapy arm, there were no treatment-emergent adverse events that led to permanent discontinuation of ivonescimab as of the data cut off from the ESMO 2024 presentation. Subsequently, as I said, this Phase II study was expanded to include additional patients from the U.S. and China to study ivonescimab in combination with FOLFOX chemotherapy.

The data from the initial patient cohort presented at ESMO 2024 have continue to mature in addition to the global Phase II data generated in combination with FOLFOX in the United States and China, which supports the design of Summit Phase III HARMONi-GI3 study. In addition to the announcement of HARMONi-GI3, a new global Phase III study in first-line unresectable metastatic colorectal cancer, Summit today announces its intention to expand its ivonescimab clinical development program with an additional set of Phase III clinical studies. We intend to provide additional color with respect to these Phase III studies in the first quarter of 2026.

With that, I will now turn the call over to Manmeet to provide an operational and financial update for the quarter. Manmeet?

Thank you, Maky, and good morning, everyone. Today, in addition to providing with you an update on our cash position and operating expenses, I will also provide color on our clinical operations. Let me start with an update on the clinical operations product. The HARMONi-3 study is enrolling ahead of our goals. And as Maky mentioned, we have enrolled over 80% of the newly planned 600 squamous patients cohort, and now expect to complete enrollment for the squamous cohort of HARMONi-3 during the first quarter of 2026. To remind you, the non-squamous cohort in HARMONi-3 was initiated during first quarter of 2025, and that too is enrolling ahead of the plan. And now we expect to complete enrollment for 1,000 patients during the second half of 2026.

Our HARMONi-7 study was initiated during the first quarter of 2025 and we have activated over 50% of the selected sites globally. And for our newly announced Phase III, the HARMONi-GI3 study, we have already started planning and sites are planned to begin activating in the United States prior to the end of the year 2025.

On the financial front, let me start with our cash position. We ended the third quarter of 2025 with a cash position of approximately $238.6 million. Turning to operating expenses. I'll provide details on both GAAP and non-GAAP numbers. You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures. As a reminder, our non-GAAP expenses exclude stock-based compensation expenses.

Our total GAAP operating expenses for the third quarter of 2025 was $234.2 million, compared to $568.4 million for the second quarter of 2025. The decrease in GAAP operating expenses was primarily due to the higher stock-based compensation expense of approximately $348.2 million as a result of the modification of unvested stock options recorded during the previous quarter.

Overall, our non-GAAP operating expenses during the third quarter of 2025 were $103.4 million, compared to $89.6 million for the previous quarter. The increase in non-GAAP operating expenses was primarily related to an increase in R&D expenses related to HARMONi-3 and HARMONi-7 trials. And with that, I will hand it back over to Dave. Dave?

Thank you, team. We'll now see if there are any questions that our team can help answer. Kate, if you could please open the line for questions.

[Operator Instructions] Your first question comes from the line of Yigal Nochomovitz with Citi.

So the first one I had is, when could we expect to see the first OS cut from HARMONi-6? Would it be before the second half 2026 PFS readout for HARMONi-3 and squamous? And then the other question is given HARMONi-6 was powered 86.3% for a hazard ratio of 0.7 but you hit on a lower hazard ratio of 0.6. I'm curious what that may imply about OS powering for the study given that was powered at 80% for a hazard ratio of 0.73, the implication potentially that you may have more OS power than originally designed?

Very good question. Dave?

Thanks, Yigal. This is Dave. So one thing that I want to make sure is clear, as we mentioned, this is a study that was designed and conducted by our partner, Akeso. And so one thing that we don't do is get in front of Akeso with respect to disclosing additional details beyond what they have currently disclosed. And so I think if we look overall, obviously, the protocol is included within publication. And I want to congratulate again our partner, Akeso, for both the presentation and the Lancet publication that became available yesterday.

But in terms of differentiating details between the planned and adjusted power and whatnot, I leave that to our partners at Akeso. But I think one thing that you can see from, in general, the plan for testing is that there's likely something that can be reviewed in 2026. But it's important to remember that from a time to event perspective and a prespecified number of events in an analysis, we hope patients do well, and we hope patients continue to exceed expectations into knowing exactly the order of events becomes a little bit difficult. But this is events driven. So at some point next year is probably a fair estimate, but more specific to that is a little bit beyond where we would like to disclose at this point and defer to our partners there.

And then just the other follow-up. Obviously, Maky, you talked a lot about new studies, CRC, and then you mentioned additional set of Phase IIIs where you might get more details in 1Q '26. So all of that points to questions around funding. I'm just curious if you could speak at least to some extent as to what options are being evaluated to extend the runway, what the priorities are in terms of how you may raise additional capital?

Maky prefers that I answer the questions.

[indiscernible].

She doesn't have [indiscernible]. Yes, we have an ATM out there with give or take $350 million. I have already had some inbound interest in additional capital. I'm interested. I've invested a few weeks ago additional capital. So yes, we'll move straightforward on that. And I'm happy to have the opportunity and I think others are too. So you'll see that as it plays out. I won't predict the amount right yet, but I'm aware of all the numbers and aware of the plans going forward. We have empirical evidence that this is a product that is crying out for significant investment. It is to demonstrate its capacity to enter into a business that the leading player is generating roughly $34 million in revenue over the next 3 years, $17 million, $18 million, [ $3 billion ] in free cash flow. So this is a significant opportunity, and we do not want to miss it. We have -- we also feel that the key to making that happen is for this team to have control to be able to start, stop and change a number of variables leading to our ultimate success, and we're happy with the position that we have. So I hope that gives you some addressment to the issues of finance.

And as soon as we have more information regarding other clinical trials, for sure, we are going to communicate as time allows.

Your next question comes from the line of Tyler Van Buren with TD Cowen.

Congratulations on the unprecedented HARMONi-6 results. I guess I want to ask about the BLA submission. Given the confirmation of the ivonescimab BLA by year-end based upon the HARMONi data, can you provide any color as to how your interactions with the FDA have gone? And how the present approvals with amivantamab or Dato might support approval of ivonescimab?

Thanks for the question. So yes, we announced today [indiscernible] that we are planning to file in the fourth quarter of this year. We are actively finalizing and putting the match together. We have continued interaction with the FDA. And obviously, after we have made the submission, we are looking forward to getting specific feedback and giving some color earlier next year after the submission. We have indeed reviewed the most recent doctor's approval backwards, as you mentioned, [indiscernible], the approval of [indiscernible] previously treated EGFR patients that [indiscernible] actual approval in also previously EGFR patients. And as you are aware, and obviously we are fully aware that neither of those other people included a significant OS benefit. We have also disclosed previously, but I'm just repeating that FDA has told us that they are looking to inspecting OS in our setting.

But we do think that the totality of our data from a combination of efficacy and safety is a strong package and should be moved forward to becoming available for these patients. So therefore, we are moving forward with the submission as we have announced.

That's great. And just as a quick follow-up, did you discuss the latest overall survival data that surpassed the statistical threshold at World Lung with the FDA?

Yes, we are not going to go into the details of exact discussions with the FDA, but I can confirm that we are in close contact with them and will be sharing information whenever appropriate with them.

Your next question comes from the line of Brad Canino with Guggenheim Securities.

Great to see the data at ESMO and a large crowd yesterday. Maybe another follow-up on the BLA. I understand the logic of trying to get this drug to patients as quick as possible, given the data that you have, but from a business perspective, can you help me understand the strategic thinking of now wanting to submit the HARMONi study and undertaking that review issue of how to deal with the OS as the first time the FDA will review a BLA package for ivonescimab especially when you have HARMONi-3 potentially coming as soon as second half '26 for PFS and OS. I guess my thinking was that might be a better package to submit first and then have HARMONi come as a supplement or something like that. So just how you're thinking about that would be helpful to hear.

Sure. So we have had certainly many discussions just to confirm internally and there are many open scenario. But in principle, our thinking is that each indication will have its own submission. This particular package is ready now. We have mature data. We have shown consistency in the data with our long-term follow-up between the rest of patients and the Asian patients. And we think this is the right opportunity, and we are going forward. That doesn't mean in the future we will continue going to look at this as we might do other packages in the future. And depending on exactly what comment or feedback we ultimately also get from FDA, we will make those adjustments to support it in the future.

And then separately, just quickly on the colorectal Phase III. You mentioned there's some undisclosed in-house data. Can you talk qualitatively about what that is, the extent of it and what thesis were explored? And then when we expect to see those data presented to further support the Phase III?

Sure, Brad. This is Dave. And so I think one of the things that Maky spoke about was we had previously presented data with our partners at Akeso in 2024 at ESMO. And that was validating with respect to not just colorectal, but head and neck as well as triple negative breast cancer. What then has since happened, both Akeso as well as an expansion of that Phase II to include patients in the U.S. was conducted. And so with that, we've had multiple backbones of chemotherapy, which have been reviewed with ivonescimab as well as a novel-novel combination with ivonescimab in this setting. And so what that's done is it's given a bit of exposure to the drug as well as the ability to compare historical results with different chemo backbones in order to kind of validate what we're seeing and the consistency of that data. And so we ultimately chose based on the standard of care that exists in the strong preference for both patients and physicians to move forward with the FOLFOX regimen.

But there's quite a bit of data that's been generated across a number of different backbones, which gives us quite a bit of confidence. And it is -- I'm sure you're aware but also to note our partners, Akeso, are running a Phase III study in this setting as well. And so it's another -- just another data point with respect to confidence that we have in terms of ivonescimab's opportunity in this setting.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

With regard to HARMONi-6, the PD-LI by status was interesting, and we see -- PD-L1, sorry, negative outperformed PD-L1 positive. Could you just help us maybe understand what's playing out there and then the translational work that you're going to be doing to kind of help the oncologists with determining how to best position here?

In terms of HARMONi-6 and the PD-L1 expression, I would say that it's not -- I don't see it as necessarily that the negatives are outperforming the others, but rather that the differential effect is a little greater in the PD-L1 negative patients. To me, that's not that surprising. I would say that as a clinician talking with all of my other clinician colleagues, we've long recognized that although other regimens that are FDA approved here have some incremental benefit from the addition of the checkpoint inhibitor that benefit is tepid. It's rather minimal, and these are patients -- this whole group is one that has disappointing outcomes even with our current standard of care. And so there's really a lot of room to do better.

In this case, I would say that it may be suggested that this is a setting where there are -- I'm sorry, this may be a setting where VEGF components may be especially relevant. And I will say that it's important to also recognize that these are subsets. We're going to have additional information to look at these, whether it's consistent trends between HARMONi-6 and HARMONi-3, but that it's important to note that in the patients, particularly with the high PD-L1, that group had a smaller -- that was about half of the size of the other groups. And so I wouldn't want to put too fine a point on any of these subset analyses. They're just suggested and all of them showed the same trend or the same overall conclusion of being superior with [indiscernible] just to varying degrees.

Brad, if I may just touch back on your question on EGFR. We were really pleased that the FDA approved or taking that trial on. There were a number of major issues to hand on that trial. One of them was China versus U.S.A. data translatability. That was -- we put a real feather in the cap that there is some significant translatability. That's obviously a very dynamic issue. There was also the issue of bleeders in EGFR and we certainly put that one to rest. There was also the issue of brain mets, something very serious, that's members of my own family. We put that issue to rest. Then there was the bispecific, very novel, and we put that issue to rest. So that would not have happened had the FDA not allowed us to move forward. Now in a continuation, our trials will always have China patients. It won't be 2/3 to 1/3, it will be more like to 1/3 to 2/3, and we're very pleased about that. But on the record ivonescimab performed incredibly well. We had a progression-free survival hazard ratio of 0.52. We did better than any other drug in that marketplace. On the p value. We had [ 0.57 ]. [indiscernible] It's important to note that when you receive feedback from the FDA, it's a game you got to play and we played it. We needed 150 at least patients from outside of China, and we were able to get to 175. What really wasn't told was we underestimated the degree of difficulty to get the to doctor to take this trial on. There was an inertia there. And that inertia caused us to get off to a very slow start. So we think as all that becomes incredibly available to others, they will look at it as a very successful human patient trial and we certainly appreciate the fact that the FDA allowed us to move forward on that. So that gives you a little background on why we'll submit.

We feel -- we are a patient-based company, and we feel patients can benefit and did benefit, and we would like to see more of that, and the FDA will make the final decision. There probably isn't a U.S.A. agency today that has more respect around the world than the FDA, and we totally support that. So I hope that gives you a little bit of color as to we've made the investment, and we'll make a further investment. And if it goes well and we get into patients' hands, everybody will have a win on it. If it doesn't, we certainly will try to make [indiscernible].

Your next question comes from the line of Cory Kasimov with Evercore.

Curious, was there something in the HARMONi-6 data that prompted the protocol amendments to HARMONi-3 beyond this kind of the staggered enrollment run rate? And what impact will these changes have on the powering of the HARMONi-3 subset?

Cory, this is Dave. So thanks for your question. So I mean, I think there are multiple reasons in terms of updating the design of HARMONi-3. So one, it accelerates our frontline lung cancer opportunity as a whole. Since we began enrolling the squamous cohort first, we believe that we'll be able to complete enrollment in the first half of next year, and this will allow for a data readout in the second half. And because we're rapidly enrolling the squamous cohort as well, we can complete that enrollment in the second half of next year. But two, it reduces regulatory risks by separating the 2 histologies to individual ITT analyses, we do not risk the overall population being statistically significant, but one subgroup looking a little better than the other mainly through sample variability, and this could lead to risks regarding approval for one histology and the other. And so -- and additionally, we've seen advisory committees from the FDA earlier this year that there's an increased importance on the results of U.S. patients, which becomes a subset of the 2 histologies.

So without the change, U.S. patients are effectively a subset of a subset at that point. And now we have individually powered squamous and separately powered non-squamous histologies for both primary endpoints of PFS and OS. And so they're individually powered at the histology level now, and so 2 ITTs. So separately powering the individual histologies is effectively a cleaner assessment of the data.

And three, it allows us to keep pace in non-squamous as well because given the PD-1 plus chemo therapy performs a little bit more favorably in non-squamous patients, i.e., typically, it has a longer overall survival than squamous patients. The progress in additional targeted therapies that we see in non-squamous mutation, variability, some historical results in non-squamous trials. We really want to ensure that there's a little statistical variability like an overperforming control arm or something like that, that can raise issues. So we -- again, we increased the sample size. But because we're rapidly enrolling the cohort, the analysis is driven by a readout of events, it's an event-driven analysis. Increasing the sample size for non-squamous really had very little impact on the timing of the readout there. So we don't see a change in probability of success in either of the opportunities. We view them both as being cleaner.

However, really specifically to your question, Cory, with respect to what we saw with HARMONi-6 yesterday, what that does is allows for a direct read-through now to an ITT population in the HARMONi-3 study. So it's effectively the same comparison now, ivo plus chemo versus PD-1 plus chemo in the squamous population. It's now just in a global setting instead of a single region in China. So there's a direct read-through here. We've seen historical comparability in terms of the data generated in Asia versus rest of world. And so we're very excited with the ability to have that direct read-through in accelerating that squamous opportunity by breaking out into 2 separate ITTs.

Your next question comes from the line of Mohit Bansal with Wells Fargo.

Congrats on all the progress. One repeated question we get from experts is that when you compare a VEGF PD-1 to PD-1, or previous PD-1 VEGF combo, it is very clear that the VEGF component is better than the VEGF component that was tested before, but it's not clear that if PD-1 component is better. Now where do you stand on that? And if that is the case, isn't that an issue for OS benefit here because it does seem like PD-1s are the ones which are causing the -- using the long tail in those trials. So I think that's the biggest issue right now. If you could help us understand the confidence around OS here.

Yes. This is Jack West. I think it's difficult to impute too much into the value of one side of a molecule or another. We don't -- we haven't historically done that with other molecules that target met and EGFR and say, well, that -- you don't dismiss or minimize that because, oh, this is just working on the met side. I would say that the most important thing is, we should see what the data show at the subsequent final ongoing reading. So if the efficacy is there, and the tolerability is favorable, you look at the totality of the data, and you decide whether that is enough to change from whatever you're competing current standards. And I don't think that we have or should have a separate set of criteria for a presumption that this is working through a VEGF action or immunotherapy action.

I think we just make inferences. And I think different clinicians or others make inferences based on their own suppositions or biases. So I would say that -- yes, I'm not sure it really matters. I think that the reality is you look at the efficacy, you look at the tolerability and you weigh all of that against what the current prevailing options and standards are. And if it bubbles up is better, we have lots and lots of therapies that have a benefit that is not sustained over many, many, many years, and that's still valuable. So there are many different kinds of efficacy benefits that have varying degrees of appreciated utility to clinicians and patients. So I think I would focus more on what the actual clinical outcomes are than a supposition of which side of a molecule is more important in one setting or another.

Yes. William, I'll add. This is Allen Yang. I'll add that we've always been under the hypothesis, and I think the data are showing that the 2 put together are cooperating and better than the sum of the parts. Akeso smartly designed this molecule such that the PD-1 and VEGF work together. So the HARMONi-6 data reading out positive doesn't indicate that it's just the VEGF. And it's not just an indication. But again, I think VEGF is important in a lot of different diseases, and this puts them together a smart way. If you look back to the HARMONi-2 data, remember, there was an improvement, not only in the low PD-L1 expressing, that was probably indicative of the VEGF, but also the high PD-L1 expression. This is the sweet spot for PD-1. So the VEGF clearly makes it better.

I think [ John Heymach ] also alluded to in the discussion of that, that not only were they cooperating, that the VEGF may play a role in immunotherapy as well, and there's growing data to support that as well. So the answer to your question is, we think, again, both sides are important and how they're engineered and put together indicates that the MOA is important. I also want to add that the safety that we've seen across 4 randomized double-blind placebo sites suggest that this is not [ VEGF ].

Your next question comes from the line of Clara Dong with Jefferies.

Congrats on the impressive HARMONi-6 data. So I think there's a lot of great questions on HARMONi-6 already. So I want to actually talk about your plan for colorectal cancer. So for the Phase III study, are there any plans to stratify or analyze outcomes based on the presence of liver versus non-liver mets given some prevalent evidence of their impact on treatment responses in MSS CRC? And then you mentioned the global components of the Phase II FOLFOX combination study. So what's the expected time line for the next update on whether we should expect some U.S. data from this trial in the next update as well?

Thanks, Clara. I think all good questions. And I think we do -- we certainly do have stratification factors within our current trial. I don't think at this point quite this early we're looking to make public all of those individual factors just yet. Your points are well taken in terms of the specific patient characteristics that you mentioned. And I would say with respect to the publishing of additional data, including those data that were based on U.S. patients, we're determining the appropriate time if and when that -- if and when we do that. And part of that is we continue to have Phase III readouts that becomes important to prioritize that.

Publishing data across multiple different chemotherapy lines for us or chemotherapy options important for us to make decisions. It is not necessarily something that we need to individually go through. And so I think there's a piece where the Phase III will become very important to publish. And obviously, our partners at Akeso are running a Phase III as well, which will provide significant additional context when that study concludes.

Your next question comes from the line of Asthika Goonewardene with Truist Securities.

Also my congrats on all the progress and the great data presented yesterday. To start off on HARMONi, the takeaway from World Lung was that your OS benefit would become more pronounced with the appropriate level of follow-up. So the HARMONi filing with the FDA, do you need to take a new data cut or are you filing what you have right now? And then I have a follow-up.

Yes. Thanks for the question, Asthika and appreciate the words at the beginning. I think we haven't publicly spoken to the specific details with respect to how we'll work with the agency. As Urte mentioned earlier, we maintain communication with the agency. It's important to work through the submission process. And so as she mentioned, currently working on the application at this point. So I think that is clearly just given where we are today, only 1.5 months later from the data cut based on what we saw at World Lung. And I think in terms of next steps with that, I think part of that will involve discussions with the agency.

Got it. And then just on the amendments to the HARMONi-3 study. So the original HARMONi-3 study, which was in -- originally was restricted to just squamous patients, that had about a trial recruitment of about 400 or 450 patients or so. The HARMONi-6 data came out showing a really great benefit in similar kind of patient population. But now you're expanding the recruitment for the HARMONi-3 squamous cohort to 600 patients. I know that's also in line with what KEYNOTE-407 recruited. But I just want to get your guys' thoughts on the rationale for increasing the target size?

This is Urte. [indiscernible] We are basically splitting the cohorts into 2 parts. There will be separate analysis and it's very important that we are powering for both endpoints for PFS and OS. And this is a very good sample size. We have obviously high confidence in the readout of the squamous cohort, but this is appropriate to cover those endpoints.

Your next question comes from the line of David Dai. with UBS.

I also want to add my congrats on the great data here. So a couple of questions. One, just a clarifying question on HARMONi-3 Phase III trial update. So Dave, you mentioned that the trial update derisk regulatory aspects. I just want to clarify that, does that mean that you're able to file each histology separately? I'd say if one histology failed while the other succeeds, then you can file for the successful one irrespective of the failed histology?

In short, yes, they're independent ITTs. So they're independent analysis.

Got it. [indiscernible].

It's just the nature of what has happened. So they will not need on executives [indiscernible].

Got it. Okay. Great. And then secondly, just on the combo strategies for non-small cell. I know a lot of other companies are thinking about doing ADCs and chemo combos. What are your thoughts around like combination strategies with ivonescimab in different solid tumors?

Yes. And David, I think you talked about novel-novel combinations, if I understood that right. And so yes, I think we've talked about this a little bit in the past, but we're very excited in terms of our clinical trial collaboration with [ RevMed ] in terms of evaluating multiple RAS inhibitors in combination with ivonescimab. And so I think we'll be able to, in collaboration with [ RevMed ] dosing patients earlier, early in 2026. But in addition, there too, I think we're planning on multiple additional combinations, and those would likely be with ADCs to where I think you were heading with that, David. And so part of what we believe is a strategic advantage for Summit as a whole, ivonescimab, in the global development of ivonescimab is because we don't have specific ADCs that are part of our portfolio as well. It allows us to follow the data. And so we're working with multiple other companies in terms of collaborating in order to test ivonescimab in combination with multiple ADCs that are multiple targets with multiple different payloads, different structures. And that will allow us ultimately to follow the data.

I think you've heard us speak to in the past in reality. What we don't believe -- and similar to -- if you look at solid tumor therapy today, there is not a single chemotherapy or chemotherapy regimen that is applicable across solid tumors, right? There are different regimens that are applicable even in non-small cell lung cancer. Pemetrexed is used very frequently in non-squamous tumors and it is not used in squamous tumors and paclitaxel as the backbone. And so as we think about -- just within non-small cell lung cancer, key difference is in terms of the chemo regimens.

That implies, as you keep going beyond into additional histologies and additional solid tumor settings, but certainly different payloads will be very important in terms of being most effective for the tumors in those settings. And so the MOA will be very important. The safety will be very important. There are different tolerability thresholds within different tumors in different settings. And so what we want to do is follow the data. So what we won't be is encumbered by maximizing our own internal pipeline, if you will. And we think there have been mistakes made in the past on that. And we think we have the opportunity to follow the best data, follow the right combination with ivonescimab and ultimately maximize the potential for patients in terms of what can be done to take the power of ivonescimab with some of the novel components that are in development that are exciting right now, whether it be a RAS inhibitor like [ RevMed ] has, multiple RAS inhibitors or different ADCs with [ many structures ].

And obviously, Akeso has multiple ADCs in their pipeline as well that they're going to be taking a look at, in particular, in their own trials to start. And so that will also inform us going forward as well.

Your next question comes from the line of Ren Benjamin with Citizens.

Congratulations on the very impressive data yesterday. I guess the first question is the HARMONi-6 safety profile, I mean, really reaffirms to us like ivonescimab's tolerability especially given it's largely comparable control arm. Were there any specific like -- squamous specific related events that's different from the non-squamous cohort in HARMONi? And related to that, I think there's just an apparent kind of underdepreciation for the safety profile, specifically bleeding. I think discussion brought that up. I'm kind of curious as to how you guys are addressing that especially with KOLs?

This is Jack West. I would say there's differences between the squamous and the non-squamous largely based on the characteristics. Squamous tumors tend to be larger and more central than non-squamous tumors and then the fraction of proportion of brain metastases is present. There are some in HARMONi-6 and in other squamous cohorts. But it's far less common in patients with squamous than with adenocarcinoma and especially patients with EGFR mutation positive non-small cell where brain metastases are leading concern. But I would say, as I had alluded and the presentation yesterday as well, this is not just allowing patients with advanced squamous lung cancer, but this was bold and courageous in enrolling patients with several features that have historically been challenging, if not prohibitive with bevacizumab.

And frankly, in China, they have years of experience, many of these investigators and growing comfort with that, that I would say that clinical oncologists outside of China or anywhere where they have less experience will need to not only look at these data, it's definitely going to be a point of education that we cannot be limited by and should not be limited by the historical precedence of a different drug with a very different safety profile. These are new times as the eligibility should be very different and liberalized. And yes, I think it will take both a combination of education and gradual experience for oncologists to get it, treat patients and reassure -- be reassured by their own favorable experiences with it over time.

Got it. And then just as a follow-up, do you think that the filing, has the FDA kind of indicated that this goes to ODAC. Will you be applying for accelerated or full approval? And your thoughts on European filings?

Yes. We think this is a good [ small ] package. We have statistically significant PFS. We have supportive OS data, which we think is very meaningful and will be evaluated in context. We have supportive efficacy data from OR and duration of response. So all seems to be a good [indiscernible] package for full approval.

We cannot foresee what exactly the comments and the opinions of the FDA are. And as we said, as we're going through the review process and very specific information we get, then we will provide color on that.

Other policy issues, I cannot comment on. We look all forward to FDA end up sharing with us what their plans are in terms of external feedback and those kind of things. So we will be watching that along with you.

Your next question comes from the line of Mitchell Kapoor with H.C. Wainwright.

Congrats on the data. Can you point to relevant regulatory precedents where a strong PFS benefit without a statistically significant OS benefit at the time of filing was still sufficient for FDA approval? And how do you think that -- can you just remind us how these situations were handled by the FDA? And then separately, can you just comment on the business development front on the change in the volume and the types of BD discussions you've been having lately?

I will take the first part. So in this exact setting in EGFR-positive previously treated patients, there were 2 relevant approvals, both of them occurred last year. The first one is for the [ Amuvatinib molecule ] based on the [indiscernible] study, which was approved on statistically significant [indiscernible], and was accompanied by a positive trend [indiscernible] OS. The other approval that happened as the accelerated approval is [indiscernible] molecule. Wording is slightly different, but it's previously treated patients with both chemo as well as [indiscernible] therapy, and that accelerated approval was based on ORR with the duration of response. And I can also note that the confirmatory study for that module in EGFR-positive in the frontline selling. So there isn't going to be any additional generation of statistically significant PFS, OS [indiscernible] was coming.

Business development question?

Bob do you want to conclude with the business development.

This is Bob Duggan. We want to thank you for your attendance today. I only wish you could be at ESMO. There's at least 25,000 people here. We were really honored and Akeso was honored to be the first presenter at the presidential presentation with 9,000 people packed into a very large hub program. They gave resounding applause as they heard the data. This is a breakthrough. It's a break of magnitude. Undeniably, we have an excellent product. Lung cancer is the #1 killer. It's not going to be that way for long. We really are in the mitigation and hopefully, in some areas, we would move this forward even into [indiscernible].

Our team is very excited. We're very excited to have the product in our hands. The doctors, physicians those that support them are really excited. We've seen them in the hallways and in other meetings. We've been just packed with attendance and appreciation. You have to kind of be here to see. It's my first trip to Berlin, I must say it's a beautiful city, even for someone who lives in Miami. So yes, we're going straight ahead here, and we're enjoying ourselves.

The future looks incredibly bright. Opportunities like this I haven't seen in my brief investment lifetime. I'm just really excited about helping patients here and making a significant difference [indiscernible]. I will say you see people from all cultures, all walks of life here. This health care business is one that brings the world together, not separates it. And we're just really happy to play a significant role, and we're thankful to our Akeso partners from China and to the FDA for giving us the platform which to really move forward. So thank you for being on the call. We look forward to talking to you soon. Have a great day.

Ladies and gentlemen, that concludes today's call. You can disconnect. Thank you, and have a great day.

Thank you for standing by. My name is Tina, and I will be your conference operator today. At this time, I would like to welcome everyone to the Summit Therapeutics Update Call. [Operator Instructions]

It is now my pleasure to turn today's call over to Dave Gancarz, Chief Business and Strategy Officer. Dave, please go ahead.

Good morning and thank you for joining us. We issued a press release yesterday morning relating to the Phase III HARMONi data featuring ivonescimab presented as a part of the Presidential Symposium at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, otherwise known as World Lung or WCLC 2025. The press release is available on our website, www.smmttx.com. Our 8-K was filed today and is available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will also be made available later today on our website.

Joining me on the call today is Bob Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Mahkam Zanganeh, our Co-Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; Dr. Urte Gayko, our Chief Regulatory Quality and Safety Officer; Dr. Allen Yang; and Dr. Jack West, our VP of Clinical Development.

Before we get started with the rest of the call, I would like to note that some statements made by our management team and some responses to questions that we make today may be considered forward-looking statements based on our current expectations. Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements, except as required by law.

One item of note, this presentation is being webcast with slides, we'll be referring to the slides being displayed in the webcast link. I'd encourage you to use the website link to see the slides being presented this morning or otherwise to take a look at the slides that are on our website. Following comments from our team, we will take questions.

Before I hand it over to Jack to walk through the details of the presentation, I'd like to give a little bit of an overview based on presentation yesterday and the details in our press release.

HARMONi is a multiregional study, evaluating ivonescimab plus chemotherapy against standard of care chemotherapy alone. This study represented a continuation into a multiregional study -- into a multiregional setting of the original single-region HARMONi 8 study that was performed by our partners at Akeso in China.

We in-licensed ivonescimab effective January 2023 and immediately went to the U.S. FDA in order to discuss bringing the open study from a single region to a multiregional setting. Once aligned, we began enrolling in mid-2023 and completed enrollment in the beginning of October 2024. This resulted in sequential enrollment of patients first in China and then in the Western regions of North America and Europe. As a result, at the time of our prespecified primary analyses of both primary endpoints, PFS and OS, the majority of events were driven by China.

Let's discuss the timing of the analysis performance. The primary PFS analysis was performed in July 2024 as per the protocol as a prespecified number of events. Due to the sequential nature of the enrollment, as I mentioned, these events were reached prior to completing enrollment and hence, there are fewer patients in that analysis in the 438 patients noted in the chemo, mostly coming from Asia. As a result, we performed a total PFS analysis when we perform the primary overall survival analysis in April 2025. This allows for the inclusion of all Western patients and more maturity of these patients, roughly 9 months of median follow-up time to evaluate the global view or multiregional view of progression-free survival in the multiregional set.

However, for the primary OS analysis taking place in April 2025, which we noted in our press release, the prespecified number of events was reached as per our protocol, but the follow-up time for Western patients, again, that was approximately 9 months was not mature as it was far short of the median survival in either arm.

We, therefore, noted at that time in our May press release, that we would continue to follow Western patients for additional time on study. We launched the database in September 2025 when there was a longer follow-up and 76 events in Western patients. The number of OS events in Western patients at this point in time was in alignment with the estimation of events for Western patients expected to be included in the primary analysis for our protocol, and to be included in yesterday's presentation at WCLC 2025, the updated OS analysis that we just completed that included a longer-term follow-up of Western patients.

When we in-licensed ivonescimab in the beginning of 2023, we sought to bring ivonescimab to patients, one as quickly as possible; and two, in particular, with respect to the setting those patients with EGFR mutant non-small cell lung cancer who progressed after targeted therapy where there are very limited options and many drugs have failed to show a benefit here. We sought to bring an opportunity for those patients to have an additional therapy option.

As I mentioned and as we've discussed over the past 2.5 years, the setup of this study was a bit unique in continuing a single reason study into a multiregional study. And therefore, the follow-up post-hoc analysis are uniquely critical to evaluating the study with sufficient time line study for Western patients. So as Jack walked through the details of the presentation, we felt it would be appropriate to provide this background and understanding prior to Jack's taking you through the results.

And with that, I'll hand it over to Jack to walk through the presentation.

Thank you, Dave. Yesterday, as you're aware, ivonescimab data were featured in a presentation at WCLC 2025 as part of the presidential symposium for the second straight year. The presentation titled ivonescimab versus placebo plus chemo, Phase III in patients with EGFR-positive non-small cell lung cancer progressed with third-generation EGFR TKI treatment, HARMONi. It was given by Dr. Jonathan Goldman MD, Professor of Medicine at UCLA in the Hematology Oncology Division as the UCLA Director of Clinical Trials in Thoracic Oncology and also Associate Director of Early Drug Development, and Chair of the University of California Lung Cancer Consortium.

Revisiting the schema for the HARMONi trial. HARMONi evaluated ivonescimab in combination with platinum double chemotherapy compared to placebo plus platinum double chemotherapy in patients with epidermal growth factor receptor for EGFR-mutated locally advanced or metastatic non-small cell lung cancer, nonsquamous non-small cell lung cancer, who has progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor, or TKI. This was a global Phase III clinical trial conducted and sponsored by Summit for which top line results were announced in May of this year. Key eligibility criteria are shown here.

Patients were randomized 1:1 and stratified by geographic region and presence of brain metastases at baseline. Patients received either ivonescimab at 20 milligrams per kilogram plus pemetrexed carboplatin or placebo plus pemetrexed carboplatin, then received ivonescimab or placebo in combination with pemetrexed for up to 24 months. Treatment was to be discontinued for intolerability, progressive disease, or initiation of new antitumor therapy. The study had dual primary endpoints of overall survival and progression-free survival by Independent Radiologic Review Committee.

Secondary endpoints included response rate, duration of response and safety. The dual primary end point is important. As you know, the study was a positive study based on achieving its PFS primary endpoint. The baseline characteristics showed ballast arms for age, gender, region, race, smoking status and the presence or absence of liver and brain metastases. Patients in this study received a prior third-generation TKI either in the frontline or after an early generation agent. Approximately 60% had a deletion 19 mutation, 35% had L858R and about 5% had a noncanonical mutation. Brain metastases were present at baseline and 25% of the patients on HARMONi. The trial included a total of 438 patients, including 165 from North America or Europe, representing 38% of patients in the study.

In several EGFR mutation positive global Phase III lung cancer study, over half of the patients who are randomized coming from Asian territories. And so this enrollment breakdown is in line with other multiregional studies of this tumor type. The progression-free survival curves show the trial met the primary endpoint with a hazard ratio of 0.52 with a corresponding p-value of less than 0.0001. Median progression-free survival was 6.8 months for the ivonescimab with chemotherapy arm compared to 4.4 months for those patients receiving chemotherapy alone, a difference of 2.4 months favoring the ivonescimab arm. At 6 and 12 months, almost 20% more patients taking ivonescimab in combination with chemotherapy were progression-free.

When we look at various subgroups, it's important to highlight that the size of the subgroups is smaller. And by definition, it's not designed to be statistically significant on their own, but the subgroup analyses can be very informative, nonetheless. The subgroup analysis for progression-free survival confirmed benefit in all preplanned subsets as indicated by plots for each subgroup landing on the left side of the dividing line favoring ivonescimab.

So there's really not a situation where one subgroup is an outlier of the study results were driven by a specific subset or a subset of patients. Ivonescimab benefit was demonstrated across all clinical and molecular subgroups that were evaluated. These progression-free survival curves showed benefit in both patients with and without brain metastases at baseline. Patients with no brain metastases at baseline had a hazard ratio of 0.59, which is very good and clinically relevant. But a particular importance in the EGFR mutant lung cancer setting is the results in those patients with brain metastases, with a hazard ratio of 0.34. Ivonescimab showed strong clinical performance against brain metastases, and in this setting, it's a cornerstone importance, particularly post TKI because ivonescimab appears to overcome the poor prognostic implications of brain metastases.

As Dave noted earlier, we performed a total PFS to include all Western patients. This analysis shows the consistency of patients in Western regions versus those in Asia. These curves show the consistency of data with additional time for Western patients from the primary progression-free analysis, [indiscernible] free survival analysis in the solid line to a later analysis at the time of the predetermined overall survival readout in the dotted line.

The highlighting -- I'm sorry, overlapping curves and the consistent hazard ratio between the primary analysis and the total PFS analysis demonstrates that the multiregional benefit holds with more mature data. The hazard ratios were consistent and favorable and highly clinically meaningful in both Asian and Western patients. Recall from the baseline characteristics of the study was approximately 62% Asian patients, which is in line with historical multiregional studies conducted to patients, the EGFR mutant lung cancer and is representative of a multiregional study from a breakdown perspective.

We specifically overlaid the curves to allow for visual to show the primary analysis conducted with a prespecified number of PFS events occurred for the protocol, primarily driven by events in Asia and the total PFS when all Western patients were enrolled and the median follow-up time for Western patients was over 9 months.

You can see highly concordant curves here, showing you visually that the data are highly consistent when including all Western patients. The hazard ratios are highly consistent overall from the 2 time periods, 0.52 to 0.57. And the regional differences, both of the regions are within 0.10 or 10 basis points of the global hazard ratio. These are consistent with highly overlapping confidence intervals.

We wouldn't and don't expect the exact same numbers for hazard ratios for subgroups, which are smaller subsets of the total population. The overall survival curve separate with the difference at the median of 16.8 months versus 14.0, with a hazard ratio of 0.79 and a p-value of 0.0570. This was a strong result in this patient population. To date, there are no drugs approved in this setting that have demonstrated a statistically significant overall survival benefit. Our data showed a hazard ratio of less than 0.80 and clear separation of the curves.

Note that the curves begin to separate at approximately 9-month follow-up. As well, you can see Western patients' median follow-up time just over 9 months. Based on the follow-up time of these patients, as we stated in May, our top line press release, we noted that we would continue to follow Western patients for additional time on trial as we felt that, that was clinically relevant to the results of this study. Because Asian patients had been followed for over 30 months and exhausted complete follow-up at the time of the primary OS analysis, we used the agent patient data from the April 2025 data cut and an updated -- and updated the follow-up of the Western patients.

We launched the database in September 2025 when the median follow-up for Western patients was approximately 13.7 months, and with approximately 4.5 months of additional follow-up for western patients. There were a total of 76 OS events in the Western patients, which is in alignment with the original expected number of events in the primary analysis for Western patients when we began the study. Hence, we included in yesterday's presentation, the updated OS analysis that included longer follow-up of Western patients.

The long-term hazard ratio was consistent with the primary analysis, at 0.78 with a nominal p-value of 0.0332. Median OS for this analysis remain the same in both arms from the primary analysis. Median OS in Western patients receiving ivonescimab of 17.0 months compared to 14.0 months for those receiving placebo with chemotherapy. Median OS and North American patients specifically had not yet been reached in the ivonescimab arm compared to 14.0 months in the placebo arm.

Median overall survival in this longer-term analysis is highly consistent here. With the 2 regions, Asian and Western patients, both showing highly consistent results in both the ivonescimab arm and showing identical results in the control arm. As we noted in our press release yesterday, the statistical analysis plan for the study required a p-value of 0.0448 or less in order to achieve statistical significance at the time of the primary analysis of overall survival. These results show the impact ivonescimab had versus standard of care in this setting.

With the curves maintaining their shape and their separation of approximately 9 months. The additional median follow-up time of Western patients demonstrates the consistency in the data between Asian and Western patients. Of course, the nearly identical median -- in the median overall survival also drives the regional consistency point home and punctuates the level -- the value that ivonescimab can bring to patients globally after its success thus far in China.

This demonstrates both the consistency in the results across regions and the strong performance of ivonescimab in this second, a setting where no drug has shown an overall survival benefit. Important in this setting as well is the safety and tolerability, where ivonescimab can play an important role as an option for physicians and patients facing this disease and the need for treatment.

The overall survival force plot shows consistency across the trial subgroups. In particular, as it is important to acknowledge that results in North America are of increased focus in today's environment, it's encouraging to note a hazard ratio of 0.70 amongst North American patients. There were no patients that -- there was no patient that was a detrimental impact on survival, and we see stability over time on primary analysis.

Both objective response rate and disease control rate were improved for ivonescimab by an absolute difference of 11%. The median duration of response was improved from 4.2 to 7.6 months. I'd like to pause here to reemphasize what we have just seen.

The primary analysis for PFS, which was strongly positive in July 2024 was backed up by the consistent results with Western patients having more maturity in the total PFS analysis that was performed. The overlap in Kaplan-Meier curves, the curve saw a moment ago where we overlaid the primary PFS analysis and the total PFS analysis, showed a high level of consistency between the data with mature global PFS data included.

The primary overall survival analysis was performed in April 2025 and with a follow-up time for Western patients that was less than the median survival. Given the clinical relevance for following these patients, we did a recent analysis that lets us evaluate the results in the Western patients where there -- when there were the number of Western events expected in the protocol in the primary analysis. These results were highly concordant in hazard ratios and medians in overall survival, including Western versus Asian patients, demonstrating the consistency of the data.

When we look at HARMONi-3 and HARMONi-7 -- sorry, when we look at HARMONi-3 and HARMONi-7 in the front line, driver mutation negative non-small cell lung cancer setting, the importance of overall survival is only further highlighted. The regional consistency seen in HARMONi is very encouraging in that light.

Treatment-related adverse events showed small increases in the ivonescimab group. Any grade events were increased from 93% to 95% and Grade 3 events from 42% to 50%. Treatment-related adverse events leading to discontinuation of ivonescimab or placebo occurred in 7.3% versus 5%, respectively. Based on the dual targeting of ivonescimab, we analyzed adverse events that were thought to be immune related or VEGF related. These were increased from to 6% to 9.6% for Grade 3 and higher potentially immune-related events and from 3.2% to 7.3% for potentially VEGF-related events and will be detailed in the next slide. On the right, events are split out by specific terms. The most common events were lab abnormalities, nausea and decreased appetite consistent with the chemotherapy backlog. As such, there is a little difference between the arms.

Focusing further on immune and VEGF-related events, we see that most events were low grade. The most common immune-related events were thyroid abnormality, and other events were at low rates and similar whether the patient received immunotherapy or not. Among the VEGF-related events, proteinuria, hypertension and hemorrhage, each was seen in 10% to 14% of patients, but were not general -- I'm sorry, but were generally low grade and the Grade 3 rate of hemorrhage was under 1%. Venous and arterial thrombotic events were similar in the 2 groups.

I do want to pause here for a moment and speak to the highly validating and strong safety profile seen in the Asian patients that was also validated globally with the results of the study, where we saw generally consistent results. This again differentiates ivonescimab from the results seen in prior studies of PD-1 plus VEGF monoclonal antibodies being administered together and the difference in VEGF associated toxicities from previous studies with anti-angiogenic therapy.

In summary, ivonescimab provided a significant and clinically meaningful progression-free survival benefit in patients with EGFR-mutated non-small cell lung cancer after progression on a third-generation TKI, with a hazard ratio of 0.52, which was consistent across predefined subgroups, including those with brain metastases and consistent with the total PFS analysis that included all patients, including all western patients.

Overall survival showed a favorable trend with a hazard ratio of 0.79, response rate and duration of response were also increased. Ivonescimab was well tolerated with less than 1% Grade 3 or higher bleeding events and low grade -- sorry, low [ grades ] of adverse events leading to discontinuation or death. Most adverse events incidences were similar between the 2 arms.

One additional point that I would make with respect to this particular setting and that Dave acknowledged earlier, is that there are very limited treatment options available for these patients. With such limited options available to patients with EGFR mutation positive non-small cell who progress after a third-generation TKI with only a single approved regimen in the United States of ivonescimab plus chemotherapy, that regimen was approved based on the PFS benefit, reasonably similar to what we've seen here in a cross-trial comparison admittedly.

And with a favorable trend in overall survival without showing a statistically significant benefit. I'd also note that there may be meaningful tolerability differences between these regimens based on data, not only in this specific setting, but data presented as a whole, considering both compounds, ivonescimab and amivantamab, this underscores the specific value that ivonescimab an HARMONi regimen could bring to patients in this setting with the opportunity to include a differentiated mechanism of action for physicians and patients to choose from.

Importantly, we want to thank patients and their families, the site personnel and the Summit and Akeso team for the many roles they collectively played in carrying out the HARMONi trial.

And with that, I'd like to turn it back to Dave.

Thanks, Jack. Finally, there's one additional point that I would like to emphasize. If we look at the read-through of this study, of our other ongoing Phase III studies in frontline non-small cell lung cancer. Just about everyone would agree that EGFR-mutated non-small cell lung cancer post targeted therapy is biologically quite different than frontline non-small cell lung cancer that is driver mutation negative. The way to show that the existing treatment options is the PD-1 therapy is the overwhelming standard of care with or without chemotherapy, depending on PD-L1 status in the frontline driver mutation negative lung cancer setting.

Those same PD-1 therapies did not show a PFS or an OS benefit in multiple multiregional studies in the post-TKI EGFR mutant setting. Ivonescimab clearly outperformed the results of the PD-1 monoclonal antibodies previous studies. From a market opportunity perspective, there are fewer patients suffering from EGFR-mutated lung cancer. In this HARMONi setting represents much less than 5% of the potential market opportunity for ivonescimab long-term. But when we look at these much larger frontline settings, overall survival will be important. The highly consistent results in overall survival in the HARMONi study, taking a look at the North American results based on today's -- including taking a look at the North American results based on today's environment and seeking consistency there specifically.

But seeing regionally consistent results and seeing consistent hazard ratios and medians is very encouraging when we look at the HARMONi-3 and HARMONi-7 and beyond where overall survival will be highly important. These results presented yesterday are highly encouraging and showing the regional consistent performance of ivonescimab and ivonescimab's ability to break into a setting where historically immunotherapy has struggled. Anti-VEGF therapy has not yielded much in terms of overall survival here in previous studies, and continues to validate the opportunity presented by ivonescimab to make a significant difference across a vast number of patients facing solid tumor diagnosis.

Thank you, team. And with that, we will now see if there are any questions that our team can help answer. Tina, if you could please open the line for questions.

[Operator Instructions] And our first question comes from the line of Yigal Nochomovitz with Citigroup.

Could you comment, please, on the path forward with respect to our regulatory interaction on HARMONi? Presumably, you're going to have a meeting with the FDA to discuss these results. Are you going to do that with the current OS cut, or will you wait to do potentially another cut? And could you comment at all on what FDA has said with respect to the level of evidence that they want to see on the U.S. patients in addition to the overall statistical significance on OS to support a U.S. approval?

Thank you, Yigal. This is Dave. So we believe the data is very encouraging and is fileable. We previously disclosed that the FDA is looking for a statistically significant overall survival benefit in the study. And what I would say is the data cutoff for this analysis that we presented yesterday is September 2025. And so obviously, given today's date is only days old at this point. So we're highly encouraged by this data. But we do need to plan the appropriate next steps in terms of ensuring that we provide ivonescimab with the best opportunity to reach patients as quickly as possible. So we plan to finalize that strategy in the coming days and weeks.

Okay. And then the other question I had...

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Any hypothesis here as to what is driving the differences in PFS between the regions when you look at China versus ex China?

So I'll make a comment, and then I'll look to anybody else. This is Dave. But with the total PFS analysis, you can see that the curves are highly concordant when you overlay those on top of the primary PFS analysis. And that's usually striking way to show that they're highly consistent when you include the Western patients. So the hazard ratios are highly consistent overall between the 2 time periods in total. The 0.52 to 0.57 and the regional differences are highly consistent with highly overlapping confidence intervals is being included in this line.

So we wouldn't expect, and we don't expect the exact same numbers of hazard ratios for subgroups. And in particular, when you have small subsets of patients or smaller subgroups that you'll have some variability in the exact numbers. But as Jack mentioned on the discussion from a PFS perspective, both in the longer-term follow-up, both the Asian patients as well as the Western patients were within 0.1 of the median for the study, as a whole. And so those are statistically highly consistent results.

And of course, for overall survival, you see overwhelming clear consistency within the median, high consistency across the board in total and the median overall survival is nearly identical Western region to the Asian groups. They were exactly the same in the control arm. Every none -- these are mutually dependent patients who each showed a control arm 14 months at the median for overall survival and between 16.7 and 17 months of overall survival in the ivonescimab arm. So highly consistent across the board.

I would just add that in my earlier comments, we emphasize not to overread too much in a subgroup analysis in terms of you can't evaluate each one separately, is hypothesis generating. But I think we should be reassured that when we look at the subsets based on geography for both PFS and overall survival, those results address the question in a reassuring way that say, this is not a China-specific benefit that it's overall looking very strong, particularly in the North American population that is right at this moment, a particular priority. And that even if we don't want to say, oh, this is better, there's certainly no suggestion that it's worse and I think is very reassuring that the impressive observations that we've seen with this out of China, not just here, but in other studies, are not remotely suggestive of this being a benefit that stops at the border of China.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

This is Greg on for Tyler from Cowen. Congrats on this data. I'd be interested to hear what feedback are you hearing from physicians at the conference following this data set?

Yes. I -- this is Jack West. I have had very little time to sleep in between all the conversations I've had with my colleagues from the U.S., from all over the world, even some in Asia. And I would say that it has been interesting as people are well aware, there have been kind of mixed messages and responses to the results in what's been written about so far, largely in the financial settings. But my colleagues have been congratulatory has felt that the characterization of the results as negative for OS is something that maybe you should have an asterisk next to it or with caveats that this had many practical challenges with it. We have already acknowledged the sequential nature and the -- what we would now with hindsight call in opportune timing of the final OS analysis.

But when you actually look at what was achieved a hazard ratio of 0.79 a p-value where it was, this is not a hazard ratio of 0.89 and a p-value of 0.62. And so we would not want to have the risk of this being potentially a false negative almost. And so to my colleagues who are treating patients going back to their clinics this week and seeing patients with EGFR mutation positive disease. They say that they would be very eager to use the HARMONi regimen. They would prefer it over the alternative. Even some of the people who have been more critical of the trial still acknowledge that this would very likely be their preferred choice over what's currently available.

And so when you look just in absolute terms that what was achieved in efficacy, the safety profile and the remarkably favorable, I would say, tolerability, particularly in the context of what else we have. This is something that I believe patients and physicians would eagerly welcome to have available. And they have also said they consider these results overall to be very favorable and don't discount the potential utility of ivonescimab in the first-line trials that are ongoing.

And our next question is from the line of Brad Canino with Guggenheim.

Great to hear the updates from you all. One of the top investor questions I get is, will the HARMONi-2 interim OS of 0.777 hold up over time. I noticed that this analysis included 15 extra months of follow-up for the Asian subset since the last time Akeso cut the HARMONi-A OS data, I think it was December 2023. Is there anything to learn about the ability for PD-1 VEGF to maintain OS from this analysis?

Thanks, Brad. And I think that's a good question. So a little bit on the specific point here, and then I think we can further from that. And so if we look at HARMONi-A, which was the study sponsored by Akeso. And that was highly overlapping, but not the exact same patient population. So about 86% of the patients from that study included here. And those who received third-generation EGFR TKI are the ones that are included here.

And so the -- but we saw the overall survival analysis. The Chinese health authorities, the NMPA has requested during the approval process for ivonescimab in China back in 2023 and 2024. And so a 30% data maturity, we saw a hazard ratio of 0.72, and at 52% data maturity, and when I say data maturity, I'm talking total events divided by the number of total patients in the study, just to be clear.

We saw at 52% data maturity; we saw a hazard ratio of 0.80. And so a little bit of commentary has taken place with respect to, therefore, as sometimes had been seen in historical studies associated with anti-VEGF therapy, a degradation of OS was a concern. And so we have maintained from the beginning that the 30% data maturity was a very early cut. And that's not exclusive ivonescimab to be clear. That's much more of a general comment. But when you get to 52% data maturity, you have stabilization that takes place, if anything else.

And so now what we're seeing -- you see within our forest plot, you see the Asian cohort, right, it's not exactly the same patients. It's highly overlapping, but not exactly the same patients, right, who show a hazard ratio now for overall survival of 0.76. And so what we're seeing here is not a degradation of overall survival, but actually comparable, consistent, it's a tick towards favorability. I'm not going to make a larger, broader statement on that. But that is a piece of evidence now that we have a long-term follow-up on a randomized Phase III setting with ivonescimab that shows no degradation in overall survival.

The other piece I would say is that that's really addressing the VEGF component. If we look at this study and on the slides that were presented yesterday as well as are available on our website, you look at the long-term overall -- sorry, the longer-term follow-up of Western patients and you look at the overall survival Kaplan-Meier curves.

And what we see from our perspective, in our opinion, is an IO tail. And that tail seems to be clear present to us, and that represents what we see in other immunotherapies. And so what we are seeing as a result of taking a look at this data is both the PD-1 and the VEGF components of ivonescimab coming into play as well as a differentiated efficacy profile from what has been seen historically with anti-VEGF treatments. And we see a tick -- again, a tick favorable. I'm not making a larger conclusion there, but a tick favorable in terms of the hazard ratio associated with patients in Asia.

While undisclosed, our colleagues at Akeso have also announced that the HARMONi-A study showed significance in OS. That's their announcement, and they haven't given any further data, so I won't speak any further to that. But that also backs up that same point with respect to the utility of ivonescimab and what it can -- what it has the potential to do and what it can be in that setting.

And our next question comes from the line of Asthika Goonewardene with Truist Securities.

Good additional color on the call today. I've got a 2-part question here. So the discussion at Lung took a very conservative view and some form of KOLs called it a little harsh. Jack, I was wondering if you could tell us what is your biggest disagreement with Raj's comments -- sorry, Ram's comments?

And then second, the OS curves do not -- that were presented do not lose separate until maybe about 9 months in. And this certainly underlines the importance of data maturity and suggest that the ex China component, the data can continue to improve the follow-up in time. But any hypothesis as to why you're seeing that early overlap?

Okay. I didn't quite hear the second part, but let me get into this and we can see.

I'll preface this by saying that Dr. Ramalingam and I have go back 25 years as respected colleagues and friends, we are not any -- no, I'm just kidding. We are still, friends. But the -- I would say that to me, the biggest issue is that he really minimized, I would say, the foreseeable understandable issue of the overall survival cut, the relative immaturity of the OS data and our ability to -- we had called that we would -- what would loom large is how do things look as we get more data from longer follow-up of the Western cohort and knew this was going to be a problem. And I would say that the issue is just potentially throwing out the baby with the bathwater. And to say none of us is claiming that this is statistically significant. It will not be. That is the way it went.

But as I said, I think we are always, as clinicians looking for truth within the reality that the trials don't always provide clear answers. And I think that this one was fraught with challenges in how it was developed and how the data ended up getting analyzed. But -- so we don't want to dismiss truly beneficial therapies inappropriately. And my concern is that -- and I'd also would say this is based on conversations with many other colleagues in the last 28, 30 hours. I think a lot of us come into it with biases about whether we believe that it's all going to be anti-angiogenesis anyway. And so if that's your view, it's very hard to overcome that bias. I believe that was the case here.

So I would also say that the reality is that Dr. Ramalingam is not coming in with experience with ivonescimab directly or with bispecifics. Some of the conversations I've had just in the last few hours are with people who have actually used ivonescimab who are extremely committed to it, who have participated in this trial or others, and are strong believers because, first, they've put patients on trials and said, you cannot tell the difference in who's randomized to placebo or ivo, and that's something you really like in the drug. And they've seen what they've come to conclude are really good results as well. And so there's nothing like that clinical experience. So that's my view.

I would say that no one would ever say that Dr. Ramalingam is not knowledgeable or unfair necessarily. But I think that his view was about as far in the negative range of the confidence intervals of fairness as you could get within the admittedly ambiguous setting of the trial. This couldn't be said to be a slam dunk. So it's subject to interpretation.

But I think it was a quite uncharitable one and more important than what I think because of where I'm sitting, colleagues have unsolicited come to me saying that they're talking with each other. And without having a horse in the race, they really feel that, that was not a really balanced and appropriate interpretation of admittedly still somewhat ambiguous data.

Our next question comes from the line of Cory Kasimov with Evercore.

I recognize this isn't the subject of today's update, but is there anything you can share with regard to your latest strategic thinking with ivo in terms of both interest in a potential partnership as well as plans to move ivo into Phase III trials in additional tumor types like your partner has been doing?

Cory, this is Manmeet. To take that and give you an update. First of all, yes, I would say we have full intention and plans to initiate a few more Phase III outside lung and also export more in lung in coming months, and you'll hear that in the coming months from us.

On related to strategic activities, we've always said, we are always looking to expand the portfolio as soon as possible and as appropriate and we have also mentioned earlier, we are open to partnerships, right, to do and collaborate, which is -- which should be and would be beneficial for both partners for ivonescimab for all the patients to ensure that the drug can be got accessible and can accelerate development. And I would say that what I could see over here right now, and we are always open to do all those strategic developments.

Okay.

Yes, I will just reiterate, Cory, the comments that Manmeet made with respect to continuing the development of ivonescimab as well, as we said in the beginning of this year, fully intend to continue and more to come on that point. So we look forward to that later on as well.

And Cory, I can only add one more thing, right? Every month, we are seeing more and more positive news on a ivonescimab. You just heard, right, a couple of weeks ago, from our partner, Akeso, we announced the first OS for HARMONi-A, right, which was an EGFR, right? That was in China population, and they will provide more update in the coming months at appropriate conferences. You already know, right, HARMONi-6 a couple of months ago had -- was talked earlier, and that data will be announced in upcoming conference pretty soon.

And our partner also mentioned ivo has HARMONi-2 updated OS, if you recall me this 0.77, which was a very earlier cut the more mature OS data would be coming in the next, I would say, 6 months or before, which our partner has said. So all of those catalysts are upcoming and near-term catalysts, which just open up the value of amivantamab and would allow us to expand our portfolio pretty significantly.

And our next question comes from the line of Mohit Bansal with Wells Fargo.

Great. Thank you very much for this update. I would like to go back to the discussant topic from the presentation yesterday. So I fully appreciate the maturity of the OS cuts and all that. But I mean -- [indiscernible] made a comment that it does seem like Western patient population does dilute the impact or effect of ivonescimab overall even from ORR point of view, it does seem like lower response rates. So how do you respond to that?

And then, I mean, I'm still going back to the fact that between a lot of the investment thesis is dependent on Chinese data being translatable to Western patient population. So why do you think this is not -- this should not be read -- this should not be a read for your broader lung cancer development program.

I don't have the response rate. My understanding is the response rate in Western patients actually is -- at least shows a difference that is stronger between the ivonescimab and placebo arms than was seen in Asia, even if the absolute numbers are different. But the relative difference is the delta between them is actually greater.

I don't think we would differ in -- the general conclusion that the Western patients diluted the effect of the Asian patients, but that's a time-dependent issue. It's just that, yes, if you -- if you have immature short follow-up in Western patients added to the much, much more mature data out of China, you dampen the effect short term, but that doesn't mean that long-term, that's going to be the case. That's why I would say it was a very inopportune time to do that final cut.

But if the timing based on the number of events in the West would have been corrected for the actual delay and time it took to get the trial up and running in the West and it was done now, we would be talking about it differently. That's also something that some of my colleagues have said, when we talk about this as a negative trial, you're talking about the outcomes of a few patients. And if it had broken the other way, this would be hailed as a triumph in every way.

And so I think it's really worth bearing in mind that this is a very time-dependent effect, and it was just very unfortunate that that's when the official final primary -- the primary OS was done. Yes, it did end up diluting that effect at that time. But we have seen and expect that we are prone to see in the future that any follow-up if subsequent work is done, will demonstrate at least a stable, if not growing improvement in OS as time goes by.

Yes. The only thing I would add to that, Mohit, in Jack's first comment that I made with respect to response rates. It's not necessarily a direct one-to-one to take the HARMONi-A overall response rate. Keep in mind the 14% of patients who did not come on to this study, also going to receive a third-generation TKI. So it's not necessarily that those numbers are identical. So just -- I think that's a conclusion a step too far in terms of speaking of the dilution of response here.

Because that's not the exact same population that actually entered into HARMONi.

That's right.

Our next question comes from the line of Eric Schmidt with Cantor Fitzgerald.

This is [indiscernible] on for Eric. Just curious as to if you have an explanation for why the EU patients are a little bit more poorly in the study and what the PFS hazard ratio is in North American patients?

The question was what about -- what happened with the European patients and why they may have fared less well.

Got it. Yes. So this is [indiscernible], right. So from the analysis point of view, right, we have a subset of subgroups that we are prespecified looking into. For this particular study, the study was stratified by region combining both Europe and North America together. So the most important point is to look at that as the Western patients in terms of what it tells us and the results we see there for both PFS and OS at the time.

When we look specifically into Europe, it's a little bit what Jack also has talked about. So Europe has 2 things so to speak against it. One is it's actually the smallest subgroup within the region. Europe is smaller than the North American region. And on top of that, it started to enroll last, right? Because the study was, we started enrollment in U.S., specifically Canada right away and only then a few months later in Europe.

So we -- I don't have any concerns about the Europeans. I know in this particular study; we talk so much about subgroups and trying to take each subgroup of itself. But I think what we can say is there is no subgroup here that has shown any detriment in terms of look and prespecified. And there's also not one subgroup that overwhelmingly drives the benefit. And that's really the purpose of looking at subgroups. We can take every individual number and go into a clinical study that has variance and noise and think that every number comes up exactly perfect, being exactly in alignment with each other, identical et cetera. So that's what I can add to that question.

Yes. And what I would say is I'll look at a different study that we don't have a horse in the race with that we're not in the same setting. But yesterday, the overall survival results were announced for osimertinib plus chemotherapy versus osimertinib, the FLAURA2 study in frontline EGFR mutant non-small cell lung cancer.

It was a statistically significant benefit that was announced, and it should be treated as such and a win for patients. Underneath that in their disclosure of forest plots in regional differences, one of their defined regional subgroups had an overall survival hazard ratio of 1.00, right?

And that is not something that people have talked about. And I agree with that, they shouldn't see because everything that Urte just said, looking that far into individual subgroups starts to make a bit of noise. And so I think that's an important context. Some of the analyses looking at like the very small differences in certain points here are a bit more granular than statistics are intended to take into play.

Yes. Subgroups of subgroups. And then the other thing is that I think clinicians and the broader world has been looking to see, does ivonescimab and some of these other agents that have looked promising in China, do they work outside of China. But if you see that there's a good result in a Western population, it is biologically implausible that you would see an effect that is very good in North America, but not a very similar biology in Europe. So I think that is very hard to tease apart how you could have China and North America look singularly similar, but different from the European population.

Our next question comes from the line of Kelsey Goodwin with Piper Sandler.

In terms of locking the Asian population for OS, but then continuing to follow the North American and the European, was this agreed upon with the FDA at any point? And is there any precedent for this?

What I can say is we did not go into detail with this additional longer-term follow-up with FDA. We discussed that it would be valuable to look at it because the maturity of the Western patients itself is informative. The maturity of the Asian patients have completely been reached and exhausted at the time of the primary OS follow-up. So it's way beyond the median for both of the arms. And it is very hard over a long period of time to actually follow patients and everybody dies.

I don't actually think any clinical study has accomplished that. So this is an appropriate way of analyzing that, and we can discuss that with statisticians and use of it, but this is an appropriate way. And we admitted from the very beginning that our intention is to follow-up long-term the Western patients after the primary analysis.

Yes. And I think that was clear in our press release in May as well.

Our next question is from Daina Graybosch with Leerink Partners.

Let's say that you don't receive FDA approval ultimately based on the data. In that scenario, will you do another trial in this setting? And if yes, how might you design that trial?

Daina, thanks for the question. This is Dave. I think I'll probably go back to my earlier comments from a moment ago with respect to the fact that the data cutoff for this study ultimately being in September has not given us a lot of opportunity in terms of planning exact next steps with respect to agency interaction, how we will take this forward, what the next points become. And so I'm not sure we're at a point of going any further than that at this point.

Our next question comes from the line of Clara Dong with Jefferies.

So for the HARMONi study, is there any additional analysis you plan to provide to us, especially overall survival data from the Western populations at a later data cut down the road or it will kind of depend on your regulatory interactions later on?

And then also for the forthcoming data readout from HARMONi-6 for the combo of ivo with chemo in frontline squamous non-small cell. Would you be able to share the scope of data we should expect to see there? And what do you believe is the bar for success?

Thanks, Clara. I think on the first question, yes to the -- your implied answer, which was that would -- I think that would have to do with further interactions. I think on the second point, HARMONi-6 I just want to be careful in the sense of that is the study that is sponsored by and conducted by our partners, Akeso. Very excited for that data to be shared.

However, in terms of bar for success, I think these are predefined statistical analyses. The comparator arm, obviously, is extraordinarily high as a bar with PD-1 plus chemotherapy. And importantly, from a timing perspective, this was a success on an interim PFS analysis, right? And so hopefully, that -- those bars are high across the board, high comparator, high-quality comparator, patient population that previously wasn't able to be treated with anti-angiogenic therapy. And so that's an important component here with the PD-1 VEGF bispecific of ivonescimab. And so...

You're talking about treating 266 or so patients with advanced squamous lung cancer with a myelosuppressive doublet combined with ivonescimab and being able to complete that, not stop the trial, I believe no new safety signals, we'll see the data. But along with the efficacy, the safety will be very reassuring and important to the clinical community.

Yes. We're very excited for our next steps on that data. But given that, that is a study sponsored and conducted by Akeso. I'll leave it at that.

Our next question comes from the line of Reni Benjamin with Citizens.

Congrats on the data. Maybe just based on these data, can you talk a little bit about how this might be -- the slight differences might impact your statistical plan kind of going forward with your Phase III trials, could we expect any sort of changes maybe in the number of patients being enrolled just to make sure that statistical significance has helped? And then does -- have you -- are you doing any other sort of additional evaluations to look at what these patients might be getting post progression? And does that vary based on geography?

Let me start with the second one and then we go back to the first one. We have looked at the next time therapy for the HARMONi study and obviously, because of progressive disease was much further in the control arm compared to the IO arm there is already much more treatment in the control arm in terms of percentage of patients getting it, but they are getting it. In the control arm, there was 50% or more that have already started to get second-line treatment.

What we have seen in the second-line treatment is very much what we would expect. Majority of treatments was with additional chemotherapy, but there was a meaningful cohort, approximately 20% of those patients that also get further EGFR-targeted therapy. So normal distribution would suggest to us there is also normal follow-through for the patients that can still get next-line therapy.

Very good. And I think on the first question, I'd reiterate some of the earlier comments with respect to the idea that, again, with the September 2025 data cut off, and I think it's important to dig a little bit of time to take a look at, given the [indiscernible] at this point.

And our final question comes from the line of David Dai with UBS.

So just regarding the nominal p-value based on the ad hoc analysis. I'm curious hat kind of statistics analysis have you done to drive the nominal p-value? And then at the same time, just wondering what do you -- how do you think the FDA will view this nominal p-value given that's less than 0.05 now. Is there a potential for them to view this as favorable and can potentially get approval based on?

Let me take the first one because the first [indiscernible] I am not the biostatistician. So I'm just going to comment my ability to understand this, but the general methodology in terms of assessing the p-value based on the Kaplan-Meier methodology is the same or similar between the primary analysis and this analysis. But we have been very direct, and Jack made a couple of comments in this regard that we know. And of course, we would have loved to that we know that we did not reach significance. So we are not explaining that.

But the tool of assessing a p-value tells you still how much variability or lack of variability or uncertainty is in a given data set that you look at, because we are not claiming significance here, it is more about the descriptive that there is not a lot of variability and tightness of the data at this long-term OS analysis.

And the directionality of it.

And the directionality of it and being stable, right, or stable for us is good. That's what we are looking for and bringing in obviously the follow-up for the Western patients. What was the -- sorry, what was the third part of the question?

The FDA.

Yes. So that's right. And so with respect to the FDA, I mean we have a high amount of respect and appreciation for our work with the FDA, including our appreciation of they're working with us from the beginning of this process, as we said during this call, we in-licensed ivonescimab in January 2023.

One of the first things we did was go to the FDA with respect to looking for a way to expand a single reason study that was opened at the time into a multiregional study. So we have an immense amount of respect and appreciation for the work that the FDA does as well as their collaboration efforts as a whole.

And so I think just a comment on how we think they will think about it something just doesn't feel appropriate to us. And so we'll kind of leave that piece there. Our -- we are encouraged, as we said, by this data, but I'm not going to comment with respect to how we think the FDA will feel it. It's very important that we walk through more details if that were to be the case.

Dave, this is Bob Duggan. Can I expand on your comments a couple of things to point out. At the time the trial was launched, we were very, very appreciative that the FDA leaned in and allowed us to include China data and to do this -- to pull this trial off. That was something that people did not expect and we, in retrospect, they obviously made the correct decision. But at that time, I believe all of us underestimated the level of conservatism and caution amongst North American physicians with regard not only to bispecifics here, that this was going to be novel, but also with regard to China data.

So this was the first and it took a lot -- took quite a bit of time to gather momentum to get off the tarmac, so to speak, and into the air. And that's why the estimated time for completion of the trial then came in a bit shorter than had we been able to evaluate that properly, it would. And that's the only reason why there's a -- the only reason why we have -- we extended and allowed the maturity of the data to be equalized so to speak, so that one could get a fair analysis as to the response. And you can clearly see it from the statistics it was a very good idea that we did.

The last comment here, I know Yigal was cut off on his second question. Many of you appropriately were able to ask a second, Yigal if your second question is still of interest to you and of us or has it been answered, feel free to jump in.

And with no further questions, I will now turn the call back over to Dave Gancarz for closing remarks.

Thanks very much. We're just checking to see if Yigal was still there.

But in summary, I think we're -- appreciate Bob's additional comments and appreciate the team's participation here. We're very happy as we currently stand and with respect to this updated data analysis, the presentation from yesterday, and I want to take this time now to thank each of you for attending today's call and your interest. And reminder that an archived version of the webcast will be available later today on our website.

And with that, thank you very much, and enjoy the rest of your day.

Thank you for joining us today. This does conclude today's presentation. You may now disconnect.

Great. Good afternoon, everyone. Thank you so much for joining us. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, and we're really pleased to be joined by the Summit team who's rather patriotic today. So to start here next to me, I have Maky Zanganeh, who's Co-CEO; Bob Duggan, Co-CEO; Manmeet Soni, COO and CFO; and Dave Gancarz, Chief Business Officer.

So with that, to start here, could you provide an overview of your lead molecule ivo and where your programs stand, your strategy for your company and the key events we should focus on in the second half and beyond. Dave?

I was going to give it to Maky. Maky is the cover girl of the upcoming Forbes Magazine and you'll hear plenty from her today. But Dave, go ahead.

Sure. Thanks for the question, Salveen. So I think as we take a look back over 2025 thus far. So we had announced at the beginning of the year that there would be 3 clinical catalyst events and 1 operational catalyst event. And so we began the year stating that there would be -- we would focus on the ability to translate PFS into OS in the HARMONi-2 study, monotherapy, ivonescimab and pembrolizumab in the PD-L1 positive non-small cell lung cancer front-line setting. We would focus on the success that took place in HARMONi-2 in the monotherapy setting and seeing that translate -- that benefit translate into the chemo combination setting.

So as we look at non-small cell lung cancer and solid tumors as a whole, the overwhelming standard of care in the frontline setting is often immunotherapy plus chemotherapy. And then third, we would look to show that the success in single region, albeit randomized Phase III studies in China would be comparable to the results in a multiregional setting, HARMONi-A to the HARMONi trial in second-line EGFR mutant non-small cell lung cancer.

So all 3 of those data points read out earlier this year. And so we saw a strong positive trend in overall survival in a health authority requested first look at overall survival in HARMONi-2. That showed a hazard ratio of 0.777 at a nominal alpha spend given that, that was requested by the health authority as opposed to preplanned analysis. And so that showed a strong favorable trend. And so we see -- oftentimes, we look at clinically meaningful as being about 0.80. And so the first look at 39% data maturity showed positive and encouraging trends from there. And also important to note that this trial at 398 patients was not intended to evaluate statistical significance of overall survival as this was a primary endpoint of PFS in that indication for ivonescimab, has since been approved in China.

The second aspect, chemo combination in HARMONi-6, looked at frontline squamous non-small cell lung cancer. And that took a look at ivonescimab plus doublet chemotherapy against PD-1 plus doublet chemotherapy. In that trial, our partners at Akeso announced was strongly positive first look at PFS. That was, again, a PFS primary endpoint. And that data will read out in full at a major medical conference later this year. But that data at a -- it's a first interim look. So obviously, it's a relatively high bar from a statistical plan perspective. And therefore, it continues the favorable news and data with respect to ivonescimab now in a chemo combination, which is important as we look at the opportunity in solid tumors as a whole, and in particular, in non-small cell lung cancer.

And then finally, with respect to the data comparability from single region China to a multiregional setting, the HARMONi trial read out just before ASCO and that showed a statistically significant and clinically meaningful progression-free survival and a strong trend in overall survival, the 2 primary endpoints, which was consistent with what we saw in the HARMONi-A trial from the single region study in China, further validating the randomized Phase IIIs that we see in China continue to validate the opportunity as a whole for ivonescimab in a global setting.

The final operational catalyst that we discussed earlier was the expansion of our clinical development plan later this year, and we continue to effectively reaffirm our intentions from that perspective. So hopefully, that gives decent color in terms of overall summary to date on where we are and what's taking place over the last few months.

I just want to add as well, for sure, we have our partner, Akeso, as you know, in multiple different meetings we announced as well that we have over 22, 23 different trials going on or completed or going to start what 11 of that is a Phase III that China and us we are combining. We are doing that. Over 3,000 patients is enrolled. So we have a very good safety profile, efficacy profile in many different therapeutic areas. As well as from a commercialization point of view, we already -- in China, we got FDA -- 2 Chinese approvals, which is significant from the progress that we are going to have here in America. And the fact that right now, they are selling the drug, and it's more than 20,000, 25,000 patients already enrolled with this product. And that is already talk a lot from, as I said, safety and efficacy point of view.

Maybe we can start here with the HARMONi study, just given we saw the data recently ahead of ASCO, Help us understand next steps from here for you in terms of providing data to us, but also in terms of what you might want to provide to the FDA down the road? And then also just the meaningfulness of this indication in the context of the total opportunity that you're pursuing.

Sure. So for the last question first, I think from an opportunity perspective, this was an important setting from a speed perspective as we look to enter the market for ivonescimab. From a total addressable market perspective, think of it as probably 1% to 2% of the total addressable market within the possibility for ivonescimab. When we look at the data itself, so we were statistically significant and clinically meaningful in progression-free survival and a strong positive trend without hitting statistical significance in overall survival. When we look at this setting, so you had asked, Salveen, with respect to filing and whatnot. We noted in our release that we intend to file a BLA, but we want to make sure that we think through strategically the right next steps with respect to how to do that.

So we're -- when we entered into the agreement with Akeso, this was a specific opportunity, as I mentioned a minute ago, to move quickly in this setting. This is a setting where PD-1 therapies have looked to become a part of, but both pembro and ivo had unsuccessful trials in this setting in both PFS and OS. So this was a differentiation point for ivonescimab against the existing PD-1s. So we were very thankful in working with the agency from the beginning in 2023, and we appreciate the agency working with us in terms of moving forward here in this study immediately.

And so we, at the agency's request, included overall survival as a primary endpoint along with progression-free survival. And so when the study read out, we were, again, statistically significant, meaningful, progression-free survival, but the agency asked for statistical significance as well with overall survival. When we look at the landscape for this particular patient setting, we see 1 approved regimen in this space that also showed a PFS statistical significance and an OS trend without hitting statistical significance.

So as we look at the overall package, we just want to work through strategically the right way to bring this forward as we work with the agency with respect to next steps. At ASCO, as Salveen mentioned, we're -- it was just ahead of the conference where we disclosed this data. We had a couple of hundred interactions with either KOLs or other physicians who are attending the conference and was overwhelmingly positive in terms of the opportunity that ivonescimab plus doublet chemotherapy, the HARMONi regimen, if you will, what options that could provide in this particular setting.

So we think it's a very good overall data package, and we're working with internally to determine what are the right appropriate next steps, if you will, strategically. We had mentioned in our release, the Friday before last, that the patients from the Western countries -- the median follow-up time was actually less than the median overall survival in this setting. So we think there's value in continuing to follow all patients but in particularly the patients from the Western countries in terms of adding to the overall package here.

Bob, do you want to add something?

No.

Maybe a twofold follow-up to that. So one is, do you have an understanding of what's required from your clinical trial program in the context of ex-China data sets versus China data sets and how you think about that in the context of your overall program on the Ford? And then the bar for approvability at the FDA with these dual endpoints and the optimization that you have done to ensure you can hit on overall survival as well as PFS.

Sure. And so with respect to the first question, yes, for each of our trials, we work with the agency in advance in terms of proportion of enrollment amongst other factors, design of the trial, et cetera. And so going forward, you can expect much more of -- in -- for example, if there's 3 regions within the study about 1/3 in 1 region, 1/3 in another region and 1/3 in the final region, more even split. As we mentioned with EGFR, it's a higher prevalence in patients of Asian descent. And so typically, you see EGFR mutant trials have a higher proportion of enrollment from Asia. But going forward, in other indications, you would expect much more of an even enrollment across. And that's effectively what we have planned for our 2 enrolling trials at this point.

With respect to the approvability again, as we continue to have conversations with the agency, these details are worked out. I would say we started HARMONi-3 with an overall survival primary endpoint and part of the reason for adding a dual primary endpoint when we added nonsquamous on top of the squamous population was in response to the data that we saw in HARMONi-2 that had such a profound PFS benefit that we wanted to at least ensure the ability to have a conversation with the agency should PFS read out with such a significant difference in the HARMONi-3.

However, we started with OS as the sole primary endpoint in that trial. And I think it's very clear that within the frontline non-small cell lung cancer setting, that will become extremely important in terms of showing an overall survival benefit over PD-1 plus chemotherapy in terms of realizing the potential of the market. And as we -- I mentioned in the opening, HARMONi-2 had early look, but had showed a very positive or favorable trend in terms of its first look, so that continued to provide positive data that was encouraging.

And then also, we have obviously a significant amount. Maky mentioned, the number of trials, well over 20 trials that have been enrolled or enrolling. Those include a number of Phase II trials as well in this particular setting where we can see the follow-up that's much longer now than what you see in the Phase III, and we're very encouraged by what we see there. So you see the powering of our clinical trials in -- that we run on a multiregional basis, and those are intended to and are powered for statistical significance and overall survival.

Just one last question on HARMONi. What do you think played out here with regard to the trial that OS was not statistically significant. Was it powering? Or was it tumor type or other factors? Maybe help us understand what you think played out.

I can start and then after that, I mean, these study was very interesting study. It was already enrolled in China. When we did the deal with Akeso, which was around February 2023, we started right away, we were in discussion with the FDA. And for sure, the discussion was to add additional patients into the Chinese patient populations, which is 1/3, 38%, 40% of these trials is ex U.S. patients. And we enrolled -- we started the enrollment as soon as possible.

For sure, at this moment of time is as well, it was a time that we take a little bit to everybody questioning what is the bispecific, everybody questioning, what is the China data, everybody -- it just was so much question. So the first 3 months took us a little bit time and especially for a company like us that we didn't have Phase I, Phase II, we started right away on the Phase III to bring awareness to the physicians, to the patients, took a little bit longer time to take off on these specific trials. And for sure, last ASCO and September, when we announced our data, the enrollment went really, really fast in this regard.

I know sometimes the people say the study was not statistically significant, but if you really look at it, the p-value, I mean the hazard ratio was 0.79, which is already unbelievable for category of patient population. There is no other drug at this moment of time, got the OS, one. Second, if you really look at the safety profile of these -- for these patient populations compared to existing drug, I mean, you cannot compare, which is a better safety profile. The efficacy was good. The only thing I can say, you say significant, and that is the difficulty when you look at the OSP value of 0.057 instead of 0.05 is really you're playing with the penny numbers. It's not -- you cannot say that if the drug is not working, you cannot say the drug is not good for this patient population.

So if you take a little bit another look on it, at the end of the day, as a physician, as a human being, as a patient, you cannot just go and say, because you didn't hit 0.057, you cannot prescribe this drug to the patient. And some moment of time will come either rule beyond the NCCN guidelines. We are trying to go back to FDA to present our case. And there's a lot of other things. At the end of the day, we have to do everything possible to bring this drug in the hands of patients. That is bottom line. So therefore, yes, perhaps this number shows that say, "Oh, we didn't hit it." But in the reality, I believe the study was very positive scientific point of view about it.

Yes. I'd like to give Dr. Pazdur a lot of credit. He could have easily agreed with the early take from the FDA was too much China data, and we just don't do that now. And he stepped in and took a look at it, and he is familiar with Maky and myself from Pharmacyclics stage and put a call and just said, I have a question. What is it? He said, "Why did you do this?" We said, "There's a major unmet need around the world. We think this molecule has some real life to it. And honestly, given what we've seen, we just felt we had an obligation to try to work this out." He paused and said "well, makes sense." He said, "I'll let you do it, but the challenge is going to be OS." Now there had not -- that was like impossible. But we took it because what it could possibly show even if we didn't hit the OS at 0.05 is that the data is translatable, the progression-free survival was spectacular. OS is not even a question in EGFR TKI post TKI.

So we thought all those would be wins. And in fact, they were. That's why you can look at the trial and say, it did succeed. But I give him a lot of credit for one, helping the 2 countries come together under something very substantial. We are exporting China technology from -- China is exporting the technology. We're importing it. We exported money. It's exactly what the country wants. They want the money in and the tech out around the world. So this is just one small step really for mankind and human kind. We're not in the war business, we're not in the IT business, we're not in the AI business, although we use AI a lot. It just shows there's 2 people -- these 2 people can't get along. And we do and we did, and we'll continue.

Our top partners from Akeso are like many Chinese educated in America, they're culturally Chinese. They speak both languages. They have American passports. And we see every reason why we should get along, not why we shouldn't. And we did this before Jamie Dimon and Henry Kissinger, rest his soul, went over to China to say, these 2 countries are really ought to be getting along.

So if you're going to get something going, this is the easiest patch in which to launch this. So we're happy with our partner. We're really -- there's no question about it. Ivo is a working drug and we're pleased to find post a relationship that outside of NSCLC, there may be a bigger opportunity than Insight. So that's what I can say about this.

And the last thing for us was really important because instead to do a Phase I, Phase II, you go right away in the Phase III and shows the Western patients versus Eastern I mean, China versus ex China, U.S. and this consistency of the data, that was the biggest win that everybody wanted to see what's going to happen, what is the China data. So if you look at it in a different angle at the end was a lot of win-win position in this situation to do this study no matter the challenges. But the rest of the study is different because, as you know, the global study mostly is 1/3 China, 2/3 ex China is always now is 1/3 Europe, 1/3 U.S. So it's a different dynamic. This one was very interesting, exceptional trials that we wanted to finish it.

I want to touch on one of the biggest opportunities you have in cancer in your frontline non-small cell lung cancer opportunity here with HARMONi-3. So you've talked about how it's enrolling faster than expected. I don't believe you're going to give us time lines yet, but we'll wait for them. But in the interim, maybe walk us through the Akeso trial from HARMONi-6 that looked at their combination of ivo with chemo in frontline squamous non-small cell lung and just frame that result in the read-through to your study and also the differences that are playing out with your program versus the Akeso trial.

Yes. I think you framed that well, Salveen, in terms of frontline squamous non-small cell lung cancer, ivo plus chemo versus Tislelizumab, which is the PD-1 from BeiGene -- PD-1 inhibitor plus chemotherapy and tisle plus chemotherapy, for example, is approved in Europe as a standard of care for frontline non-small cell lung cancer. And so that study, PFS primary endpoint, squamous but it's PD-L1 all comers, right? So negative low and high. And so compare that against our HARMONi-3 study, which we're enrolling on a multiregional basis. PFS, OS, dual primary endpoints, and we talked about OS a minute ago.

The PD-1 is pembrolizumab in that setting, and it's squamous and non-squamous and of course, multiregional versus single region, right? And so I think as we see -- now as I talked about at the beginning, we saw the PFS to OS and HARMONi-2. We saw the top line data readout from HARMONi-6 in the squamous chemo combination setting. And so now as we look at HARMONi-3, the read-through also is further backed up by the consistency of the results from HARMONi-A and HARMONi as well, right? So more multiregional studies will continue as we go into HARMONi-3 and 7, but it's important that there's now been 3 successful Phase III -- randomized Phase III trials against standard -- globally reputable standards of care, if you will, now run by our partners at Akeso and so as we look at the data, that -- there'll be more data that's disclosed on that in the fall at a major medical conference.

But in the interim, it gives us -- it further validates our confidence within the frontline setting. and it provides additional data points as we look at all of the major milestones that need to be accomplished in terms of the opportunity for ivonescimab to eventually change standards of care on a multiregional basis.

Can you touch on the strategy here for execution across this very broad space with this drug and how you intend to do that and move into various tumor types in a very quick fashion, recognizing that now you have all these followers with other large biopharmas that are doing partnerships with drugs in the same class.

Yes. The ivo is the best drug from everything we've seen and understand. The source of ivo is Akeso and they started in 2013 and brought the product out. As Maky said, there's over 20,000 patients dosed majorly successfully. They're dosing 200 patients a clip a day. Our trials are enrolling -- they're enrolling fast. So we're pleased with all of that. It doesn't surprise us that there are a lot of followers who could be in this business and not see someone with a loss of entity value and approval going in 2028 off-label and not one after. It's a $30 billion business plus there's usually another $20 billion off target from NSCLC.

So when we did IMBRUVICA, we were the only ones until we showed that it worked within 6 months, there were 100 IMBRUVICA patents. So it's not difficult to come up with a molecule. No one has matched the molecule. Those that have created it, have looked at it and said, we are the best. So if you're in a horserace, you want the fastest horse. If you're the fastest horse, you still need the best jockey and we think we're good jockeys, but we think partnering is going to be the way to go to really get it across the finish line.

So we're going to actually engage in that activity. We wanted to show what we could do, what we should do and let the field settle down a little bit, but we're going to be very active in that area. So with the right partner, with the right drug, with the leadership from Akeso in terms of pushing outside the NSCLC arena, we think we're pretty pleased with where we stand here. And we do appreciate competition. It's basically a validation that what we have is right. The great thing about this business is the FDA gives you an AMA work hard on to make sure that this happens, you have a monopoly unless someone is better than you.

So it's not going to be easy to fund the other businesses that have to go head to head with pembro, much less ourselves. We then beat pembro, but we need to establish that partnership and get rolling. But we've let no grass grow under our feet. We've got over 50 ISTs. We also have -- 6 of them have already launched. We have a big partnership with Md Anderson. So there's no one out there now unlike the first 4 months. when we took the drug over, no one knew bispecifics, their activity. No one knew that EGFR was not going to be a major bleeder in this space. No one wanted to partner with China and no 1 really heard the name of Summit. That was a real stiff wall decline, but that's been climbed now. So this is our game to win.

And how are you thinking about it from a combinatorial strategy standpoint across the cancer space with different modalities or target?

The good news is -- and I will let after that, Dave answer more details. But the good news is that we have a very nice safety profile, you can combine with any drug that you want to. We do not -- I mean if it's a combination with the ADC of the world or any other combinations, we are working on that. And while we come up, we will announce it. But you go like any other -- at the end of the day, you are in solid tumors. At the end of the day, you have a patient perspective. At the end of the day, every month count, every day count. At the end of the day, you want to give the best, safest product in the hands of patients at the same time the most efficient drug in the hand of patients.

So we will do everything possible to figure it out what is the best combination that they give these safety and efficacy to the patients. But we have to try it. And on our side, we have 1 product that we can combine it to any other product that we want to with any partners that we want to use. There is no restriction if we did a collaboration with Pfizer doesn't allow us to do with other people on the collaboration with [indiscernible].

Manmeet, maybe you could touch on the balance sheet at this point and what it covers in terms of clinical development.

Sure. So as you know, we finished our Q1 with over $360 million in the bank. We raised around $400-plus million last year. We know that we need capital, right, to continue the development. But we have sufficient -- our run rate for Q1 was approximately $50 million, which will continue to increase, but we have sufficient capital to continue to execute on our current plans. And as appropriate, Bob have always said that when appropriate, we will raise money.

Can you also speak to the manufacturing strategy here?

Sure. On manufacturing front, as you all know, Akeso being the partner and developing ivo, we have been relying on them for doing our clinical trials, and they have been producing. They have gone through their inspections, including FDA inspection for another product. So they have passed through that. In the meantime, we have right to develop in our territories and our territories include U.S., Europe, Japan, Africa and Middle East. We have full rights to develop and manufacture ivonescimab. We initiated tech transfer last year, and we are progressing pretty well on the tech transfer. So we believe pretty soon we should have capability to produce ivo in our own territories, which will help us.

On the cash side, you all are our investors, and you wouldn't be here if cash earned a super huge return annualized, it doesn't. You need to get into equities, you need to get into real estate, you need to do something alternatives to cash. As Buffett said, he's 94 years old. The dollar lost 92% of his value during that period of time. That's not going to change in anybody's lifetime. So there's plenty of cash out there. The question is, does the owner of the cash have confidence in the business and their opportunity. When that answer is yes, the cash transfers, whether it's a recession, inflation or rapid growing economy.

So we have not only the molecule, we have the source of the molecule and relationship with them. We have a -- you check all the boxes, and we are really set to go. We didn't want to compound a potential relationship in the making with raising cash. So we don't need $2 billion on our balance sheet because we're talking about how we can put this company together and maximize the wealth opportunity for the stakeholders in the business in addition to the opportunity for patients and society at large. So when those chips fall, then we can further entertain the question of cash, whether we need or we don't, I don't think we will.

As a last question here. Could you speak to the data sets that we're going to see over the next 6 to 12 months across both your portfolio and Akeso's portfolio? And if there's anything that I didn't ask about that you want to highlight, I would do so as well.

Sure. So -- great set of questions. So thank you very much. So nothing too profound to highlight other than -- so data sets, we'll see HARMONi over the course of fall meetings or whatnot. We'll also see HARMONi-6. So we'll see a multiregional HARMONi, second-line EGFR that we sponsored, HARMONi-6 frontline squamous combination with chemo sponsored by Akeso. I think we'll also -- not a data set, but we'll also give further clarity with respect to the expansion of our clinical development plan. And I think we'll also likely start to give a little bit more for time lines with respect to HARMONi-3, which we started a little while ago. So I think in terms of that, we'll likely have additional other components, but there's no reason to give away the full story before. And it's always good to have something else come into play.

But overall, we have a great product. We have a great team. We have the speed of light. I believe we show it with 185 people. We really did an outstanding job in the past 2 years. We show to the world, and I believe you saw it with every bispecific like a mushroom is coming up that is kind of -- we show the molecule is a significant and important molecule to have. And I -- at the end of the day, again, people, they are afraid of competition, which I'm not because I believe every patient deserve to -- the product that is working on you perhaps is not going to work on me. So at the end of the day, we'll do everybody possible to bring the best product in the hands of patients.

So we are in a great shape. That's the only thing I can say. The entire team is working very, very hard, and we have a great physicians, as Bob said, our ISV program is moving very, very nicely in the different indications. Our partner did an outstanding job as well. Bringing 11 Phase III trials in such a short period of time is important and significant. And we are very, I cannot say lucky, but I'm just saying we are pleased that they start the Phase III, and we can take it and bring the data and start our Phase III. So we don't need to go to the Phase I, Phase II process right now. We can catch the data from our partner, Akeso, and start right away another Phase III for sure. Our regulatory group from China and U.S. is different. That is why we powered our trials there have more patients because we power for the OS and PFS. So that's where we are.

Before we end off, let me give a shout out to Salveen and her Goldman Sachs team. They do an unbelievable job of following this company in depth. it's not easy, but we're really appreciative in the work that Goldman does for all of us to bring liquidity to markets like we participate in. So thank you so much, Salveen.

Thank you.

Thank you.