IDEAYA Biosciences Inc Aktie

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's a great pleasure that I'd like to welcome the IDEAYA team today. We've got Yujiro Hata, the CEO; Josh Bleharski, the CFO; and Mike White, CSO. It's fireside chat format. To start off, Yujiro, maybe give a brief intro to IDEAYA, and you guys had an announcement this morning with the collaboration with Roche. Maybe provide some key highlights for that.

So Maury, thanks for the introduction, and thank you to Jefferies for the opportunity to participate at your Annual Global Healthcare Conference. So Maury, as you noted, in terms of IDEAYA, we did have an announcement this morning, which we'll cover. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We just came from ASCO where we had a late-breaker oral presentation this past Monday, which was the full complete data set around our top line results for the frontline HLA-A2-negative metastatic uveal melanoma. We have begun the -- under RTOR, the pre-submission process -- pre-submission module 1 has been officially submitted as of a few days ago. So all of that is tracking forward. In addition to the frontline HLA-A2-negative metastatic uveal melanoma with our global partner, Servier, we have two additional randomized Phase III studies that are now either kicking off or ongoing, including in the neoadjuvant setting as well as in the adjuvant setting. Beyond that, we have a very deep pipeline, including a Phase II DLL3 Topo-ADC molecule that is being advanced for both small cell lung cancer and neuroendocrine carcinoma. We also have two clinical assets in PRMT5 and MAT2A, in the area called MTAP deletion with a significant focus in pancreatic cancer as well as non-small cell lung cancer. We did announce this morning a new collaboration with Roche, specifically to do a combination with their Phase I pan-RAS inhibitor. with IDE892, our potential best-in-class PRMT5 inhibitor. And this is specifically going to target MTAP deletion pancreatic cancer, and I'm sure we'll talk about that. Perhaps the last asset I'll mention is IDE574, which is a first-in-class dual inhibitor of KAT6, 7. Here, a significant focus in breast cancer, colorectal cancer as well as other indications.

Got it. Great intro. And we always run out of time at the end. So maybe let's start off with Roche first. Maybe talk about why you picked that compound. Did you see preclinical data or something that gave you confidence that this is the best drug to combine with? Maybe talk about that.

Yes. Look, the parties did your typical diligence as part of the discussion around the clinical collaboration. Our perspective on this is that the real, we think, significant opportunity moving forward is can you deliver a greater efficacy and patient value in the earlier line settings of indications like pancreatic cancer. And we believe a lot of that is going to be through enabling rational combinations. And within that context, Maury, our view is that we have the opportunity to have a potential best-in-class combination with their pan-RAS inhibitor with our PRMT5 inhibitor. Beyond that, I think Roche should be the better group to answer questions as it relates to their specific molecule. But we feel very good about what we're able to observe, and we're excited to get this collaboration going.

And anything more on where you're at with your PRMT5 and anything on time lines for getting to the combo and what that could look like?

Yes. So what I can tell you with IDE892, and we also have Mike White here, our CSO. So I'm sure Mike could also jump into why we're excited about the mechanistic rationale of this combination. The dose escalation has been going very well. We believe based on the human PK data that we've seen, we're going to have a very favorable pill burden size. We also believe we've substantiated some of the key sort of premises of this molecule and why we believe that has a potential best-in-class profile. We will be commencing the combination phase for this program in about a week. I actually just checked in with the clinical team yesterday. We already have multiple patients in screening to start the IDE892 and MAT2A combination, which, as you know, Maury, is a big focus for us in MTAP deletion lung cancer. So that should be within days that combination is going, which implies we've already cleared multiple dose cohorts. The monotherapy expansion will also begin here relatively shortly, we anticipate in the second half. There's significant focus on pancreatic cancer, obviously, to also generate the contribution of components data we would need for combination work we would do ultimately moving forward and then as well as in non-small cell lung cancer.

Got it. And all really helpful. And for your PRMT5, maybe talk about how you think about the dose range compared to the Tango drug and the Bristol drug.

Yes, Mike, do you want to take that? And obviously, we can't specify a specific dose at high level.

Yes. So we're very excited about this compound. When we made this, it was really with an eye towards optimizing specificity for MTAP, making sure that we were MTA cooperative, but also SAM competitive. So we're very clean. That meant that we have a safe starting dose that's very close to our anticipated efficacious dose. which means that we're going to be ready to go into combinations very soon. And we have a PK profile that together with what we're seeing with respect to tolerability and our perceived tolerability with respect to this profile, also a very nice PK, no pill burden, no getting up to high doses where we're going to start to engage other targets. So we're excited about that aspect of the combination as well.

And also, Maury, I did forget to mention for the Roche collaboration. I think what is also unique about our collaboration with them is we also have the ability, and this would require approval by both IDEAYA and Roche, but a combination triplet with the pan-RAS, our PRMT5 and MAT2A. And we do think that could be a key point of differentiation. Obviously, that's going to be further afield, but we think a key potential path to differentiation.

Got it. Really interesting. And then for the combo with MAT2A, how are you setting expectations there for what you want to see on response rate and safety? And I don't know if you're setting expectations for what you want to see with the pan-RAS inhibitor, too, if you've kind of thought about that already. Some other companies have commented there, but...

No. Look, I think for both combinations with non-small cell lung cancer, maybe we'll start with that one. We've already seen some clinical combination data and at least Mike should comment here. But our anticipation is that we will likely be at an efficacious range at the first cohort, the first combination cohort. Based on what we've seen in the past, our anticipation is that we should have the ability to identify several combination cohort doses we should be able to move forward with. Second is that we should see responses at subtherapeutic doses of PRMT5 monotherapy. And ultimately, the real premise of this combination is going to be to drive greater -- both response rate and durability. So I think that's our expectation. We're not going to throw out a specific number, but the bar will be high. So I don't know, Mike, do you want to comment on that or also on the pan-RAS comment?

Yes. So one of the things that's important to us is that combination, the PRMT5/MAT2A combination allows us to really reduce the dose intensity for both of those molecules and get spectacular preclinical efficacy and durability. And the durability piece is very important because what the MAT2A inhibitor brings on board is intercepting escape mechanisms, particularly escape mechanisms due to cell fate transitions and epigenetic alterations. And I want to bring that to the pancreas cancer piece, very excited there because the KRAS combination or the pan-RAS combination in the KRAS mutants, that's exciting in pancreas cancer. All -- virtually all MTAP pancreas cancer patients have KRAS mutations. And this combination, in particular, the triplet gives us multiple mechanisms of action that will combine with each other, we think, to give deeper and more durable responses. So one, you have the co-alteration piece of hit it from two different sides. But two, as was presented by a number of laboratories at the AACR this year, the mechanism of action of MAT2A and PRMT5 to perturb splicing also directly perturbs the machinery that KRAS uses to activate the MAP kinase pathway. So we actually weaken the ability of RAS to drive tumors. And the third piece is that the MAT2A inhibitor restricts the cell fate transitions that occur, which seem to be one of the major mechanisms that drive bypass to monotherapy, mono-RAS therapy.And the third piece is that the MAT2A inhibitor restricts the cell fate transitions that occur, which seem to be one of the major mechanisms that drive bypass to monotherapy, mono-RAS therapy. So that triple combination could do something really important in the pancreas cancer setting.

Got it. All really helpful. And let's shift gears. The daro story has been front and center for IDEAYA for a while, and you guys had positive Phase III data with a 6.9 months PFS, 0.42 hazard ratio, and you just presented this at ASCO as a late breaker. Maybe talk about just the key takes that investors need to know from this program and next steps as well.

Yes. I would first start with metastatic uveal melanoma continues to be extraordinarily high unmet medical need. Unfortunately, for patients, there are currently no FDA-approved therapies in HLA-A2-negative metastatic uveal melanoma. And we believe, based on the data that was just presented at ASCO has the opportunity, as the discussant noted at the presentation, the opportunity to be the new standard of care in HLA-A2-negative metastatic uveal melanoma. So that's extraordinarily exciting, Maury. And what is that based on? That's based on the strength of the data that was presented on Monday. First, just for the listeners that may be less familiar, when you look at the clinical efficacy profile, we demonstrated a confirmed response rate by both central review as well as investigator scoring that was trending towards 40%. Just put in context, the control arm response rate was sadly mid-single-digit percent. And in fact, by investigator scoring, it was roughly 2%, which shows you how challenging this indication is. Next, when you look at median progression-free survival, here, we more than doubled what was seen in the control arm, which was primarily ipi/nivo. So I think the clear win on progression-free survival. Hazard ratio was 0.42, was less than that by investigator scoring and a p-value of less than 0.0001. So all statistical measures, it's clearly mission accomplished. From a safety perspective, just high level, we saw less SAE rates, less discontinuation rates than the control arm. So as well as from a safety perspective, we think significant potential advantages when you look at safety. So obviously, with any kind of new therapy as a potential standard of care, you always want to look at both the risk as well as the benefit in both parameters, we think the molecule is positioned extremely well.

Got it. That's helpful. And you mentioned that the first RTOR module was submitted. Can you just clarify what was in there? And then what the time line could look like for the remaining modules?

Yes. So the FDA with the RTOR presubmission module 1, 2, 3, there's actually some fairly clear defined parameters of what they want to see within those modules. I'm not going to go through that -- all those specifics. You can actually go to the FDA website, and that's all available online. The next presubmission module is a few months away. And then the final third is typically filed with that final submission process. And typically, that would see companies in our peer group try to get that filed within roughly two quarters. And so we're tracking along that. As you know, Maury, we also have Fast Track designation. So we would get expedited review. And now with RTOR, we would anticipate having a further acceleration of that review process since they're now reviewing the data real time. So I think that's going to be great and hopefully can pull in that launch timing.

Got it. And you commented on the potential to include the HLA-positive data in the filing. I guess, where are you at with conversations with FDA around that? Have you already spoken with them on that point?

Yes. So the quick summary is, yes. Discussions have occurred with the FDA on the HLA-A2 positive piece of it. And those discussions will continue, including for the pre-NDA meeting that's already penciled in the calendar. So -- but the preliminary discussions have occurred.

Got it. And so that will be confirmed at the pre-NDA meeting. Are you saying more about timing for when?

We're not saying more about the timing. But yes, that's correct. We would anticipate we'll have further clarity as part of that pre-NDA meeting.

Okay. And would that be included as a rolling -- part of the rolling submission? Or would that be a major amendment for the HLA-positive data?

So one is we would have that conversation as part of this pre-NDA meeting. I think, Maury, here we probably don't want to get into too many specifics on regulatory pieces there. But I would say kind of base view is if that is the path forward that is available, we will submit that as part of the NDA. It would likely be staggered from the full submission.

Got it. Okay. And you've highlighted an early OS trend at approximately 10 months of follow-up with the potential to extend that by 6-plus months. What are the key drivers and options involved with your next OS cut for FDA? And do you see a path to stopping the study early given control patients can't cross over to combo?

Yes. So we are seeing an early trend in OS for the treatment arm versus the control arm. We noted that as part of the top line results. That was with fairly minimal follow-up with just over 7 months, but I think that's encouraging when you see an early trend even with only a fairly minimal follow-up in the study. So in terms of additional updates moving forward on OS, our view here is that the current projection for the interim OS analysis is middle of next year. But you are correct, Maury, that at the time of the NDA submission, the FDA will want to have as part of including the safety database update, where we are on the OS events. And as part of that, because there is no crossover in the study, there is a scenario we may get full approval. But just so this is clear, that is not what we view as base case, but potential upside scenario.

Got it. And for the amount of time of OS follow-up that you could have, are you commenting more on what that could look like, what the range could be?

In terms of -- at the time of the NDA submission, no, we're not. The cutoff for the top line results was end of January. So I think here, it's going to be roughly 6 to 7 months more follow-up, something in that time frame.

Got it. Okay. And you showed -- you got the hazard ratio of 0.42 from the study, which is meaningfully better than KIMMTRAK's 0.76 hazard ratio. How do you think about pricing here? Could you price at a premium versus KIMMTRAK -- or what other variables should we be thinking about?

Yes. So that's work that is ongoing right now, Maury. Obviously, as the data evolves, we want to take that into consideration as we think about pricing. I know as you throw out other competing drugs in the space, KIMMTRAK is obviously one analog. Yes, I think depending on how the data shakes out, we do think there's an argument to be made for pricing at parity or even at a premium to KIMMTRAK. But ultimately, we want to make sure that we take the full data set into account as we make those decisions.

Got it. That's helpful. And for the pivotal study, what are you seeing on median duration of treatment?

Yes. I mean what we've seen so far is 10 months. So that's sort of what our clinical trial experience has shown to date. I think there's a path for that to extend beyond that in the real-world setting, depending on where we are. But that's sort of what the data has told us thus far.

Got it. Okay. And for later this year, you're going to have the HLA positive data update expected at a medical conference. How should we think about the frontline versus second line post KIMMTRAK split within the 85-plus HLA-positive patient cohort? And how are you setting expectations for median OS, median PFS and ORR relative to what you've observed with the HLA negative?

Yes. So the majority of the patients, Maury, will be pretreated patients. So we're not sort of specifying beyond that, but the majority will be pretreated. And as you noted, we'll have a full data set for all comers as well as the frontline patient subset. -- including response rate, PFS as well as median overall survival, which will be important, obviously, because we are going into an important interim OS analysis. And then this will be the second time we're now sharing median OS again, granted it is from a single-arm study, but I think hopefully a useful data point. I would say the high-level takeaway, Maury, hopefully, people will take from the data set is that our view is the data is very robust and also consistent with what we've seen in HLA-A2 negative. And we've said that in the past that the fundamental underlying biology is around the activating mutation of GNAQ/11, and it is agnostic of specifically HLA-A2 status.

Got it. And for patient baseline characteristics, overall, those are pretty similar to the HLA-negative patients.

For -- yes. For the frontline patients, we would anticipate that would be the case, but this is a much more limited data set than what we just shared at ASCO, right? That was at least from a safety perspective, and that was over 400 patients.

Got it. Okay. Makes sense. And you're going to have the neoadjuvant data update at a medical conference second half of this year as well. How mature will the data be across the plaque brachytherapy and nucleation cohorts? And how many patients are going to be evaluable for radiation reduction?

Yes. So there will be roughly just about 100 patients. There will be more follow-up from what was provided in the past. That will be split a bit more, I believe, nucleation than plaque therapy. We're not saying how much data as it relates to actual visual acuity data.But Maury, as you know, even for that, it's still, I would say, early. I would say we need to have continued follow-up. We will have a refresh on the percent of patients that we preserve the eye, which just as a reminder, that is the primary endpoint for full approval in the nucleation cohort. So I think for the plaque therapy, it will likely be more related to this predicted visual acuity tools that we've shared in the past. And I think for EFS as well, we may have some high-level commentary, but I suspect for event-free survival, it will also be still immature. But we are tracking the EFS data from the single-arm study piece. And since we're on the topic of neoadjuvant, one other I will mention is that similar to our strategy for HLA-A2 positive with compendia, we will also likely pursue the neoadjuvant indication as well in the U.S. for compendia based on this data that we'll be publishing.

Got it. Okay. So that could get added to guidelines. You could potentially start getting some uptake there commercially once you're commercial setting. Okay. And for the adjuvant study, I wanted to ask about that, too. So starting first half of this year. It seems like the base case -- base case scenario, the study could take about 3 to 3.5 years. What can you say on powering assumptions for interims relative to Immunocore's adjuvant Phase III, which assumes hazard ratio of 0.55 with an interim analysis at 76 events and 56% probability of early stopping.

Yes. So the study, maybe just kind of base parameters here. So it's 450 patients. Primary endpoint is superiority for relapse-free survival, target hazard ratio of 0.65. So our study is more powered than the peer company that you noted. The randomization will be 1:1. The randomization will be against observation. And importantly, it will be agnostic of HLA-A2 status. So much larger pool of patients will not require HLA-A2 status testing. So I think those are hopefully answered most of your questions there.

Yes. Yes, that's helpful. And let's shift gears to -- well, I guess, anything more about getting that study up and running and how should we think about that?

No, we're ready to go. So we had the Type C meeting with the FDA with Servierrecently. We essentially got everything that we had hoped for and asked for. So now we have obviously a very deep relationship with all the key sites globally. And I think what we can say is there's a tremendous amount of enthusiasm to get this study. And our anticipation is that this study should enroll very rapidly. So -- and again, here, the drug is clearly working in the metastatic setting, including at least based on single-arm data survival. So we think this is a very high probability of success study. We're essentially randomizing against nothing.

Got it. Makes sense. So let's shift gears, talk about DLL3, your ADC there. Maybe starting off with the small cell update. How are you setting expectations on PFS? And could we get other efficacy details based on the patient's prior line and/or breaking it out by dose.

Josh, do you want to take that?

Yes. So we'll have 2 updates on DLL3. The first is actually Hungary's update from their Phase I study in China. There, we anticipate updates in both small cell and neuroendocrine. It will be a refresh of the data they shared last year at the World Lung Conference. We'll see updated PFS, obviously, safety, response rate, PFS. And then importantly, for the first time, landmark OS data. So that will be sort of, to our knowledge, the first look at how a DLL3 type 1 ADC performs from an overall survival standpoint. So that's very exciting. And then in parallel or sort of a similar time frame, we're going to have our update from our ongoing Phase I global study. And I think there, the focus will be primarily small cell. We do have some early look at safety and probably response rate. I don't think we'll have enough to comment on PFS at that point, but we'll see. And we anticipate that will be roughly 30 to 40 patients.

Got it. Okay. Helpful. And should we expect intracranial overall response rate data in patients with baseline brain mets in this update?

Yes. I would expect -- definitely Hungary had that data set originally in their data last year. We expect there'd be a full refresh of that as well. So yes.

Got it. And for the next -- the NEC population, should we expect a similar number of efficacy evaluable patients relative to Zai Lab's update where they had about 34 evaluable? And how should we think about tumor heterogeneity in the setting?

Yes. So the exact numbers, we're not going to specify here, Maury. But look, there will be enough patients on the neuroendocrine carcinoma. This is not for Hungary's data, where I think people will have a good sense of what we're seeing both in terms of response rate as well as progression-free survival. In addition, we've also begun enrolling in the U.S., Europe, outside of China, and we've also -- probably about half of our patients have been in neuroendocrine carcinoma. And really, the quick summary there is we believe we're seeing activity that there should be a monotherapy approval path forward here based on what we're seeing and based on what else is out there. In terms of the heterogeneity of this population, maybe Mike, you can talk about that. But yes, there are several indications of note. Some have higher DLL3 expression than others, but Mike?

Yes. We're obviously focusing on those indications where DLL3 positivity is known to be high. And that's something that we also are excited about with respect to IDE161, our PARG inhibitor. So what does heterogeneity mean? It means for an ADC that you could get less tumor exposure to the payload. IDE161, the PARG inhibitor, its mechanism of action is to amplify the therapeutic effects of what would otherwise be a suboptimal delivery of that payload. So that's where we see a real opportunity in the combination setting.

Got it. And for picking tumor types, that's one thing, but I guess, could you select for patients that have high DLL3? I think Amgen's moving forward with a higher 30 mg dose, and they're seeing better efficacy in patients that have a higher DLL3 expression.

Yes. So for small cell lung cancer, we don't think that's going to be needed. For DLL3, that's something that we're discussing. So I think we don't want to give too much visibility in our regulatory strategy for competitive reasons. But I think here, I think more big picture, there are some neuroendocrine carcinomas that have very high DLL3 where we think that's not going to be needed. And then you can think about following that with, let's say, a pool of NECs where something like a diagnostic could be more helpful. So more to come on that front. And hopefully, we'll be able to share more before the end of the year on that. But we are clearly -- we have our strategy, and I would say we're -- we have a strategy on what we're going to do on that question.

Got it. Okay. Mike, you mentioned the PARP combo. Could we see some data from that by the end of this year?

We're pushing the team. So the dosing has just begun. For those that may not be as familiar, this is a proprietary combination that we have clinically. Our view is that the PARP mechanism may have the opportunity to extend the durability of the topo ADC class. We have very strong preclinical data to support that. We've now begun the combination dosing in patients with DLL3. So we'll push as hard as we can, Maury. I think a lot of it will just be about how many patients do we have. And to really get good visibility on this question, I think durability is going to be important.

Got it. Okay. And at ASCO, I was part of conversations around KAT6. People were talking about KAT6 and breast cancer. You've got the KAT6/7 that you're dose escalating in breast, prostate, colorectal and lung. Can you talk about the strategy here and what improvements you want to see in some of these indications, including breast cancer?

Yes, Mike?

So this is a very exciting asset. This is something where I think people are really starting to appreciate the importance of maximally suppressing the epigenetic mechanism. And to do that, you need to bring KAT7 on board. And so having a dual KAT 6/7 inhibitor, we've shown -- now Pfizer has shown as well that, that's an optimal profile to be able to drive monotherapy responses in a preclinical setting. We're expecting that to happen in patients as well. very excited about the opportunity in p53 mutant MSS, colorectal cancer, especially because that tumor is very heterogeneous because of epigenetic mechanisms that promote diversity. We intercept that with a KAT6/7 inhibitor. If you don't have KAT 7 inhibitor -- inhibition on board, you can't get that phenotype. We're also very excited about large lung cancer cohorts that are addicted to the alveolar type 2 lineage program. That's a large section of lung adenocarcinoma. Again, you cannot get efficacy in models, PDX models without having KAT7 on board as well with the breast cancer setting. Estrogen -- positive estrogen receptor positive breast metastatic breast cancer, we're expecting to see monotherapy activity there equivalent to what you might otherwise get with a KAT6 inhibitor together with an estrogen inhibitor. The reason the KAT6 inhibitor needs the estrogen inhibitor is because it cannot sufficiently suppress that pathway on its own. A dual inhibitor can do so independently of the presence of an RB mutation, independently of the presence of an estrogen receptor mutation. So we're very excited about that one.

And I think we're out of time. So maybe to close up, if you just want to highlight key catalysts ahead for IDEAYA.

Yes. I think the message for the second half of this year is we have a lot of catalysts upcoming. So I know we've covered a lot of it already today. But for darovasertib, obviously, everything that we're doing on the NDA submission in the second half, commercial preparation. We have about 100 patients worth of data in HLA-A2 positive. That's already been submitted for a major medical conference. The roughly 100 patients in neoadjuvant as well has already been submitted at a major medical conference. We have the DLL3 Phase II Topo-ADC. Our partner, Hungary will present about 100 patients worth of data in small cell neuroendocrine, including with landmark OS data. We'll also present on our side from the U.S., Europe, non-China studies. And we're pushing hard also on the bispecific ADC. We didn't cover B7-H3/PTK7. We have a clinical update. We're guiding towards by the end of the year. And obviously, now with our Roche collaboration moving forward, hopefully, we'll be announcing our MAT2A PRMT5 FPI combination start here very soon as well. So look for a very catalyst-rich second half.

Got it. Thanks so much for joining us today.

Thank you so much.

Hello everybody. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the senior biotech analysts here at the bank. Our next presenting company is IDEAYA Biosciences. And sitting up here on stage with me are two members from the management team. We've got Yujiro Hata, who is Chief Executive Officer; and Josh Bleharski, who is, of course, CFO. Gentlemen, thank you for making the trip to see us today.

Tazeen, thank you.

Thanks so much for hosting us. Tazeen, really pleasure to have us. And Josh and I are looking forward to the discussion today. Thank you.

Okay. So really quickly, for those who may not be as familiar with the company, can you just give us an overview of IDEAYA sort of the platform, where you are in terms of developing some key data catalysts and we can go from there.

Sure. So IDEAYA Biosciences, we're a leading precision medicine oncology company. Our lead program is darovasertib. We just recently had top line results in first-line metastatic uveal melanoma. We also recently just received Fast Track designation. So we'll be submitting our first pre-submission for the NDA next week. And so that's all going as planned.

We also have two additional Phase III registrational studies that are ongoing beyond metastatic uveal melanoma, including in a neoadjuvant setting as well as in the adjuvant setting outside of the U.S. We have a global partner in Servier, which we're very excited about as well.

Beyond that, Tazeen as you know, we have a very deep pipeline precision medicine oncology. We're very excited about what's coming ahead as well in our next assets. And here, I will probably next focus on DLL3, our Topo-ADC IDE849. We are targeting to start a registrational study by the end of the year. Our partner Hengrui in China as well is planning to start registrational study by the end of the year. Here, the key indications are in small cell lung cancer as well as neuroendocrine carcinoma. We have 2 clinical data updates we're guiding towards as well in the second half.

Beyond that, we have a deep clinical pipeline and MTAP deletion, both what we believe is a first-in-class PRMT5 inhibitor as well as a potential first-in-class MAT2A inhibitor. Here, we have a significant focus on MTAP deletion PDAC as well as in non-small cell lung cancer.

We are also evaluating opportunities to enter into the RAS, KRAS space in terms of combinations, so more to come on that front, which we're quite excited about. Beyond that, I would say probably the next program I would mention is a Phase I KAT6 dual inhibitor. There are only 2 clinical assets here. It's us and Pfizer. We have key focus here in breast cancer, prostate cancer, CRC and so a lot of excitement and enthusiasm. So as you can see, a very deep pipeline going after very large solid tumor indications.

Okay. Yes, you've got a lot going on. Let's try to do some of these in order of near-term events. So for the top line that you reported for the OptimUM-2 study, can you give us a little bit of detail on that? And what the next steps are in that program?

Yes. So here, for folks that may be less familiar with this study. So this is a combined accelerated approval and full approval study that we designed. The primary endpoint for accelerated approval is median progression-free survival and for full approval is OS. What we reported was a PFS of 6.9 months in the treatment arm and 3.1 months in the control arm, which led to a hazard ratio of 0.42 with a p value of less than 0.0001. So great result really puts us on track for that NDA submission. So that's really been the focus.

You may also know that last fall, we also reported OS data. This was single-arm OS data just over 21 months. We think a historical OS here is going to come in roughly in that 12- to 13-month range. So we feel also good about OS. We did note as part of the top line results, a preliminary trend, a favorable OS trend as well. We will have an ASCO late-breaker oral presentation on Monday, June 1. So that's exciting. Here, we'll just provide a more fulsome update. So in addition to the PFS Kaplan-Meier curve, which we showed, we'll have a full CT scan waterfall, both treatment control arm, both by central review as well as investigator scoring, including just a full safety data set as well.

Okay. And can you just talk to us about what the competitive landscape looks like here?

Sure. Josh, do you want to take that?

[indiscernible] There really isn't any improvement. Current standard of care is checkpoint inhibitors and chemotherapy. And that was what we had in our control arm in the study that we just reported out. On the A2 side, there is an approved agent. So we'll also explore the efficacy of the [indiscernible] combo in that setting as well nature of the authorities with the FDA on that as well.

And what do you think is the total addressable market opportunity for your product once approved?

Yes. Look, we think this could be a very significant opportunity, obviously, within the A2 negative setting which is where we're primarily focused with A2. We think there's roughly what -- 1,500 patients in the U.S., the majority of which are A2 negative. Again, it kind of comes down to where we land on pricing and duration. Those would be 2 of the major drivers that dictate kind of market opportunity. But we think it's quite significant and you start to factor in a potential uptake in the A2 setting as well as in the primary setting in neoadjuvant and adjuvant setting, those opportunities start to add up.

Okay. For the A2 negative population, how easily are they found?

Yes. I mean so a lot of those patients are treated in concentrated centers [indiscernible] Fortunately, through the work we know where patients are, but there is a long tail of patients that are treated in the community setting. So we're working hard to identify them so that we can reach as many as quickly and efficiently as possible if and when we get approved. And that will rely on sort of a grassroots kind of feet on the ground strategy as well as data and analytical strategy that will complement our sales effort.

Okay. And so given that this is an ultra-rare indication, what's the range of pricing that we could use as comps. Obviously, you're not going to announce price to us today. But as people try to think about range, what do you think would be good comps here?

Yes. I mean that's work that's underway right now. As you said, I don't think we're ready to comment much specifically around pricing. Look, I think what we want to do is look at the totality of our data and price the drug appropriately based on the benefit that we deliver. There's obviously an approved analog out there that I think many people point to. That's not a bad place to start. Again, I think it will have to -- we'll have to see how our data matures, both on the PFS and then overall survival side. But we feel pretty good about the profile and the benefit that we've delivered.

Okay. And so in terms of investments in setting up for a commercial organization, how big of a footprint do you think you'll need for this indication?

Yes, that's a great question. So we think it's a pretty modestly sized sales force based on some of our peers in the industry and the model that they have employed, we think this would be a pretty conservatively sized sales force, and we will be able to effectively target this opportunity in the U.S. And that work is all underway right now.

Okay. And how long do you think it will take over time to expand into those larger populations that you just mentioned?

Yes. So I mean, I think, again, we'll -- we have those registrational studies up and running in the neoadjuvant setting. In the adjuvant setting, we will start that trial imminently with our partner, Servier. That data is going to take a little bit longer to develop and mature. So those are likely several years out on the metastatic launch. However, we will look at ways to accelerate getting into those patients, particularly in the neoadjuvant setting using some of the data we've already generated in the 09 study. So we're going to be looking to publish that data and look for ways to maybe accelerate that potentially through a compendia guideline strategy.

Okay. Go ahead.

And I think just on the other -- on the adjuvant side, we'll be launching that study here shortly, 450 patients. We think enrollment should go quite rapidly for that just based on the demand. There's nothing approved in the adjuvant setting. We will be HLA agnostic. And then also because we'll be focusing on the high to high medium metastatic risk population, also that RFS readout, hopefully will be expedited based on that as well.

Okay. In the few minutes that we have left, maybe we can talk a little bit about some of the pipeline programs, Yujiro, that you mentioned. Maybe let's talk about 849. You mentioned DLL3 positive tumors. How should we be thinking about the opportunities there?

Yes. Look, it's a very sizable patient population. So in terms of the indications of focus for DLL3, I would say first is small cell lung cancer, right? You're talking about an annual incidence globally that's at least 100,000 patients or more. Here, DLL3 is broadly expressed in small cell lung cancer. So we don't anticipate we're going to need to patient select. In neuroendocrine carcinoma as well, also a very sizable population. U.S. alone, you're talking 20,000, 30,000 patients a year. So I think a lot of significant interest there, very high unmet need, as you know, in the neuroendocrine carcinoma space, response rates are even in the teens range, typically, when utilizing chemotherapy. The last indication, we do have quite a bit of interest in is also in melanoma. We know DLL3 upregulation has been high there as well. We have not evaluated patients there yet, but that's also another area that we'll be focused on.

Okay. So how do you prioritize which indications you want to focus on first?

So I would say that right now, our primary focus is in small cell lung cancer and in neuroendocrine carcinoma. I would say the first registrational study we want to launch will be a monotherapy registrational study. We're evaluating both later-line small cell as well as neuroendocrine carcinoma. We're also considering sort of a basket type approach as well to see if we can pool all those populations together.

In terms of frontline strategy there, I think that's going to be mainly focused on small cell lung cancer. And for that, you will likely need to do that in combinations, looking at assets like PD-L1. You may know we've recently put a relationship in place with AstraZeneca. We're also doing a proprietary combination with our PARG inhibitor. That could also potentially enable a chemo-free regimen as well. So I think a lot of opportunity there. That will likely be more focused on for next year.

Okay. So in terms of data catalysts for this program, are you going to have -- it seems like you'll have a few next year.

So on DLL3?

Yes.

Yes. So actually, by the end of this year, we'll have 2. One will be our partner, Hengrui's update from their Phase I China study. So that will be over 100 patients. It will be a pretty robust data set both small cell and neuroendocrine carcinomas. And I'd expect that to be a pretty fulsome update from what they showed last year at the World Lung Conference, including potentially an OS cut, so landmark OS data for the first time. So that's exciting. And then in parallel, we'll look to provide an update on our Phase I, IDEAYA sponsored trial with DLL3. And that will be obviously in small cell and neuroendocrine carcinomas. We'd be hoping to show response rates in different tumor types and just probably get a sense of initial activity. It will be probably too early for PFS data, but hopefully, we'll get to see safety and some preliminary signs of activity.

And how many patients' worth of data would that be?

Hopefully, it's 30 to 40. That's what we're hoping for.

Okay. So it's basically a basket study.

Correct. Yes.

Okay. And sorry, Yujiro, you were going to say something.

And Hengrui's data is going to be over 100 patients. So in aggregate, it's going to be a large data set. And I think the other piece we can mention, even based on the early data, the data has been very, very consistent in China and outside of China.

Yes. How derisking is that Hengrui's data going to be for your own study?

We think it's going to be very derisking. And look, we think a lot of the key questions around the DLL3 Topo-ADC space is around durability and we did share some preliminary PFS data at the World Cancer Lung Conference last year, but there wasn't a lot of follow-up. Now there's a year more follow-up, a much larger denominator. We're seeing consistency with the China and non-China data. And now for the first time, we'll also have some landmark OS data. So we're going to answer a lot of questions. In our view, based on what we've seen is we believe we've got a potential best-in-class asset here. So definitely want to pay attention to it.

Okay. And are there other companies looking at the same mechanism?

So in terms of DLL3 Topo-ADC, there's us, there's another biotech company, Roche is also in Phase I with their asset. On the T cell engager side, there's Amgen and Delta. There are several other pharmaceutical companies. So a lot of activity here. I think our view is we have the opportunity to have a best-in-class DLL3 Topo-ADC, but also potentially have a backbone type therapy broad across all of DLL3 and small cell lung cancer.

Okay. And then last question is how do you think about the toxicity profile?

So, so far, it's been very, very solid. I mean I think here, it's been mainly around myelosuppression, I would say consistent with what you've seen with Topo-ADC. I think the advantage we may have with the DLL3 antigen versus, let's say, B7-H3 is I do think we are seeing less ILD in particular, and which we think makes it potentially the preferred antigen target for small cell lung cancer and that could become important as you start thinking about other combinations, whether that's with PD-L1 or with T-cell engagers.

Okay. Perfect. With that, our 15 minutes is up, but thank you guys for making the trip over here. And we appreciate you taking the time, and thanks, everybody, for listening.

Great. Thanks so much.

Thanks, Tazeen.

Good morning, and welcome to the IDEAYA Biosciences webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the IDEAYA Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host, Yujiro Hata, Founder and Chief Executive Officer of IDEAYA Biosciences. Please go ahead, Yujiro.

Good morning. I'm Yujiro Hata, CEO of IDEAYA Biosciences, and I will be your host today. Please note, we'll be making forward-looking statements, and please refer to our SEC filings as appropriate. I welcome all of our online attendees and speakers to discuss the top line results from the OptimUM-02 study. I'm delighted to introduce our webcast participants, including Dr. Meredith McKean, a distinguished KOL and oncologist from Sarah Cannon Research Institute, alongside Chief Medical Officer, Darrin Beaupre; and Chief Financial Officer, Joshua Bleharski. For today's agenda, Darrin, our CMO, will provide a brief introduction of darovasertib and the OptimUM-02 study design, followed by a summary of the top line results.

Once the prepared remarks have concluded, we will open up the line for the analyst Q&A portion of the webcast, where Dr. McKean will also participate alongside IDEAYA management. Today's Phase II/III registrational trial results are an accumulation of over 5 years of clinical development activities, where our organization worked in close partnership with the U.S. FDA, patient community and leading clinical investigators globally. Importantly, the PKC and c-MET combination rationale was discovered by IDEAYA scientists, and we went from research bench discovery to dosing our first combination patient in the clinic in less than a year.

The OptimUM-02 study represents the first frontline randomized registrational trial in HLA-A2-negative metastatic uveal melanoma, which we believe represents the majority of the mUM patient population. Next, this study is also the first randomized frontline registrational trial in mUM to utilize ipi/nivo in the control arm, which is the preferred investigator choice therapy in the U.S. versus PD-1 alone. Lastly, as Darrin, our CMO, will share, this is also the first time frontline randomized registrational trial in HLA-A2-negative mUM to demonstrate a statistically significant clinical benefit versus investigator choice therapy arm for both PFS and ORR, highlighted with a p-value of less than 0.0001. With that, Darrin, please take it away.

Thank you, Yujiro. So let's start the discussion this morning with a little background around uveal melanoma. Next slide, please. Uveal melanoma is the most common ocular tumor of the adult eye. Although fortunately, it remains relatively rare and is an aggressive form of cancer with a poor prognosis. In the United States, there are about 3,000 newly diagnosed cases per year and approximately 10,000 cases reported globally. Uveal melanoma comes in 2 forms, one that is HLA-A2 positive and a more common type, which is HLA-A2 negative. With respect to primary management of localized uveal melanoma, approximately 20% of patients will require enucleation for which the eye is removed.

The remainder typically undergo either proton beam or plaque brachytherapy, which may create permanent vision loss. Unfortunately, about half of the patients diagnosed with this disease will develop metastases, which is associated with a median overall survival of approximately 10 to 12 months and a 5-year survival rate of approximately 15% to 20%. There are limited treatment options available for patients with metastatic uveal melanoma. Liver-directed therapy is sometimes utilized, but most patients require some form of systemic therapy. For HLA-A2-positive subjects, there is one approved product known as KIMMTRAK. For HLA-A2-negative subjects, there are no approved therapies, although immune checkpoint inhibitors are often used off-label and have very limited clinical activity.

Next slide, please. The important biology associated with this disease is noteworthy for the majority of uveal melanoma tumors harbor mutations in G-coupled protein receptors that are responsible for the constitutive activation of protein kinase C. This pathway drives uveal melanoma growth and survival and is the harbinger of the disease. Darovasertib is a potent and selective inhibitor of protein kinase C and was found to have significant antitumor activity in preclinical models. In addition, overexpression of MET is often found in advanced uveal melanoma and is thought to play an important role in metastatic spread. It was determined in preclinical testing that the combination of darovasertib and crizotinib, a MET inhibitor, resulted in greater antitumor activity than either compound alone. This novel combination was, therefore, studied in Phase II in metastatic uveal melanoma subjects and was found to have a high response rate with an associated prolonged progression-free survival in treated subjects. This set the stage for the randomized Phase III trial, which we will discuss today.

Next slide, please. OptimUM-02 is a randomized Phase II/III trial that completed enrollment in December of 2025. 313 HLA-A2-negative metastatic uveal melanoma subjects were randomized 2:1 to receive either darovasertib 300 milligrams twice a day and crizotinib 200 milligrams twice a day orally each day versus standard of care therapy, which included either single-agent checkpoint inhibitors such as pembrolizumab, combined immunotherapy with ipilimumab and nivolumab or dacarbazine for those who would not tolerate immunotherapy. The primary endpoint was progression-free survival by blind independent central review for potential accelerated approval. And for Phase III overall survival was the key endpoint for potential full approval.

Secondary endpoints included progression-free survival by investigator, overall response rate, duration of response, disease control rate, of course, safety and several quality of life questionnaires were included. Next slide, please. The top line results from the study are presented here. With respect to the primary endpoint of progression-free survival, the darovasertib and crizotinib combination had a statistically significant improvement in median progression-free survival by blind independent central review of 6.9 months compared to 3.1 months in the investigator choice arm. The provided hazard ratio of -- this provided a hazard ratio of 0.42 with a 95% confidence interval of 0.3 to 0.59 with a p-value less than 0.0001, which equates to a 58% reduction in the risk of tumor progression in the treatment arm.

Next slide, please. Also highly noteworthy was the overall response rate. Darovasertib combined with crizotinib delivered an overall response rate of 37.1% compared to only 5.8% in the investigator choice arm with a p-value less than 0.0001. There are 5 complete remissions seen in the treatment arm, none in the control arm. There was also a trend in improvement in overall survival. In terms of safety, both arms demonstrated a safety profile that was expected based on prior studies, and the full data of this trial will be presented at a future medical conference. Next slide, please. In conclusion, the darovasertib and crizotinib combination represents a novel emerging therapy for those subjects with metastatic uveal melanoma who have HLA-A2 negative disease and has shown a significant level of superiority relative to standard of care immunotherapy and is likely to represent a paradigm-shifting therapy in a disease that has high unmet medical need.

With respect to darovasertib itself and the fact that it targets the driver of uveal melanoma, protein kinase C, we believe darovasertib either as a single agent or in combination with crizotinib has the potential to have a major impact across the entire uveal melanoma patient journey. And we have several trials either underway or being initiated to uncover the promising activity of this agent. In the neoadjuvant setting, darovasertib is being tested in primary uveal melanoma with very important endpoints that include both eye and vision preservation. Post primary local therapy, darovasertib combined with crizotinib will be tested in the adjuvant setting in subjects that are high risk for metastases to determine whether this combination can reduce both local and distant relapse.

And lastly, of course, in the metastatic setting, the OptimUM-02 trial has provided evidence of promising activity of darovasertib and crizotinib in HLA-A2 negative disease, but it's also being tested in the OptimUM-01 study in subjects who are HLA-A2 positive. Upon completion of these trials, we believe darovasertib will become a backbone therapy for all phases of uveal melanoma and will improve the lives of subjects that have to live with this life-threatening disease. I'll remind folks today that darovasertib is a breakthrough therapy drug designated by the FDA. And today is the first study where it's shown a really significant impact in patients with uveal melanoma, and we have several trials underway with more to come. So with this, I conclude my remarks, and I'll pass it back to you, Yujiro.

Thank you so much, Darrin. This now concludes the prepared remarks. And operator, let's now please transition to the analyst Q&A portion of the webcast. Please ask for our analyst to keep it to one question. We will also ask the operator provides a status check when we reach the 30-minute mark. Operator, you may now proceed to the first question.

[Operator Instructions] So our first question comes from Anupam Rama at JPMorgan.

Congrats on the data. Just a quick question. In the full medical conference presentation, will you be quantifying the overall survival separation? Or is this really a wait till the full analysis type scenario? And if the KOL is on the line, just based on this data as well as the early-stage clinical experience, where do you see the combination fitting into both HLA-negative and positive patients?

Yes, Anupam, on the OS question, we will not be specifically at the upcoming medical conference. As we noted, we have observed an early trend, which is encouraging. There's been about roughly 10 months of follow-up. So to see that early separation, we're quite encouraged. And as you know, we did report a robust survival result back in the fall at the Society for Melanoma Research. With that, Dr. McKean, if you're on the line?

Yes, sure. So it sounded like the question was where do we see this in practice for both potentially HLA positive and negative patients?

That's correct.

Okay. Yes, I mean I think this data, obviously, the randomized trial was for patients that were HLA-A2:01 Negative. However, the data that we've presented before at ESMO in 2023 and ESMO 2024 included patients with both HLA-A2:01 positive and negative, and we saw similar response rates. And so I think the excitement here is certainly that we've never had a systemic therapy with this type of response rate for these patients to be able to feel like we really have the opportunity to see improvement in their disease from the time of onset of medication. And so I think there's really kind of limitless possibilities of where we could use this medication for patients with metastatic uveal melanoma.

Our next question comes from Maury Raycroft at Jefferies.

Congrats on the update. And I'll follow up on the overall survival topic. So Yujiro, you've talked about a potential interim OS readout in first half '27. Could that time line change based on what you're seeing in the current data? And then also for Dr. McKean, if you could just talk more about how these data could influence your use in the frontline HLA-positive patients? And are the PFS and response rate data sufficient? Or is there something specific on OS you want to see there?

Darrin, do you want to take the interim OS?

Yes. So the interim OS is planned for midyear, of course, next year. But there'll be opportunities as we get into the filing to discuss with the FDA the progress of the trial and the data itself. So it will be evolving, but the plan is for the interim. But if an earlier look with the FDA makes sense because at this stage, we have such a very positive study here without an ability to cross patients over. So it really just depends on the maturity of the data, to be quite honest.

I can jump in. So obviously, this is just a huge day for patients with metastatic uveal melanoma. For patients that are HLA-A2:01 Negative, the only systemic therapy option we've had with ipi/nivo, right? And you can see how well that performed and really what we have been able to offer patients. So I think [darovasertib] is going to be an exciting option for those patients. For patients that are HLA-A2:01 positive, [indiscernible] there's still some questions about the long-term benefit with the overall survival that was seen in the clinical trial, but the response rates are single digits, right? So when patients come in with large volume disease, extrahepatic metastases, you still just have not had good options for those patients. And so I think this really is exciting for all patients with metastatic uveal melanoma to be able to have an agent, like I said, that shows such a significant response rate, allows stability of disease and potentially shrinking the disease to be able to get to the next line of therapy.

Our next question comes from Tyler Van Buren at TD Cowen.

Congrats on the data and a great execution of the study. So the 7-month median PFS clearly hit the bar and is consistent with what you guys have shown in the past. But just wanted to focus on the 0.42 hazard ratio for a bit. That's clearly an incredibly impressive PFS hazard ratio by any standard. So can you elaborate just on the significance of that magnitude of benefit in the context of the data that's been reported in the uveal melanoma population historically as well as the fact that ipi/nivo was included in the control arm?

Yes. Dr. McKean, do you want to maybe discuss the hazard ratio and kind of your view as a clinician? And as we noted in the beginning, I think the usage of ipi/nivo in the control arm, this is the first frontline randomized study where that was incorporated. So your comments here would be helpful.

Yes. I think there's going to be a lot of discussion in the field that -- the way the trial was designed, as investigators, we have the opportunity to give patients ipi/nivo, the only other combination systemic therapy option. And you saw the results here, and that's really what we felt for our patients. The only other data that's available has been retrospective single institution data sets. And there's obviously a lot of selection bias in which patients you're able to give ipi/nivo to versus central liver-directed therapies as the only treatment options. And so I think this is an important data set for the field as well because this is the most data that we have for patients treated with ipi/nivo.

And we've known that the response rate in uveal melanoma is far worse than anything we've seen in any of the other subtypes, cutaneous, mucosal or acral lentiginous. So I think that -- I think there's going to be a lot of discussion in the field about how ipi actually performed in a randomized trial because that fits with what we see and feel for our patients and having had kind of the lack of any other systemic therapies for these patients. And then as far as PFS and objective response rate, that really held with what we've seen for the number of patients treated on the Phase I, Phase II data. So I think pleased to see that, that was similar and what was expected from the patients we've treated before.

Our next question comes from Yigal Nochomovitz at Citi.

For Dr. McKean, I'm wondering if you could comment a little bit on how you see the potential in the other settings that IDEAYA is running studies in adjuvant and neoadjuvant given that we now have very favorable data in the metastatic setting in HLA-A2 negative.

Yes. I mean the field has really been waiting for an effective systemic therapy to be able to move these therapies forward. There's been some data presented for the neoadjuvant setting for patients potentially life-changing to be able to save their eye, not have to undergo enucleation, try to preserve vision. So I think there's certainly a lot of enthusiasm in the ophthalmology community about how else we can use this medication and the data presented thus far, I think most recently in [Rio] earlier this year, really demonstrating that using that high response rate to try to offer patients more options for local disease control.

And then the adjuvant setting is really exciting because we've had fantastic prognostic tools, whether that's gene expression profiling or chromosomal analysis to identify exactly which patients we know are high risk. So at the time of diagnosis, we can tell patients, unfortunately, you have a 50% likelihood of recurrence, but we haven't had effective therapies to then offer in the adjuvant setting. So I think there's a lot of excitement in the field about the other uses and potential situations for the monotherapy in combination.

Thank you. Dr. McKean. Darrin, anything else you'd add about neoadjuvant or adjuvant?

Well, it's funny, a few comments. I was just thinking about the prior comment, too, in terms of where we sit in the metastatic setting, when you review all the historical data, no matter what you look at, you end up at a response rate of 5% to 10% and a PFS of 3 months over and over and over. And now we're finally breaking away from that, which is great for patients. And as Meredith pointed out, I think in the neoadjuvant setting, we have shown we've been able -- with darovasertib as a single agent, able to save 60% of eyes for patients who would otherwise require enucleation.

And then for those with plaque brachytherapy being able to reduce radiation dose, improve vision while on treatment and have a predictive tool that suggests that down the road, their vision will be better for those who get plaque brachytherapy, great. But I think what everyone is really, really looking forward to is the adjuvant trial as well simply because there's a potential to save lives. Patients who are at high risk, as Meredith pointed out, with high-risk genetic features, Class II, monosomy 3, those are the folks that tend to have the highest risk of relapse.

If you could reduce that rate or push out the time to metastases, that would be incredible. And when you look at that curve that we presented, the progression-free survival curve, again, separation throughout the entire journey of that curve, the separation is real. It's big. And you would have to think that, that would translate into benefit in the adjuvant setting. And so that's why we're really excited to get that trial going as well.

Maybe just only other add is with this kind of data just gives us continued further confidence in that adjuvant opportunity. So I think with that, we'll move on to the next question.

Our next question comes from Michael Yee at UBS.

Great. Thank you for the comments from adjuvant. In HLA-A2 Positive, can you remind us, Yujiro, will you be able to have a good package of data to help file in your filing to address that with the potential also for compendia listing and with the doctors consider using that there and positive if you have compendia listing? And second question is in this study that you are reporting today, do you expect that duration of treatment is expected to be much longer than 7 months and the doctors continue to treat well past progression?

Maybe, Mike, I'll take the latter part first. So I would say, typically in the past, we've seen patients getting treated beyond progression roughly about 3 months. So -- and I think that's been consistent with what we've seen through this study, including the single-arm studies. In terms of HLA-A2 positive, very significant focus for us. So we do have a strategy both in terms of our efforts to get it on the label as well as vis-a-vis compendia. Darrin, anything else you'd highlight on this one and HLA-A2 positive?

No, I would just say with the 01 trial is continuing to mature. We have around 100 patients dosed that are HLA-A2 positive. Again, we presented data at ESMO in 2023 to show that really we don't see any difference between the 2 with respect to the kind of benefit that patients with HLA-A2 negative disease received the positives get that as well, best that we can tell thus far. So we're very enthusiastic about bringing that data forward and working with the NCCN panel as well as the FDA in order to make sure that patients have access to this kind of therapy because as shown in the randomized trial, it's making a big difference.

Mike, I think here also, we do have a very aggressive publication strategy for both HLA-A2 Negative and Positive. So you're going to start seeing quite a bit of data coming from us on that front for both fronts.

Our next question comes from Li Watsek at Cantor Fitzgerald.

I wanted to add my congrats as well, a great outcome. I guess for patients who progress, can you talk about subsequent therapies used in the trial? I'm curious if there are difference in the HLA negative versus positive patients in your observation? And then related to that for Dr. McKean, can you comment on your approach to sequencing once daro is approved just across the HLA status?

Sure. Darrin, do you want to take the first one and then Dr. McKean?

Yes. With respect to sequencing, probably we've had Meredith take that because the sequencing that occurred in this trial would be no different than the sequence of patients with standard therapy. Maybe you can Meredith speak to now in the context of the daro, crizo combination coming on scene, what your vision is of how therapies will be sort of sequenced in the future.

Yes. I mean I think to -- on study, patients could treat down progression, but you weren't able to do any local therapies, which we know is very important for these patients in their disease control. So I foresee there will be a lot of -- and we've seen other data in uveal of looking at combination approaches with liver-directed therapies. And so like I have a patient on compassionate use that has now been on daro, crizo for 3 years because we did Y90 to one progressing liver lesion. I think we're going to see a lot more of that now that we're going to have flexibility to be able to treat the patients in front of us using all the tools that we have.

So I think there's probably going to be a lot more kind of combination approaches. I think there's going to be patients that were previously ineligible to even receive liver-directed therapies. But then I think there's still probably a lot to be learned about sequencing with immune therapy. But I think at the end of the day, daro, crizo has the highest response rate, the best progression-free survival that we've seen. And so I think there's going to be a priority to make sure every patient receives this treatment and then how best can we reintroduce this later like other targeted therapies and see a renewed response rate again? Or can we -- but I think there's going to be a lot of combination approaches likely with trying to do liver-directed or other local therapies to try to keep patients on this as long as possible.

Just to add on what Meredith is saying there, too. I think just understanding the biology and protein kinase C and trying to stay on the driver and thinking about the patient journey, it's very likely that these studies all read out the way this one did, we'll be looking at the -- in the primary uveal melanoma setting, trying to get on the target with the darovasertib and helping the patients save their eyes, save their vision, also potentially maybe preventing metastases even in the neoadjuvant setting, although the current trial is not really designed to show that.

And then ultimately, after their primary therapy for those high-risk subjects, you still want to stay on the disease, on the driver and then you'd be able to continue to do that in the adjuvant setting. And then perhaps down the road, if the patient were to get their 1 year's worth of therapy and discontinue and then further down, develop metastasis, then again, you'd want to be on the driver. And then again, as Meredith pointed out, as you're thinking about combinations, you're thinking about strategies that are liver-directed it seem to me that you'd always want to be on the driver, which is protein kinase C, have that shutdown and try to take care of the rest. So I can see a therapy like this, just like any other targeted therapy like your EGFR inhibitors where people are talking about keeping folks on for as long as possible. You may see a similar thing here because it just seems like this disease really needs that pathway to begin and to thrive. And so being on top of that is going to be important.

Our next question comes from Charles Zhu at LifeSci Capital.

First of all, congratulations on the data. Can you talk perhaps a little bit about the subsequent therapies that your OptimUM-02 trial patients may be taking, whether they're post daro, crizo or post control arm and any potential impact to longer-term OS there? And maybe also related to that, I recall there was a dynamic where you had the option at some point to upsize the trial for OS. Is that the one option for you at this point? And do you even need if you could clarify that?

Yes. So I know for the therapy sequence, some of that was covered. But Dr. McKean, anything additional there? And then maybe just on the second question, we do still have additional time to ultimately make that decision, Charles. But Darrin, any comment there. I mean, based on the data we've seen and even on the early trend in OS, I think we're in really good shape. But Darrin, do you want to make...

Yes, I'd just say we're very comfortable with where we're sitting right now. We do have that option. That's the nice part of how the protocol was designed. But like I said, I think we're going to be watching the maturity of the data over the next -- as we are in the process of filing. And so we'll monitor that situation. But we're sitting in really great shape. I mean you just look at the data, you look at the separation of the curves, you look at the response rate, you look at the continuity of the data that we have now relative to what we've presented at SMR, and it's very, very consistent, which is beautiful.

I mean a lot of times you see data when you go from Phase II to Phase III, you may see some detriment to the efficacy outcomes. We haven't really seen much of that at all. Safety profile very much similar. Really, the SMR data tells it all, and you know what the OS looks like for the SMR data, that looked exciting. And so far, all the parameters that we've been following seem to be following in the same direction. So we're very, very bullish on the opportunity to get this across the finish line with full approval.

Dr. McKean, anything else you'd add on the sequencing?

Yes. I mean the reality -- the unfortunate reality for these patients that were treated on trial in HLA0201 negative is at the time of progression, right, if you were lucky enough to be on the treatment arm, you could receive ipi/nivo. Otherwise, it's just -- it's liver-directed therapies. And so for patients that had disease outside of the liver, you didn't really have any other options. And so you're -- really it's kind of local palliative radiation and in the liver, it's Y90 ablation or perfusion therapy. So there just really aren't -- this isn't like another cancer where you can just keep pulling up your next line chemo, there just aren't good options for these patients, whether they progress -- once they progress on daro, crizo or if they're on the control arm. It's really just local therapies.

Our next question comes from Paul Jeng at Guggenheim.

Let me add my congrats on the results today. I wanted to ask about the relative dose intensity that was maintained for the regimen and to what degree there were any dose interruptions or reductions to manage adverse events either for daro or crizo? And then a quick follow-up question just on the OS. So based on your doc feedback, how important is that OS data in driving uptake for daro in the HLA-Negative patients? Are there any physicians who may wait for those results before prescribing? Or is that more important as you think about potential utilization in the HLA-Positive segment?

Maybe for the first piece, Paul, we'll need to sort of stick to the disclosure. Obviously, I know we've got Dr. McKean on as well. I know there's also just sensitivity. We do have hopefully, an important upcoming presentation at a major medical conference where we'll share further detail. But I think we can say at a high level, the safety profile, including things such as discontinuation rates, dose intensity was very consistent with what we've reported in the past. And I would say also in relation to historical data on ipi/nivo. In terms of the other item here, Darrin, do you want to take that?

Well, again, as you know, the overall survival data is still maturing, and we'd be going to the FDA to talk about using the surrogate endpoint, progression-free survival, overall response rate, et cetera. The data from both what we've seen by BICR and investigator assessment of the outcomes. And if this gets approved, it's going to be used as the OS data matures. And I don't know, Meredith, if you want to pile on top of that, but I can't imagine once this gets approved, I think you're going to probably have another very important tool in your tool belt to use for these patients.

Yes, absolutely. And I think the question in regards to the HLA-A02:01 positive patients, maybe it's just we -- the Phase I/II study enrolled patients early on regardless of HLA status, right? So like Darrin said, there's a large number, it sounds like 100 patients that are HLA-A2 positive that were treated. And so I think more data to come in that space. But as a treating provider, we would generally -- the way it works is really just try to point to the data available and say this is why this is an option that we'd like to pursue for the patient.

And so that's looking at -- showing the data, hopefully, if it's added into the NCCN guidelines at some point, that will be helpful in just trying to demonstrate to the insurance companies why these patients, even for HLA-A02:01 positive, don't have a lot of options. So I think that's where as much data as we can put out there will be helpful.

Our next question comes from Silvan Tuerkcan at Citizens JMP.

This is Josh on for Sylvan. Congrats on the great data. You provided that 2 half '26 guidance on the time line to filing. Maybe if you can just discuss some of the gating factors to that filing. Will it be on a rolling basis and maybe discuss the potential for an expedited review?

Yes. So Darrin, do you want to take that?

Yes, we'll be working with the FDA in order to talk about how to most expeditiously get this filing completed. So those are on the table for sure. Now that we have the data in hand, we're going to have those discussions.

Yes. And I think on the expedited piece, we will be evaluating options around RTOR as well.

Yes, we have -- remember, we have fast track. We have breakthrough, we have Fast Track. We have orphan. We have just about every designation you can think of. So I think they're going to be very open to talking to us about that.

Our next question comes from Graig Suvannavejh at Mizuho.

My congrats to the IDEAYA team on great data. I did want to ask just about the adverse event profile. I think the syncope and hypotension were something that I had not been appreciative of before. I'm just wondering if there is a mechanistic rationale? Is it more maybe crizotinib driven? If just any color on that? And maybe for Dr. McKean, the KOL, thoughts on uptake. Does that, in any way, the safety tolerability impact how you think about uptake? And is there an immediate impact to KIMMTRAK in the HLA-positive setting?

Yes. So Graig, maybe I'll take the first part. So the hypotension, syncope is exactly consistent with what's been reported in the past, including at SMR and ESMO. So that's been known and reported for the last several years. Darrin, Dr. McKean for the second question?

Well, I can say, at least mechanistically, I mean, we think it's likely more darovasertib, and there has been some studies that imply that it may have -- may be secondary to the effect of inhibition of protein kinase C and its effect on smooth muscle cells. So -- but again, manageable, not different than what we've seen before, known. And again, the things there that we do typically is we ask patients to maintain their hydration, we stop their blood pressure medicine. We make sure that they're not running around right after they get their dose. And you can speak to the management of this and the outcomes. But I think in general, this is if you know and you expect it, it can be managed quite easily. But Meredith, I'll let you take that.

Yes. I think hopefully, this is data that we'll be kind of illustrating more as we publish the Phase I/II data because I think like Darrin said, we learned a lot, right, holding patients -- having patients hold their blood pressure medication once we got through the food effect, just seeing the significant importance of patients being able to take the medication with food, high protein breakfast. And so that's really helped navigate any hypotension or syncopal events. And then I think some of it through crizotinib can add some edema. And so just recognizing that early for patients and even short -- these medications have short half-lives. So for patients, any of the side effects, you're able to say, okay, hold crizo for 3 days and then restart, right? And patients feel immediate relief. So I think there's a lot of ways that we've learned to try to help navigate these medications and really find how -- with supportive medications, how to help patients be able to stay on treatment.

Our next question comes from Greg Renza at Truist.

Congratulations, Yujiro and the team for a really nice outcome today. Yujiro, maybe just on the OS expectations. I just wanted to ask if you could perhaps remind us of maybe some of the internal assumptions around the differentiation between the daro, crizo combo and the control arm. If the Phase III OS data were to trend shorter than, say, that 24 months previously observed, maybe just a comment on what range would you view as consistent with respect to a positive outcome?

And then secondly, let me throw in a strategic question, Yujiro. Now that you're staring at a potential filing and a transition to commercial, how do these data maybe impact your view of the IDEAYA pipeline? Does it reshape how you would prioritize and establish focus as you build out the portfolio?

Thanks for the question, Greg. So in terms of OS, I think the good news here is the response rate, the PFS, the data we observed has been very consistent from what we reported at the Society of Melanoma Research with a more limited data set to now a large, randomized Phase III study. So I think that's the good news. And Greg, as you know, the OS that we reported at Society of Melanoma Research, just as a reminder, was over 21 months. So our hope here is we showed consistency in response rate as well as PFS. And I do think that bodes well for the OS portion.

I would say on the control arm, as we've seen, the vast majority here is ipi/nivo. And I think, Greg, I know there was a lot of topic on what the PFS would come out at. And as you know, we've consistently were noting the published data, in particular, the PLOS paper, right, where that PFS came in exactly what we're reporting essentially 3.1 months versus 3 months. And also, just as a reminder, if you go to that paper, I believe the OS that was reported was about 12.5 months.

So I think that all sets up nicely. And I do think that past publication we've been pointing to did come in exactly as our study reported out. And lastly, as it relates to our larger portfolio, Greg, as you know, look, we think darovasertib is just the start for the company. We're tremendously enthusiastic about the progress on DLL3, MTAP, KAT6/7 as well as others. And we believe with darovasertib now hopefully transitioning towards commercialization phase, the tremendous progress, and we think we have one of the deepest portfolios in precision medicine oncology. What you're going to see us do as an organization is to drive forward to build that next leading precision medicine oncology. And that's exactly our vision, and this is exactly what we're moving towards.

Great. Thanks for the questions, Greg. So this hits the 30-minute mark on Q&A and all the time we have. I'll turn it back to you, Yujiro, for quick closing remarks.

Great, Tara. Thank you for that. This now concludes the prepared remarks and as well as the analyst Q&A portion of the webcast. So thank you, everyone, for participating in the webcast event today. And operator, you may now close the line.

Great. Thanks, Yujiro. So this concludes today's event. You may now disconnect.

Thank you so much to you and Evercore for hosting this fireside chat today with the IDEAYA management team. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We have 9 programs in the clinic. So a very deep and diversified portfolio.

Umer, as you know, our most advanced program is Darovasertib, which is now currently in 2 Phase III randomized studies, one in the first-line metastatic uveal melanoma indication and then next in the neoadjuvant indication, we're looking to launch our third Phase III study this half.

Obviously, very much in focus is our upcoming guidance around our top line results for the first-line metastatic melanoma setting here. The primary endpoint is median progression-free survival, and I'm sure we'll talk more about that today. But beyond that, we have a very deep pipeline.

I would say next is a portfolio of assets in the ADC space. I would say probably most attention is to our DLL3 TOP1 ADC, IDE849. We are guiding towards a clinical data update on that program by the end of the year. And we believe this molecule does have the potential to be a best-in-class asset. As both you, Umer and John know, we did present a very robust single-agent activity as an oral presentation at the World Cancer Lung Conference last September.

Beyond that, we also have a deep pipeline in MTAP-deletion. We have 2 clinical assets here, both PRMT5 and MAT2A. We think a lot of interesting opportunities, both as monotherapy as well as combination. Also, as I think both of you have been following, a lot of interesting intersections between RAS and MTAP as well.

And then lastly, KAT6/7. So IDE574 has now entered Phase I. We think a really unique opportunity and perhaps one of the largest addressable patient populations, including in breast cancer and colorectal cancer. And Mike Whiter, CSO, is here, and we can definitely dive into the science of that as well. So I think that's hopefully a good summary and encapsulation of the company.

Got it. Okay. Great. Fantastic. So maybe just as we begin, could you just remind us sort of the timing and the expectation for this upcoming readout?

Yes. So the timing is going to be in the next couple of weeks. So we've now guided on or around the very end of March. So we're obviously going towards March now. So the data update is in the near term. In terms of sort of table setting on expectations, so Umer here, our perspective is what we believe we'll see in the control arm is going to be consistent with what's been published in large meta-analysis before.

And I know there's been some questions about Ipi/Nivo in the control arm. And I think here, probably the most, at least we feel reliable paper there is the [indiscernible] paper, which was a multicenter study. And there, we believe the PFS is going to come in roughly 2 to 3 months.

In the treatment arm, we reported a 7-month PFS in 2 oral presentations, one at ESMO several years ago and then most recently at the Society of Melanoma Research this past fall. And that PFS has been solid, approximately 7 months, including with roughly 2 years of follow-up. So we feel good about that number. And if we -- if that's what we see, we feel good about our prospects to hit [ STA sig ] as our primary endpoint.

Got it. Maybe I ask before we get too far off of what the trial design is, one of the things that I know we've spoken about in the past, and I am continually curious about is given you have an investigator's choice comp arm, Ipi/Nivo probably the most relevant thing that people are asking about, but there are other options.

You've got a combination on top of Crizotinib, which is not available in the compound. Can you give us some of your thoughts about what the potential variability is in the [ comp arm ], but what the contribution of parts is in the experimental arm and how we should be balancing the expectations there?

Darrin, do you want to take that?

Well, in terms of the contributions of the 2 components in the Daro/Crizo, that's pretty clear. I mean Darovasertib, we know what it does as a single agent. It's active. We've shown that in Phase I. Crizotinib, however, has limited activity, at least the MET inhibitors in this space. They've been tested before in small numbers in clinical trials, really haven't shown much in the way of activity.

However, it's very clear, at least preclinically, when you put the 2 together and you impact both pathways, protein kinase C and c-MET, you can see enhanced antitumor activity, and we've shown that pretty conclusively in the clinic, obviously, with the Daro/Crizo combination relative to what either agent can deliver alone.

And also, we've discussed this with the FDA. So contribution of components is pretty clear. We know that you need the MET inhibitor to enhance the activity in the metastatic setting. We also know in the neoadjuvant setting, you don't need the Crizotinib. It doesn't seem to add. We already have profound activity in the neoadjuvant setting with Darovasertib as a single agent. So our thoughts are we don't need the Crizo in that setting, but however, in the metastatic setting, different story.

With respect to your other question about the control arm, to be quite honest, there's been at least 2 meta-analysis published, thousands of patients. And I think we feel very, very comfortable with where the control arm sits, whether it's Ipi/Nivo, whether it's ipilimumab, whether it's a single-agent checkpoint inhibitor like nivo or pembro, they all sit right around 2 or 3 months.

And so with our long-term follow-up from the 01 trial, 2 years of follow-up where we maintain a rock-solid PFS of 7 months, and we only need to hit maybe 5.5 in order to be -- have a positive study. We think we have a great buffer zone. And again, I think we're just as well positioned as you possibly could be to beat the control arm in this particular situation. And our OS looks profound, too.

I mean that PFS translates into another metric, which is OS. We have 21 months of overall survival in the 01 trial. And so those 2 things go hand in hand. If you combine that with the fact that we're tripling the response rate compared to standard of care, we have a really rock-solid duration of response of 9 months, we just think we couldn't be better positioned to take on standard of care in this case.

Well, since you brought up OS, Darrin that was going to be my next question.

John, can we -- maybe just one second, can we just like set the trial? I want to go through all the data very carefully, but maybe let's just set the trial. So can you remind us the design of the trial, just so we're all on the same page?

Sure. So what we're talking about now is metastatic uveal melanoma. So patients with uveal melanoma, who have metastasized. They also have to be HLA-A2 negative, which is probably about 2/3 of the patients with uveal melanoma. And so it's a simple randomized Phase III comparison of either standard of care, which in this case is either single-agent checkpoint inhibitors, a combination of checkpoint inhibitors plus other immunotherapy like Ipi/Nivo or you could, if you happen to be a patient who couldn't get immunotherapy for whatever reason, you could get chemotherapy, but we think that's going to be a very small proportion of the patients treated.

And then of course, in the treatment arm on the other side, is the Darovasertib, Crizotinib combination, which we've tested extensively at the 300, 200-milligram dosing. And again, this is a study, where the primary endpoint is progression-free survival. So that will allow us to have a discussion with the FDA. And then, of course, that study will go on to read out for overall survival for full approval.

And what has happened so far in the trial? Has there been any interim looks so far?

No. So this is what's coming up now, our top line to look at our first look at progression-free survival.

How mature do you expect OS to be at the time of PFS maturity?

Very good question. So I think the maturity is one of those things where when we talk about the outcome for this particular study, some of the things that we're likely to talk about is, obviously, the response in the 2 arms, the progression-free survival in the 2 arms, of course, maybe some durability with respect to duration of response. But survival at this stage may be relatively immature. So if we don't say anything about it, it's not because it doesn't look good. It's because there may not be enough data to actually make a call on whether there's any trend, for example.

However, there will be opportunities down the road. We'll be obviously filing the NDA. We'll have the opportunity to once again provide the FDA safety information and perhaps efficacy information during the filing period. And then, of course, our first interim analysis for OS comes up at the beginning of next year or the first half of next year.

So there will be a couple of opportunities to look at OS. And it's very possible that during that period of time, we'll have enough events -- but at the first look, it's uncertain at this time, if that will be the case to really make a call.

If I -- sorry, John, just before we move on from the trial design, there's a Phase II here and there's a Phase III here. Could you just remind us, have you guys spoken to any dynamics around the Phase II data yet?

No. So at this point, again, this will be the first time that people have seen what we have evaluated with respect to progression-free survival as well as safety comparing the control to the treatment arms. We did have -- this was a sort of a 3-component study. We had a IIa part, where we actually looked at dose optimization to show that the 300, 200-milligram dose going forward was the optimal dose, had the best benefit risk profile for patients.

And then the IIb/III is the part that we'll be reading out now, which now accumulates patients to be able to have enough data to show that the progression-free survival, how it compares between the 2 arms, and then we'll follow that up with overall survival. So 3 component study, Part 2a completed, getting IIb/III getting ready to read out and then...

How many patients were in Part IIa?

So Part IIa was designed to look at the 2 doses and without getting into dramatic detail, essentially, it was a 2-stage component. So it depends on how you define it. But long and short of it, it was approximately 80 or 90 subjects to be able to look -- take that first look. Remember, they were randomized 2:1. So 2 to the control arm -- 2 to the treatment arm, 1 to the control arm. So it took about 90 patients to figure out what was the right dose.

We had additional patients that came on after that as we were continuing to enroll that were part of the IIa, but they weren't part of the initial analyses. But essentially, that was around that 90 patients or so is all that was required to determine what was the optimal dose and then you move forward from there.

So the reason I was...

And Darrin those 90 patients, those were both A2 positive and negative. Those...

No, no. So this study is only HLA-A2 negative. So if you...

Is it pivotal. But you did have a Phase II that had all HLA subjects.

Yes, that's a different component, and we'll probably get to that later. But that is a patient population that we haven't forgotten about that's critically important to us. We think this treatment should work there, no different than it does in HLA-A2 negatives. However, we're evaluating that patient population in our 01 trial. We'll have nearly 100 patients' worth of data, who are HLA-A2 positive.

The objective would be the following. As this study reads out, our view is that it will show an improvement in progression-free survival, ultimately an improvement in overall survival. And in parallel, we'll be able to present data to the FDA as well as the NCCN panel that puts together the guidelines for treatment that shows in 100 patients worth of HLA-A2 positive data from a Phase II trial setting that we have a similar overall response, progression-free survival, overall survival, durability of response that we do from our randomized Phase III trial.

And hopefully, that will allow people to look favorably at that data set and utilize it as appropriate.

There's no mechanistic reason to expect your drug to behave any differently in these 2 populations?

Absolutely correct, right? It's all about the mutations that drive the disease to begin with. So these tumors, 95% of the time have mutations in GNAQ, GNA11, G-coupled protein receptors that drive protein kinase C signaling, and that's why Darovasertib is so effective in basically knocking the wheels out of the driver for the disease.

Yes. HLA only, but HLA-A2 only matters because of KIMMTRAK already approved in that...

Exactly.

So maybe just on the trial design again because I just want to make sure -- I want to go through all those things, but just on trial design, there's a Phase II and there's a Phase III. And maybe let me just put up something that -- the reason I'm just trying to go step by step on this.

So here's something I was looking at just for my own sort of understanding of the trial. We know there's 440 patients that came in. And you said 80 of them were in Phase II. So that's kind of like consistent with.

That's not what I said exactly. So what I said was...

Maybe I could just step in -- so the number of patients, just to be really exact, the IIa portion is 124 patients.

124 patients.

124 patients, yes. And remember, the dose that's not moved forward gets dropped irregardless, whether we included the IIa in the analysis or not. So it turns out that roughly 75 patients were in the non-move forward dose would have been dropped irregardless. So that leaves you...

Right. So 360 -- sorry, go ahead. Are we get into Phase III?

Yes. So that -- what that leaves you is with 49 patients with the move forward dose as well as the control arm. So that was the question, should those 49 get included as part of the analysis or not. The decision ultimately that was made was that we were going to utilize that IIa for the Project Optimus dose optimization portion at the end.

The IIb and III now are the same. It's -- because it's an ITT analysis and because enrollment was ahead of schedule, when we submit -- when we do the analysis for the PFS, the full enrollment for the OS has also now been complete. So the IIb and III are 313 patients. So that's how you get to that 437.

So Phase IIB and Phase III is 313 patients you said?

Total, yes. And that will be for both the PFS as well as OS analysis.

So 313 is the number we're going. Okay. Got it. That makes a lot of sense. And the reason -- that's why I was like -- when John was sort of asking this question, the reason I kept coming back to the trial design is I just wanted to be sure that I understood, PFS -- because the way OS is being analyzed here, and I want to get into the relevance and significance of that in a second as well.

But this option 1, 2, 3 for OS analysis depends on what happened on PFS, right? And what I wasn't sure about was it kept saying PFS off of Phase II, like kept saying PFS and Phase II. It's not Phase II. It's PFS across the whole trial, Phase II and Phase III, all 313 patients, correct?

Correct. Yes, yes.

So the sample size of 200 PARG 2.55 hazard ratio. So this is actually 313. So you have more wiggle room technically.

That's correct.

I see. And...

And you also have a subset of these patients that are substantially more mature than the bulk Phase III, the patients that were enrolled later on in the study.

That's correct.

And Yujiro, is it fair to say that the interim is still being triggered by 130 events?

That's correct. It's going to be the first 130 PFS events that will drive that analysis. And as you have there, the OS is 253 OS events.

So interim equals 130 events out of 313 patients.

Exactly.

I mean the trial was designed. The IIa was for optimization, the IIb was for accelerated approval and the III was all for OS. But remember, as Yujiro pointed out, the IIb and the III collapsed together because the enrollment went so quickly. And the additional patients that he mentioned in the IIa are simply because we overenrolled the IIa to make sure we had enough patients to do the analysis.

Does that mean that your 130, 140 PFS events you need for the final read, almost half of those are coming from patients in the go-forward dose in the IIa that are presumably much more advanced. Is that fair?

No, no, no. IIa has only contributed 49 patients. IIb and III is really the trial.

If that 49 patients, presumably most of which -- most of whom have progressed much well advanced of the other patients, that's almost half.

No, no ITT, the way I understood it was a Part IIb and Part III. Am I mistaken there?

Yes, that's right.

You've got it correct. It's the IIb/III that drives both the PFS and the OS analysis.

When did Part IIb start recruiting?

So we noted in December of 2024 that the IDMC selected the move forward dose. So I would assume it's roughly -- I don't know, roughly a month before.

I see, so over the course of '25, basically, you guys recruited it in about 14 months and 2:1 randomization. So 100 patients should all have had -- so I'll tell you what I'm really getting at. Of the 313, you've basically got -- if I can have my thing here, you've basically got 100 versus 200 type of randomization going on.

All these 100 patients were presumably recruited over the course of 2025. And by now, almost everybody should have had an event and almost feels like this PFS -- the 130 events could have hit even sooner? Or has it already happened? I don't know if -- maybe it's happened and you guys are not unblinded to it yet.

Yes. So we have said, Umer, as part of this most recent earnings that the 130 PFS events has occurred with BICR. So we're now in the data cleaning process.

Okay. So that would be consistent. The reason Yujiro, you can imagine the reason I was going down that path was if the 130 has not been hit, yes, it sounds like control arm might be outperforming by a little bit, but that's not -- presumably, that would have been...

Or the treatment arm is doing better.

Or treatment. No, Darrin, I was just going by...

With 100 patients in the control arm, the treatment arm would have to be doing really spectacularly to not hit events at all.

Right.

The other reason that I wanted to...

Hang on, John, sorry, hold that thought for a second. Darrin, let's just go with what you just said a little further. Wouldn't that also mean that if the active arm was, let's say, tracking more like a 5-month and compared to at 3 months, these interim would have happened back in like October, November. So we can also rule out the scenario for a more narrow PFS benefit? Or am I going to an extreme there?

Well, listen, I don't want to speculate except to say I know that we've been rock solid in 7 months. So I'd be shocked for a way off on that, but the data is going to speak for itself.

Do you disagree with my logic there?

So repeat that one more time, Umer.

My point was if we know the comparator arm tracking at 3 months or so, and most of these 100 patients would have had a PFS event by late fall last year, let's say, 75 out of them or 80 out of them.

In a scenario where the active arm was tracking at a slightly lower-than-expected PFS, let's just call it 5 months for a second, we would have seen perhaps a pretty meaningful number of PFS events in the active arm too, to the point where this interim would have gotten triggered by September, October last year, if the active arm was tracking a little lower than previously. So the fact that this interim did not hit in September, October, doesn't that effectively become a validation for your prior efficacy got replicated?

I mean I think that's a logical conclusion, Umer. I mean, look, I think the key part here is what you mentioned earlier is that it's a 2:1 randomization, right, from the treatment to the control arm. So that control arm has got to be pretty wide range to the right, if that's what's really driving the analysis, right?

If it was flipped 2:1 from control to treatment arm. But again, it's 2 to the treatment, 1 to the control arm. So I think what you're saying, just high level makes sense to me. Just factual point because the question around when did the IIb/III portion start. I just was looking at my notes here.

So in that release, when we noted the IIb portion started once the IDMC picked the move forward dose, we mentioned that 124 patients in the IIa portion, either way, 75 were going to get dropped because it's not -- that wasn't the move forward dose. We noted in that release, there were 185 patients enrolled. So to your question, even at that time, end of '24, right, we were already roughly 60-some-odd patients into the IIb/III enrollment.

There were 60 patients already enrolled.

In the IIb/III, yes. So in the December '24 release, we noted that there were 185 patients already enrolled. We talked about before was in the IIa. So that by default, that means have to be 61 or more patients were enrolled by the end of 2024.

And Yujiro remind me when did you guys say interim has happened? You guys never said that. You definitely never said that at our conference in December.

That's correct. We did not. So...

It came in '26, whenever it did.

Yes. We clarified that the PFS events were not achieved through the end of last year. End of last year, we still had not achieved.

Yes. I think -- okay. That's very, very helpful. That's very, very helpful. And you will preserve -- and you -- I mean, my understanding is there is an expectation for you to hit OS in this setting. Would you agree with that?

Well, we wouldn't have done the study without it.

Yes. I mean I think all we can see the Umer is that we presented OS data at SMR, right, and we showed roughly over a 21-month OS number. So we feel good about that. It's obviously a single-arm study, relatively small denominator, but we think it's an encouraging signal.

So is it reasonable to assume that this is where you guys want to be in terms of the OS analysis, like the PFS comes in, I don't know, 0.55 or better and then you preserve a lot of alpha for OS?

That's correct.

And if you think about it, I mean, most people would argue that the therapies that are out there for HLA-A2 negatives right now are relatively ineffective, right? So you're talking about a therapy that doesn't do a whole heck of a lot, except for a few rare patients.

And you're talking about a therapy that has triple the response rate, double at least the progression-free survival. Overall survival looks amazing. We should hit on overall survival. But you have to do the study. That's what we're doing.

One last thing...

The reason you're asking about OS earlier is about timing on that. So you're going to file with the agency on the basis of PFS data, but you're going to show them the OS data. Presumably, there probably multiple opportunities to the agency to see that. Is there a chance that there's enough follow-up on OS to get to full approval before people expect or on the same time line as the initial submission?

I'm glad you brought that up because there's one thing here you have to know is that there is no crossover permitted until the OS reads out. And so I think that is very important that we need to look at this data and just be aware that patients are going to be looking for options. For HLA-A2-negative disease, there really aren't any good therapies.

And so if you're on the control arm and you've got an ineffective immunotherapy, it would be really important to be able to offer what's going on in the treatment arm, if possible. But we can't do that until we cross a threshold where everyone feels comfortable that we're looking at a PFS that's robust. We're looking at an OS that looks like there's a significant trend that it can't -- not unlikely to be reversed. But again, that will be an FDA call, and we'll give them every opportunity to look at the data in order to make that assessment along with the IDMC.

How long will it take -- sorry, John, were you asking the same question? There was an investor question.

Maybe -- no, no, I was also going to ask about the state of the Phase IIa data.

So yes, maybe let's just ask the investor question just before we move on to that. The question was, how long would it take to get the independent review of PFS done? And if you could remind us whether this is investigator-assessed or blinded?

So we're -- this is not a blinded study. However, we have blind independent central review because of that. And so that's part of the analysis. So they are obviously doing the imaging analysis to evaluate whether patients progress. We'll be looking at both investigator-assessed progression as well as independently assessed.

And which is primary?

Blind independent central review.

Okay. Blind independent central review. Okay.

Well I was going to say, well it would take you a few weeks, you said. Is that how long it would take?

Well, it's all in the process of doing that now, right? We're in the process of evaluating -- getting the data into the database, cleaning the data, producing queries. Ultimately, once the database is locked, then basically the data between the blind independent central review and the EDC has to be merged, analyzed statistically, and that's when you'll get the output. And that's what Yujiro was referring to when we're talking about targeting the end of March because that's kind of what's going on at the moment.

Makes sense. Sorry, go ahead, John.

No, I was going to ask about the Phase IIa, which obviously is in hand. And admittedly, there's 75 of those patients that are now on the go-forward dose. But do you have plans to submit that as part of the same package to the agency? Have they seen that data already? When can we expect to see that data as well?

The agency will see everything because what they want to know is what the safety is on every patient that was dosed.

But they haven't seen it yet. They didn't see it as part of the...

But the independent data monitoring committee has seen it, and they're the ones that evaluated it, said it was still -- the appropriate dose to go forward with was the 300, 200. They felt the safety profile was adequate to go forward. And so we should let the study read out, and that's what's happening in the next month.

Will you show that to investors ahead of time as well? I mean the Phase IIa data, I mean, it's -- presumably, it's already mature.

Yes. But remember, it's got much shorter -- it's similar data than you've seen with the 01 trial, right? And so -- and the 01 trial actually has 2 years of follow-up. So it's probably more of the same, except shorter follow-up.

Fair enough.

Okay. John, there were a few questions -- more questions from investors on these. Do you want to go through those first? Or do you want to go through your side first, either way?

Sure. One of the other questions that came that just came up was on -- more on that Phase III expectation side. On the safety side, do we expect to see safety comparable versus Phase I observations? And then what are the specific criteria for dose reduction and what the protocols are in the Phase III part of the trial there?

Well, I'd say we've done a really good job. Investigators learned with 01 how to manage the adverse events associated with the Daro/Crizo combination. So we have a group of people that are familiar with its use. And so I think you'll see a safety profile that looks relatively similar to what you've seen before.

I'm pleased to say that because investigators, there's 2 things. People are very motivated to take the therapy, as you might imagine, when you have a disease, where there's no good therapies and the only good one is the one you're on. So they really want to stay on the treatment and investigators are getting better at managing the adverse events associated with it.

Because of that, I think you'll see at the end of this trial is a really relatively low dose discontinuation rate due to adverse events. It's going to be more about keeping the patients on therapy. We know that's important. And the KOLs that we've worked with are getting really quite expert in how to manage that. So I think we'll be in good shape there.

What about discontinuation -- not discontinuation, what about dose reductions? I would expect to see in later-stage trials as docs get more familiar with the drug, you see fewer discontinuations. But do you have an expectation for the number of patients who are going to down dose?

We'll have to see about that. But I would say there's a few things that are going on here. And the reason why I can't give you a number. 1, obviously, we're talking about a trial that only a few people can see the raw data to; and 2, talking about experience I've had with 01.

But there's 2 things that people do. And again, this is usually due to Grade 3 toxicity, which isn't terribly common, right? But usually, they do 1 or 2 things. They usually do a very short pause. We're being told by some that a 1- or 2-day pause is sometimes all it takes to get rid of some of the toxicity. The other thing they do is they typically lower -- if they're going to lower anything, they don't lower the Crizo, they don't lower the Daro. So they'll lower the Crizo dose slightly.

Again, I think with those 2 moves, they're able to keep a motivated patient on therapy for most of the time. And by the way, we have some data accumulating now that also implies that the toxicity happens mostly in the first 2 months of therapy and thereafter kind of weans itself off. So it gets more easily tolerated, it seems, in later time points, and we'll be sharing some of that data as this data evolves. But I think those are what I could say about managing the toxicity.

Thus far, the people that are running the trials are getting quite good at it. It's manageable. The dose reductions and discontinuation rates hasn't been high in 01. I don't think it will be any different here. And I think patients just want to stay on the study because the therapy is just so good compared to what the options are.

Makes sense. Umer unless you've got more on 02, should we.

Yes. Maybe just -- and I do want to sort of over the -- in the next 10 minutes or so bring it back to the big picture and some of the other pipeline as well. But could you just remind us for the prior data? I was trying to find it, John, do you have the prior data because I couldn't find it in our folder.

I was trying to understand maybe if you could remind us what percentage of patients had liver mets? What percentage of patients had LDH disease? I just find that as we often try to translate from prior data to the new trials, sometimes we can lose track of the baseline. So I just want to make sure I had it for my purposes.

We have to remember with uveal melanoma, virtually everybody has liver metastases, right?

So I was looking at these...

That's where this disease goes. So it's actually to have extra hepatic disease only is pretty uncommon. If you have both, that's even worse.

So Darrin, I was looking at a couple of Nivo/Ipi references like the GEM-1402 trial, it says 80% liver mets and 50% had non-extra liver mets. So I was going to ask.

That's in addition to liver mets, mostly.

Right. Sorry. So you're saying everybody had liver mets in your trial.

Well, the vast majority of patients will have liver mets with this disease because this is where -- that's where the disease metastasizes to. Additionally, some will have disease beyond the liver. And that's why things like liver-directed therapies are so big, right? Because people think, well, I can go after the liver and I can get a lot of it. But eventually, if you go after the liver too much, it will end up somewhere else if you live long enough.

Yes. So Umer, I've got the numbers here. So our frontline study that we reported at SMR.

The prior data.

Yes, the prior data, over 90% of patients were either hepatic only or had hepatic and extrahepatic. So only about 5% had non-liver. The [indiscernible] Phase III study, very similar. So roughly 95% had either hepatic extrahepatic and about 4%, so very similar to what we reported had non-liver disease.

In terms of greater than upper limit or normal on LDH status, both our study were roughly 1/3 of patients and the [indiscernible] randomized Phase III are very similar. It was roughly -- so that fine from their New England Journal paper. I'm not looking at that.

Super helpful, it's fairly balanced.

Before we move on, the one other thing that I want to make sure we talk about on 02 is when you -- how long will it take you to prep the filing after the top line?

So just so you know, sort of we're going with sort of average metrics here, right? So we're talking about probably around that 6-month time period in order to put the package together. And then, of course, the FDA has to review it. That's probably another 6 months. So that's sort of general guidepost, but we're obviously going to try to do everything we can to expedite the process for sure.

But that puts us to the first half, that's how we get to that first half '27 expected. Make sense, okay.

Okay. On 01 and the A2 positive patients, can you talk about when you'll have a breakout of that and how rapidly NCCN guidelines could proceed after a potential approval next year?

So I can sort of give you a high level of the entire package since we're probably running a little limited on time, but there are multiple things we want to do. We obviously want to submit this, get it to the FDA, get it to the NCCN panel. In parallel, what we'd like to do is get the HLA-A2 positive data out, that 100 patients, get it published so that the timing lines up, where we'll be able to, again, say something about the overall response rate, the progression-free survival, the overall survival, talk to them about the biology, how it's no different when you're going after protein kinase C.

And therefore, they'll have a couple of pieces of data. They'll have a randomized Phase III. They'll have a single-arm Phase II both relatively good size. They will show them that the data is very similar. And then the NCCN panel can decide what they want to do that. We suspect that they'll overwhelmingly welcome this treatment into both category of patients very robustly.

In addition, we're going to talk to the FDA about the opportunity to potentially get the HLA-A2-positive patients in the label. Could a real-world data set help? Are there other things that we could do in order to make that happen? That's a discussion that has to happen.

And then in addition, in parallel to all that is the neoadjuvant trial, the 09 study. We would like to get that published in parallel. Again, we've presented that data recently at ESMO, really exciting tumor shrinkage in the majority of patients, saving more than half of the eyes, improving vision, not only during the neoadjuvant period, but potentially long term based on a visual prognostication score. So it would be great, if they also had that body of data for published in their hands so that they can decide what they want to do with that as our studies continue to evolve.

Now on that neoadjuvant side, because that, as you say, very potentially very exciting. The data you showed at ESMO was excellent, but it's also 5 or 6x the size patient population-wise versus the metastatic setting. So can we talk a little bit about patient journey into the neoadjuvant or adjuvant into the surgical setting, when patients get diagnosed and how physicians are choosing the initiation versus brachytherapy and where Daro would live?

So just from a very high level. So a patient walks in and says, I have trouble seeing optometrist looks in their eye, they say, "Geez, we see something there. I don't like it. I'm going to refer you to an ocular oncologist." They do a workup, a clinical workup and they make the determination that the patient has uveal melanoma.

From there, in general, the movement is pretty rapid within weeks, the patient can be set up for either a nucleation, which is the removal of the eye, and those are tumors that are usually large and too large in order to be controlled by radiation or if the tumor is smaller and they can show a plaque to the eye, which contains radiation, they can do that. And both of these things are typically happen within weeks of the diagnosis.

And again, the problems that come downstream with that is obviously, if you lose your eye, you lose your vision. And then even if you get plaque brachytherapy, you may have saved your eye, but you may eventually lose your vision due to the radiation doses. And also there are toxicities that happen downstream of radiation, radiation, retinitis, toxicity, et cetera.

And so what we hope to see is in the future, someday, a patient will come in and get the diagnosis and instead of being sent off to having something sold to their eye or having a surgical procedure that removes their eye, it will be as simple as, you know what, I'm going to write you a prescription. You're going to take pills for up to 6 months, and then we're going to decide what we need to do. So it will be completely different, paradigm changing for this disease. And now we get prescription and you don't have to go directly into your primary local therapy.

But is that being done in the trial, though, Darrin?

Yes, exactly. That's exactly what's being done in the trial.

So like how it has 1/4 of the patients are in nucleation and the other 3/4 are not. Is that -- is the active arm not removing the eye in the nucleation subset?

So remember, it's almost like 2 studies in 1. So if we focus on the nucleation group. So these are the guys with tumors, they're going to get their eye removed. Basically, they get randomized, either you go straightly to get your eye removed or if you're randomized to the treatment arm, you get 6 months of neoadjuvant therapy. We try to save your eye. If we do what we've done in 09, we're going to save more than half of them, and they can transfer to a less invasive or less surgically extreme kind of treatment.

So you keep the eye, even after that surgery in this group then.

No, no you don't have the surgery. You don't get the surgery, and that's in the control arm, go straight to a nucleation or you don't have the surgery, you get neoadjuvant therapy instead. And if all goes well, you get maybe a plaque place there instead. Obviously, there are some patients that will have to have the surgery because perhaps the tumor didn't shrink.

But the off-ramp from nucleation is radiotherapy. And then in the radiotherapy cohort where there maybe the tumor is small enough where nucleation wouldn't be the primary treatment option.

You're mixing the cohorts again.

That's the second trial.

Just -- so focus on. There's only 2 options. You're either going to have your eye removed or you're going to get neoadjuvant therapy and then hopefully, something else will happen, right? Like they'll get a plaque placed or they'll get proton beam or external beam radiation or something. But...

But that is getting radiation. So you're moving from...

Only in the treatment arm if the eye is saved. Only in the treatment arm if the eye is saved. The enucleation group just gets their eye removed. That's the enucleation cohort.

So Darren, let's just -- sorry, before we go to the non-enucleation cohort, I guess this is a question both for you and Yujiro. Unlike a typical neoadjuvant study, because we're talking eye preservation here, could this form the basis of a very rapid filing in much more than the first-line setting?

So the only limitation is, remember, another one of the important endpoints for the study is event-free survival. So we have to show that we're not creating any detriment to delaying the primary local therapy. So with that has to read out. But the fact that we'll have known about saving the eyes very early, as soon as we hit the EFS events, you're right, we could actually take that part of the study and go talk to the FDA.

And defined by disease progression?

What's that?

Yes, it's relapse. So yes, Umer also, I would just highlight, as you know, typically, a randomized Phase III neoadjuvant study, right, you have to show superiority on EFS. Here, all that FDA has asked us is a no detriment threshold, which is much lower. And because of that, typically for an EFS readout on superiority, you got to wait for most of those events to occur, right?

Here, we think with about 1/3 or 40%, we'll be able to establish no detriment. So it could be just generally, as Darrin said, especially if we try to submit that enucleation portion first with the no detriment that's pulled across both cohorts for EFS, I think it would be faster than your typical neoadjuvant study, right?

But [indiscernible] is not sufficient.

Correct. Yes. We want to see no harm to EFS, which at least based on our single-arm data in neoadjuvant, we don't see evidence of that at this point. So...

And the definitions must be pretty well established for what -- who counts as an enucleation eligible patient?

Yes. Correct.

Exactly.

It's all about size. When your eyes -- because the radiation can only penetrate so far. So if the tumor is too big, you have to get enucleated.

Sorry, John, I guess maybe I'm curious how you guys think about it. So 6 months of -- so -- the comparator arm will have 100% enucleation right away. How does the active arm get established versus comparator arm? You just have to go all 6 months to be able to do that? Or could you just do it within the first 3 months?

So once you have a tumor that requires enucleation, you get randomized. One group will go to get their surgery. The other group will get the neoadjuvant therapy.

Right. But how long are they supposed to stay on there to establish that, there's a meaningful differentiation between the 2 arms?

I'm not sure I understand you how long are they staying on the therapy?

My point is let's say we took 120 patients, 60 got immediate enucleation. The other 60 now are on the drug. They didn't get it enucleated for now, but some of them are starting to. I guess, how much into that process on that other sort of -- on that active arm, are you able to say, okay, we're now starting to see that there's a 50% reduction in enucleation because that number itself would keep fading, right? It might start at 100 and it's fading.

We typically know in about 4 to 6 months for that patient...

This is what's happening. They're getting a scan every month, ultrasound every month, and they're getting treated for 6 months. And as soon as the tumor shows the maximum reduction in growth, that's when you take them to your primary...

Which is to say as soon as it starts to grow again, you sort of take them off neoadjuvant and go to the -- either a new vision or radiotherapy?

That happens, yes. That happens in the minority of patients, but most usually, they drop down, they shrink and then they kind of level off at the end, and that's when you take them.

And there's no Ipi/Nivo used in neoadjuvant?

No. I mean remember if you're going to be in a neoadjuvant setting, you have to shrink the tumor. These treatments completely tumor.

Right.

You remember, it's not -- obviously, the drug has got to get to the eye, right? So I mean, I think we're fortunate that clearly, we're having an effect there, but I don't think that's a given. And as Darrin mentioned, IO therapies, here, the objective is to shrink the tumor. And we know that...

IOs get used in metastatic settings, presumably because they may be doing something against the metastases, but they're not going to do a ton in the eye.

Exactly.

Exactly. So -- and Yujiro, wouldn't this recruit like right away?

I mean the Phase I/II single arm was extremely robust once we got the sites up. So that's our expectation. I mean I know the team is also...

There's a tremendous amount of inclusion.

Like with less than 6 months to recruit. So I guess let me just push it to an extreme. You started the trial in early '26. You could be fully recruited by ASCO presumably because people are getting their eyes removed, they will probably say, let me try this out, presumably, it's only 120 patients. And you track them over 6 months, you could hit all the events by December, January. Is that too extreme a scenario?

So for the full trial, we're guiding towards first half of next year, but that includes the plaque cohort. So could the enucleation enroll first and we get that readout first? Yes, that's a possibility, I suppose. But as noted by Darrin earlier, we still need to wait for the pooled analysis for the EFS, right?

Okay. And also -- sorry, my last one on this. There was -- I remember Bristol ran the study back when John and I were covering sort of all the Ipi/Nivo trial readouts. There was a trial called NADINA, I think, in Stage III neoadjuvant. I thought that had become standard of care. Is that not the case? Like you give Ipi/Nivo before resection. I realize it may not have much activity in uveal setting, but in general, isn't everybody is supposed to be getting Ipi/Nivo?

Yes, you're talking about skin melanoma maybe...

Different disease.

Different. That's why this disease is so unique, it's a...

So there were no uveal patients in those trials. Is that right?

Basically, this is a treatment that doesn't work -- the biology is completely different. Tumor mutation burden in this disease, low. RAS mutations, RAS mutation is low, if not at all. So it's just a different disease. It just happens to be -- it's a melanoma, of course, but they're driven -- ours is driven by a different set of mutations. It's wired differently.

I just confirmed.

Why do we give immunotherapy -- because we don't have anything else.

No, they excluded uveal. You're right. I just checked as well. Okay. Great. Great. Wow, so this neoadjuvant, usually, I see neoadjuvant, I was like, okay, that's like 5 years away, but that's not the case here.

We're hoping we can do faster than that.

Okay. Great. So in the last 10 minutes then, I want to do 2 things. A, I want to make sure we take care of any investor questions there are. But also just ahead of that, could you just sort of lay out for us sort of the size of commercial opportunity as well as sort of the highest conviction programs beyond this because I feel like there's other things happening, which we usually catch up on.

Sure. Josh, do you want to take the commercial market piece?

Yes, sure. So on the uveal melanoma side, so in the metastatic setting, we think that's between 4,000 and 5,000 patients incident globally. And that's really U.S., Europe, Australia. That's where those patients are concentrated.

And what's U.S.?

U.S. is roughly 1,500 a year.

U.S. is 1,500. Okay. And you're thinking of pricing as orphan?

So I mean, look, we're a big proponents of value-based pricing. It's going to come down to the sort of benefit that the therapies can offer. I think one benchmark people point to is obviously the [indiscernible] price, which is approaching $90,000 a month. So we'll see what our data looks like, but that's one benchmark out there to consider.

Okay. And then, Yujiro, from your perspective, this takes the company to profitability, this launch in metastatic alone?

So we haven't put out that specific guidance on profitability, Umer, but obviously, some of it will also be driven by our spend. We have other registrational studies across other programs we're looking to launch. So I think some of it will be depending on how we ungate a lot of upcoming studies.

But yes, look, we do think depending on the trajectory of that launch, Obviously, we have other readouts, including neoadjuvant that will be trailing. I think that's going to be part of the conversation as we move forward, absolutely.

Makes sense. And if you could remind us the cadence of readouts beyond this program for some of the rest of the pipeline?

Yes, sure. So I would say the next one probably most in focus is our [ DLL3 TOP1 ADC ]. Their enrollment in the U.S. and outside of Asia is starting to pick up. So we are targeting a clinical data update for that program for monotherapy by the end of the year. And at least based on the monotherapy activity that we and our partner are seeing, we do hope there is some monotherapy approval path that's going to be available to us.

In addition, we have current guidance around an MTAP clinical data update here with Trodelvy. We'll be pushing as hard as we can. Also, you may know we have a PRMT5 inhibitor that's now in Phase I. And so we'll see how that develops as well. So I would say those are several of the pieces. And I know our bispecific ADC is also in Phase I and that we anticipate that enrollment should also go quick. So we'll be closely monitoring the progress of that. But I would say that's probably another possibility as well.

One thing you didn't just mention that I want to make sure we touch on something we talked about at JPMorgan that really fascinates me every time we talk about it is the PARG, which I know is a potential combination agent for any of the Topo-ADCs. You said you're going to start those combinations with the DLL3 this year. Given how rapidly late-stage patients in small cell progress, fair to say that we could see those initial combination cohorts early in the next year time line, and we'll be able to look at them side-by-side with the DLL3 monotherapy data?

Yes. I mean we're planning -- Darrin, you should comment here, but we're planning to dose that combination here very shortly in about a month or so. So I think we should be in good shape on that one, John. And we've done a lot of work on PARG dose optimization. At least my personal sense is I think we'll get a sense of where we are pretty quickly, right, on that combination. So we could have data fairly rapidly on that. And I know the team is, I would say, very enthusiastic about that.

Even ahead of next year, could we have it...

Yes, it's possible. I think it's going to depend on how much follow-up we want and kind of the expectation around that. But there's obviously a durability piece, but there's also just around just pure response rate and do we...

PD-1, PARG as a mechanism with Topo is that something that we could get ahead of durability?

That's the idea. Yes. That's the idea. I mean that could be a differentiating factor for us really to put us above the rest. And it could apply to other ADCs as well. I mean that could be a unifying message that if you have a PARG inhibitor along with an appropriate ADC good target that carries a Topo payload, this could make a difference. That's -- we hope that will be the first test, but it won't be the last in DLL3.

Makes sense. Okay. So last 2, a couple of investor questions. One, expected timing of filing for accelerated approval after the March readout?

Darrin, do you want to hit that? We haven't given specific...

Yes. We kind of basically spoke to that before, right, about 6 months to put the data together and then 6 months to -- so something that's kind of where we're sitting.

And that 6 months is presumably also to get some OS looks. Is that right, Darrin?

Yes, yes, absolutely. I mean we'll share as much as we can. Again, we'll get some of that at the top line, but it may not be very mature. We'll probably get more of that during the filing period. And then, of course, the first interim will read out the first half of next year.

So you don't need to wait for first interim?

We will be providing follow-up data with the FDA. They're going to want to see follow-up safety data during -- once you initially file, they're going to ask for 120-day follow-up information. And so that could be part of the package potentially.

You give them what you have presumably at that point.

So the idea would be you file by August, September. And then the 120-day update allows you to get that first OS interim in there. Okay. Makes sense.

I wouldn't call it a first interim, I would just call it an evaluation, the data could be available for the FDA to review at that time. The official interim won't happen until the first half of next year.

Per stats plan deal.

That's exactly. Per the statistical analysis plan, right? Exactly.

Okay. The last program I think we didn't touch on is KAT6/7, which obviously is getting started in Phase I imminently. We saw Pfizer make their announcement on the dual inhibitor. Can you give us the 3 -- the 2-minute pitch on where your version of this inhibitor stacks up relative to some of the others we've seen in the clinic?

Sure. Mike do you want to take that?

Yes, absolutely delighted to talk about that program. This is potentially very meaningful for patients. It's part of our central strategy to address tumor heterogeneity. What we have found, what we've shown is you want dual potency on KAT6 and KAT7 in order to be able to intercept these tumor genic transcription factors that are present in breast cancer, lung cancer, colorectal cancer.

Our asset with respect to the clinic is the only one that I'm aware of that has that profile. We have not profiled Pfizer's asset, but we do know that the other assets that are out there in the KAT6A/KAT6B space, we think do not have the capability to deliver that profile on KAT7. And that is critical because KAT 7 can substitute for KAT6A, KAT6B and the regulation of chromatin. And that's also critical because we and others have shown that KAT7 brings on a very meaningful biology that will intercept both intrinsic and acquired resistance, and those are 2 of the big conundrums facing precision medicine.

So KAT7 inhibition together with KAT6 that can kill tumor-resistant cells that are drug-tolerant persistor cells, therapy-resistant drug-tolerant persistence. So that's an intrinsic heterogeneity mechanism. And then also KAT7 is required for the self-renewal of tumor-initiating progenitor-type tumor cells, these so-called cancer stem cells that are a wellspring of acquired resistance. So a very exciting program, large patient populations available to us based on intercepting lineage-specific transcription factor activity, as I noted, breast cancer, lung cancer, colorectal cancer.

Mike, the one thing that I want to make sure we tease out of what you just said is the dual potency against KAT6 and KAT7. We've seen numbers from Pfizer's program from some of the others that suggest that you get good nanomolar or single-digit nanomolar potency against 6A, 6B and then maybe you could have in the order of 1.5 to 2 orders of magnitude before KAT7 and then 3 orders of magnitude before you're getting to KAT5 and KAT8 where you'll have the toxicity.

So when you say you want to hit both at the same time, in your opinion, is getting 10x or 50x more selectivity for 6A, 6B, is that like enough hitting 7? Or do you really need to be right on top as your curves look like?

I think that's a great question, and it's really important for people to be able to actually deeply evaluate the mechanism of action here. So what we have seen is you want dual potency, you want low nanomolar potency on KAT6A/B and 7. I have seen a lot of data, our own data, other assets, data. When people are looking at a 10- to 50-fold window for biochemical activity, what we have seen is that translates to a 200-fold window or more, sometimes as much as a 1,000-fold window with respect to cellular target occupancy.

Biochemical activity does not take into account the multivalent complexes that are controlling these enzymes. -- and are making a big contribution to your ability to cover that enzyme in cells and compete with everything else that's going on in that setting. So super important to have a clean line of sight on your PD to understand what your target coverage needs to be.

And we have shown empirically that this matters a ton. If you're looking at your preclinical models, PDX is coming from patients that have progressed, for example, on Ibrance fulvestrant, you cannot cover these with the clinical KAT6 inhibitors. You can't even cover them in combination with palbo and fulvestrant, but we can hit them with the KAT6/7 dual. So very, very clean, very, very robust demonstration of the exposure profiles that you need when you have a dual potent KAT6/7 that you can't get if you don't have that low nanomolar potency in that very small window between the 2. And you do have to stay away from KAT5 and KAT8, as you noted.

Yes. Excellent. Well, I think we're unfortunately out of time. I feel like we could get -- Mike, I'd love to have just you on the next webinar, so we can really get nerdy on the biochemistry there.

Yes. Fabulous. Obviously, a lot to talk about. We spent most of our time on Daro today, but there's a whole ADC platform, PARG, MTAP and KAD6/7 to talk about as well. So thank you guys so much for being on with us. We really appreciate the time this afternoon. Thank you.

Thank you for having us.

Thanks so much for the time today. Bye for now.

Bye-bye.

All right. Great. Welcome, everyone, to Citi's 2026 Virtual Oncology Leadership Summit. We have a smattering of small mid-cap and large-cap companies over the next 2 days doing fireside chats. We also had a KOL call this morning on breast cancer.

But this session, a very important one, is with the senior management of IDEAYA, and it's my great pleasure to introduce three of the executives at the company. Josh Bleharski, CFO; Michael White, CFO; and Darrin Beaupre, CMO. And just remember, for those listening, if you have questions for any of these gentlemen, please e-mail me at my Citi e-mail address, and I can relay them over to the company

So welcome, everyone. Thank you very much. Josh, maybe we could just start off, if you don't mind, with a kind of a quick level set. You have a lot of programs, but you have obviously a very important catalyst coming up in MUM. So just give us a few high-level thoughts as far as where the company is now and what are some of the key things to look forward to in the next quarter or 2.

Yes, sure. Thanks, Yigal, and thanks to Citi for hosting us today. So IDEAYA is a clinical-stage precision medicine oncology company. We have about nine programs in the clinic today led by darovasertib, which is our lead molecule for uveal melanoma. I think as you mentioned, we have an upcoming top line data release for the combination of darovasertib and crizotinib in the metastatic setting of uveal melanoma.

As we noted in our Q4 earnings release, we have triggered the 130 events required for the top line analysis. And we are in the process of collecting that data and analyzing that data and expect to put it out at the end of March. So very exciting data event on the near-term horizon here. Beyond the metastatic setting, we're also exploring darovasertib outside of the metastatic setting in the adjuvant and neoadjuvant settings, we're already enrolling in neoadjuvant study and expect to begin enrolling in the adjuvant study in Q2 of this year.

So exciting to see where darovasertib can add benefit beyond this initial metastatic indication. Beyond darovasertib, we do have a deep pipeline, I'd say, next asset is our DLL3 Topo-I ADC that is expected to begin, well, it is in a Phase I study currently in the U.S., we're enrolling patients. We've guided to providing an initial Phase I data update from that trial by the end of this year. And also to initiate a registrational study as a monotherapy in sort of later line small cell or NEC at the end of this year as well.

We also have a number of assets focused on the MTAP space, led by IDE397, our MAT2A inhibitor that we've been exploring in combination with Trodelvy for MTAP-deleted urothelial cancer. We'll look to provide an update from that study in 2026 at a medical meeting. And then obviously, earlier in the pipeline, we have a number of assets that are entering the clinic now led by our bispecific B7H3/PTK7, Topo-I ADC that's entering Phase I studies right now in our KAT6/7 dual inhibitor IDE574, which is also entering Phase I studies right now.

We ended the quarter with about $1.5 billion in cash, and our runway is into 2030. So I feel like we're well positioned for 2026 and looking forward to the top line release.

Okay. So that's a very good outline for the next 45 minutes. So if we could start maybe with the immediate catalyst. I know there's a limit to what you can say since you just got to lock the database of understanding or in the analysis phase.

But can you just kind of at a high level, just remind us what the study -- how the study is designed, what are the key -- what should be the expectation in terms of a positive scenario for the study? What would you expect to see both in your -- in the combo arm, as well as in the control arm. And maybe we could talk a bit about some of the patient demographics as well after that.

Right. So I can give an overall summary. In terms of the patients that are enrolled, that we think the patient population is going to be very, very similar to what we've seen in our 01 trial and the TEVI study. So we're talking about now a study in metastatic uveal melanoma, specifically in HLA-A2 negative patients. Where we're asking the simple question is how does the darovasertib crizotinib compare to what would be considered standard of care in this space.

And today, it depends on what part of the world you're in, in the United States. First-line therapy typically is immunotherapy, which often includes the ipi/nivo combination. If you're in Europe, they frequently use single-agent checkpoint inhibitors. And if you're not a candidate for immunotherapy, occasionally chemotherapy is used. And so those are what the treatments are -- which are available in the comparator arm. That's the control arm.

So what are the expectations for the kind of output you might see? What is -- what are people aware of in terms of benefit from those kind of therapies? So focusing in on the control arm. There were two large meta-analyses that we've presented in our SMR abstract nice curves, both from PFS and OS. One of them was the Rental publication enlargement analysis, thousands of patients, same with the Australian meta-analysis. But both of them show that in general, the expectation for standard of care therapy in this space is a median progression-free survival of about 2 to 3 months. That's pretty standard.

And then in terms of overall survival, you're looking at about 13 months. Now if you look at the darovasertib in crizotinib combination, the data that we presented recently at SMR and asked, okay, so what does that data look like? There, we presented that the median progression-free survival in first-line patients was about 7 months in the median overall survival was about 21 months. So significantly better than what's been reported with standard of care agents in terms of progression-free survival and overall survival.

In terms of response, again, standard of care therapies delivers a response rate of around 10%. And then that SMR presentation, we showed that we have a 30-plus percent overall response rate. So in all of the major parameters, ORR, PFS, you're looking at, at least a doubling to tripling of what standard of care therapy does and then with OS an approximate doubling. So that sets the stage for this randomized trial, which, again, as Josh has pointed out, we have the events necessary to begin the data cleaning process. The query resolution process and the data evaluation process to generate the data set.

Again, success criteria here. We're expecting that the control arm will produce a median progression-free survival of 2 to 3 months. And based on our success criteria of 5.5-month median progression-free survival in the daro crizo arm would equate to success. But we think we're going to beat that. We think we're going to beat it by a lot. What we would implore people to consider as they look at the data as we will share it at the end of this quarter around that period of time is to really look at the hazard ratio, right?

Because it's really the comparison between the two arms that really tells you the story. We don't expect some people have are, oh, maybe the control arm is doing better. But you have to remember, we're scanning people every 6 weeks. And so therefore, we're likely to see events earlier than some of the other trials that have been conducted. And so I think it's unlikely that the control arm is going to do much better than what's ever been published before. Very unlikely.

And so therefore, this 7 months or so of what you see with darovasertib is likely to be magnified. But again, the data will speak for itself. We'll see it soon. And so what may you hear at the time of the top line, the kind of things that would likely to provide you are, what was the overall response rate for the treatment control and the control arm. What was the durability of that, maybe in the case of duration of response. We obviously will provide what kind of progression-free survival we've seen and maybe a confidence interval.

But one of the other things I wanted to point out, if we don't say anything about overall survival, that doesn't mean there's a problem with overall survival. What it likely means is that there'll be -- there's just not enough events to make a call at this time. So again, we're looking at this early. The first interim for OS happens at the beginning of 2027. However, during that period of time, the FDA will have the opportunity to look at overall survival from data generated from the study, not only at the time of the top line analysis, but also, during the filing, as we provide updated safety data, we're likely to provide an efficacy update there as well.

So long and short of it is, we think we have a high probability of success based on the data that we showed at SMR. We believe that the control arm is going to perform exactly as what's -- how it's performed in thousands of patients based on two large meta-analyses. We think the data from our SMR publication is very robust. It's got 2 years of follow-up and the data has been very solid through that entire period of time. So really, hopefully sets the stage for a very important study for patients with uveal melanoma, which you know have very few options, only one approved therapy, and that one approved therapy has a response rate of around 10% and a median progression-free survival of 2 to 3 months. So this, we think, will be an improvement on what therapy is out there for this disease.

Okay. So that's very, very helpful. So if I understand correctly, your point is that because you're scanning at this higher frequency every 6 weeks, therefore, you should be able to capture some of the early progressions. And therefore, that pushed this expected range of 2 to 3 months to the lower end?

It might. I mean, I'm speculating. But remember, when you get a scan at 3 months as that's the first time you get a scan, you could have progressed 2 months before that. You never know it because nobody scanned them, right?

So -- and with immunotherapy, sometimes they even treat post progression, right? So the progression events could actually happen earlier, not later. But you know what, the data will speak for itself. I don't believe, based on all of the data that's been published that the control arm is going to be much better than what we've seen in these meta-analyses.

And if that turns out to be the case, and we're doing earlier scans and we have a rock solid 7 months for progression-free survival, with our daro crizo combination, I just don't see how it could lose. But you know what, the data will speak for itself.

And you mentioned that you think you beat the -- the 5.5 is sort of the threshold number, whereby if you get 2 to 3 in the control and you hit 5.5% in daro criz, then it works?

Correct.

And -- but you said that you think you could beat that 5.5 by a lot. And that's based on -- tell us more about that, that's based on the Phase II experience? Are there other factors that drive that statement?

Yes. No. So well, the statement is around the 7 months. So 7 months is clearly better than 5 months, 5.5 months, right? So that's what I'm talking about. I'm thinking we're going to be better off than 5.5 months. But again, how much, I don't know. But when the data reads out, that's when it will tell us. But that number has been pretty stable, pretty stable.

Okay. And then there was also some discussion, I think, over the last several months related to the relative proportion of ECOG 0 versus ECOG 1 and that relative proportion may give you some tailwind. Can you just expand upon that?

Well, there was some more patients with -- like if we're comparing across the TEVI study to our 01 trial, there were more performance status in our study relative to the TEVI study, suggesting that the data that we have may actually be better in a similar patient population to the TEVI study. But the reality is, is in the registration trial, I suspect all these things even out. It will be a patient population that's very much akin.

Now in terms of the geographic, there may be some variance there because that's another question that comes up a lot. We're probably -- if I had to guess, we're going to have probably about 60% U.S., 40% EU, and it might have been sort of flipped with the TEVI study.

So obviously, they didn't have any ipi/nivo in that particular study, but we'll have a significant proportion of ipi/nivo in our study, probably at least half of the patients will have ipi/nivo. So those are some interesting distinctions between the two. But again, most people -- ipi/nivo, this is going to be the study where Marlana Orloff said it herself just yesterday is an interesting study because people are going to also be able to look at how does ipi/nivo compare to single-agent checkpoint inhibitors. And if you -- based on everything we know today, we would expect it to be more toxic. So that wouldn't surprise us if we saw that.

And then in terms of efficacy, many people believe especially in terms of overall survival, even in PFS, there's probably no difference between single agent checkpoint inhibitors and the combination. You might have a little bit of a leg up with a response rate with ipi/nivo, but she says, you know what, those are all been small studies. This will be the largest study that actually looks at that. And the way we've designed it, we've designed it purposely to say that, you know what, we're the king, we're the best therapy out there. You can't argue that we didn't have the right controls. You can't argue that we didn't have the right designs, I can't argue that we didn't have the right output with a strong PFS, and it all set, I think, the new standard for what goes on in uveal melanoma. But again, the data will speak for itself, and we'll be hearing about that soon.

Now what you mentioned also that OS, you may say something, you may say nothing, don't interpret saying nothing as a negative in any way. But what would -- what sort of -- what percent of events accrued in OS would be enough to be able to make some sort of statement on a trend or otherwise?

Yes. Like many people think it's around 30% or so. If you're kind of less than 30%, what can you really say? You're starting to get above that 30% threshold, you start getting some confidence. Obviously, the higher you get above that, the more confident you become. So if we're sort of at a threshold where it's still a bit too early, we'll just probably be silent on.

But it sounds like you -- I mean, it's not so far away that it's a definite no. It sounds like you may be getting close to that. Is that fair?

Well, and like I said, we have -- there's this opportunity that we have to look at the data during the filing as well, as well as the time of the first interim. So between the top line -- and the first interim that happens at the beginning of next year, there will be an opportunity to look at the data. And then we'll see how it matures.

Remember, an important factor here is this study doesn't allow crossover, right? There's no crossover because we want to preserve overall survival. That's what the FDA wants to do, right? But if there's an obvious trend to improvement in overall survival, and it's unlikely that it's going to reverse.

Now we have an ethical dilemma, don't. We have something to think about for patients. How long are we going to wait before we allow them to cross over. And so that's a discussion that has to be had with the FDA as the data evolves. It's a discussion that has to be had with our independent data monitoring committee. And again, it's all about the data and how it evolves. And if it evolves in the positive direction, highly positive, really, these are the kind of discussions we have to have.

Okay. So but for the immediate situation for the end of March, we should not expect anything to be said about OS. Is that the plan?

I wouldn't say that. I would just say that if you don't -- what I said was is if you don't hear anything, don't misinterpret it.

Okay. And then -- but the -- but then you have a formal interim OS at the beginning of 2027, which would be triggered by what percent?

Yes. So that number of events will be north of 30% for sure.

Okay. Got it. And then, maybe we could just turn to like assuming you hit as well it seems very, very, very possible with the numbers that you've cited. What would the filing time lines look like for accelerated approval? What would you -- how would you approach the HLA-positive group, for example? Can you speak to those questions?

Yes. So standard metrics just in terms of filing an FDA review in a case like ours, again, we're going to try to compress this as much as we can, but it's about 6 months to file. We'll try to compress that. And then obviously, the review by the FDA will be 6 months at least. So that's the time period.

And then in terms of the HLA-2 positives, we're very excited about that group. The biology says there shouldn't be any difference. We presented data at ESMO in 2023 to show that HLA-2 site patients behaves the same as HLA-2 negative at least when they get treated with the daro crizo combination. We have a data set that's evolving from our Phase II trial, the 01 study that is accumulating about 100 patients' worth of data who are HLA-A2 positive, some of which are treatment naive, but I think a significant proportion of them will be heavy exposed. And we hope over the next year to be able to present that data in two chapters.

Chapter 1 will be maybe the first half of the patients because there we'll have about 6 months of follow-up data from that first group of patients that was enrolled. Where we'll be able to share the overall response rate, progression-free survival and perhaps even some OS data depending on how mature the data is.

Again, what the idea is showing that the combination is very active in this patient population. And then around the time of the filing, around the time of the approval, what we want to do is get this publication out on HLA-A2 positives that will be that whole 100 patient sample size where at the minimum, we can publish that data provided to the NCCN group to evaluate to consider as part of the NCCN guidelines for therapy with patients -- for patients who are HLA-A2 positive. As you know, their treatment options are very limited. With the only approved systemic therapy being TEVI, so it will be an opportunity for patients in the United States to get access there.

But we're also discussing ways we could have a discussion with the FDA about how we could potentially get this on the label. As you know, we're talking about an orphan indication with a large unmet medical need with a very short overall survival in general. So it will be interesting to have that discussion with the FDA around their thoughts. Potentially real-world data could be interjected in the discussion.

But also, there's something to be said about just the fact that the biology says that this combination doesn't work any different. We'll have data to support that it doesn't work any different. And so talking to the FDA about the opportunities for the label will be something that we'll be doing over the next -- over this year as we get into the launch phase.

Okay. Well, let's move on to quickly talk about the other -- some of the other lines you're looking at. Adjuvant and neoadjuvant. What are the -- remind everyone what the time lines are there for getting to the critical readouts for those populations?

So just recall, the registration trial for neoadjuvant darovasertib single agent and primary uveal melanoma has two cohorts, right? The first cohort of patients with large tumors those who are destined for a nucleation where the primary endpoint is saving the eye.

And then the second cohort are patients with smaller to midsized tumors where plaque brachytherapy is the therapy of choice. And there, it's preservation of vision as the primary endpoint.

An important endpoint for both cohorts though is event-free survival. We need to show that by providing neoadjuvant darovasertib in delaying primary local therapy, we don't provide any detriment to patients. And so what we'll do that is show that by using neoadjuvant darovasertib, we provide no detriment with respect to local or distant relapse. So that's the tumor coming back in the eye or the tumor metastasizing. What we have to show is there's really no detriment to subjects when we give this neoadjuvant therapy.

In terms of enrollment, it's going to take probably a year to 1.5 years to enroll subjects and the readouts will take about 1.5 years from the time of primary local therapy. Now with respect to the readouts, it could be that the enucleation cohort actually reads out earlier than the plaque brachytherapy cohort.

You can imagine that being the case when you're only giving up to 6 months' worth of neoadjuvant therapy. And so within that period of time, you'll know whether you save the eye or not. So the rate-limiting step really will be the event-free survival readout. But again, we may not have vision data from the plaque brachytherapy cohort at the same time that we have all of the nucleation data.

So therefore, it remains possible that we read out on the nucleation first. We present that to the FDA, followed by the plaque brachytherapy data. However, if the two data sets come out closely opposed in timing, we may try to file them both together. It really just depends on the timing, but our suspicion is we'll be able to read out a little bit earlier with the nucleation cohort relative to the plaque brachytherapy cohort.

Okay. And so that would put -- if they are kind of proximal to one another, that would be roughly when in a calendar time frame?

Well, again, as I mentioned, 1.5 years to enroll and then 1.5 years from the time of the primary endpoint. So a minimum 2.5 years. We just started dosing.

Yes, Yigal, what we've guided to is being done on enrollment for neoadjuvant in the first half of next year. So that's all.

About 1.5 years from there.

All right. And then what about the adjuvant study?

Adjuvant study, great question. So that one is on the slate. We're actually putting it together now, plan a discussion with the FDA coming up Type C meeting. We have a trial design in hand. Again, there, we're going to take patients who are at high risk of metastases, which is at least half of the patient population. They're going to be randomized to your standard observation, which is what we're doing today, just monitoring patients, waiting for them to relapse.

And again, the median time to relapse is about 3 years. So there's a huge proportion of patients at least in this group, probably 70% to 80% that will metastasize by the 3-year time point. And so what we'll be looking at is a comparator of daro crizo for up to 1 year versus observation -- and so what we'll be attempting to do is show that by providing the darovasertib crizotinib combination that we can reduce the number of metastases down the road in patients who are high risk for metastatic uveal melanoma. So that trial is sort of in swing. It's underway, and we hope to get that launched by midyear.

Okay. All right. Let's move on and quickly to some of the other important topics, and we covered a lot on uveal melanoma. So for the ADC program for the DLL Topo-I ADC, maybe you could just talk a little bit about the time lines there on small cell and neuroendocrine and when we could expect the next readouts?

So that -- so you've seen, obviously, the data from China, it's presented at the World Lung Congress highly exciting, very high response rate with this molecule, 70% with progression-free survival, 6 months or better based on some of the early reads. So it looks very exciting. Our U.S. study based study has just launched just starting to enroll. We think by the end of this year, we're going to have safety data.

The nice thing about this study is we were able to start the dosing at a therapeutic dose level. So there really isn't any subtherapeutic dosing envisioned for the trial. So right from the get-go, right from the first patient, we can start expecting some efficacy data to come in. So there will be a dose escalation that goes on in U.S. patients with our antibody as a monotherapy, but in addition, we'll also be combining it with 161, which will be triggered in the second quarter as we get the first initial data from the first cohort of enrollment for this study.

And in addition, what we'll be enrolling is both extensive stage small cell lung cancer patients, but also neuroendocrine carcinoma subjects. So by the end of this year, what we hope is we'll have maybe two handful or more worth of patients where we'll be able to provide some preliminary response data, maybe some durability of response data.

We'll be able to provide safety data both as a monotherapy and in combination with 161, and we'll be able to provide some early data in some subjects with neuroendocrine carcinoma. Again, we won't have a lot of follow-up because, again, we're just starting to enroll now, so it won't be long-term follow-up, but the initial safety and efficacy data is what we hope to put out sort of by the end of this year. That's sort of where we stand with the Phase I currently.

Maybe I can ask Michael this one or you, Darrin, the combo you mentioned with the PARG, the 849 plus 161, what's the -- just remind us why that is potentially synergistic. What is the biological rationale there?

Yes, absolutely, Yigal. So first of all, DLL3, it's an amazing target. This asset is doing really well as a monotherapy. But as you know, the value proposition is also around durability. And with respect to ADCs with topoisomerase payloads, the ability of the payload to kill those cells is a function of DNA damage as well as DNA repair.

And if you get enough payload in, you kill the cells, if you don't, you get progression. And so what we're looking for with this combination is to get durability by maximizing the therapeutic benefit of the topoisomerase payload. The mechanism of action behind that is a very special role that PARG plays with the resolution of topoisomerase I cleavage complexes. So the way these inhibitors work is they bind topoisomerase I, they clamp it on the DNA together with a break in the DNA. That complex gets correlated by PARP. And then it becomes a substrate for DNA repair.

However, in order for that to be repaired, it has to be deporelated first so that the proteasome can come in and chew off the topoisomerase. There's only one enzyme in the cell that does that, PARG. So PARG is essential for the resolution of topoisomerase I cleavage complexes. So whatever topoisomerase inhibitor gets in there, we are trapping that cleavage complex on the chromatin replication for comes through and it collapses.

So we are amplifying the therapeutic benefit. If we have suboptimal payload delivery, we can get now a more optimal therapeutic response. Very exciting mechanism of action. So we are really looking for enhanced durability beyond what you would be able to get with a monotherapy opportunity. which leads us, by the way, into our selection of IDE034, B7H3/PTK7 bispecific. We have another opportunity there that's distinct, if you want to talk about that at some point.

Let's do that right now. Yes, tell us what's the synergistic thinking there?

Yes. So the point for a bispecific for us is to be able to maximize tumor-specific delivery of the topoisomerase inhibitor. And we pick B7H3/PTK7, these are both targets that have been validated in the past. Both of these targets make biological contributions to the tumor itself. PTK7 is particularly interesting because it is enriched on the surface of tumor initiating cells that are the cells that produce diversification and tumor heterogeneity that leads to adaptive bypass mechanism.

So very nice if we could get rid of those cells within ADC. The point of the bispecific is we have an asset that has been built to have enhanced binding to double positive cells, B7H3/PTK7 double-positive cells. There are abundant evidence using protein for large populations of tumors in important indications like lung, colorectal, triple-negative breast cancer, ovarian, prostate, head and neck, that have double positive tumors. And the only normal tissue where we're seeing double positivity is endometrial, otherwise is single positive.

So bispecific, much more enhanced binding to tumor versus normal, get good therapeutic window. That can come at a cost for payload delivery, the amount of payload that you get in, we are going to maximize that with IDE161. So we're expecting this ADC, IDE034 to be really exciting for monotherapy. And then in combination with IDE161, PARG inhibitor, will maximize the therapeutic impact of that payload that's delivered precisely to the tumor. So we're expecting nice response rates with durable responses in some really important tumor types.

Yes. I think that's the part, Mike. It's going after the big tumor types, too. So the potential here is very broad, and it's within the big tumor. So the commercial opportunity, this drug is active could be quite large to say the least.

So the ones that express B7H3 and PTK7 would be what you mean like lung, breast....

Yes, all the big ones, all the good ones.

Significant populations of lung adenocarcinoma significant populations of BA triple-negative breast cancer, HRP, ovarian cancer, prostate, head and neck.

And have we seen anything yet clinically for that?

Just starting to dose now, just starting the dose now, getting ready to dose.

All right. So then moving on, it's a lot to cover in 40 minutes. But so the MTAP is a huge topic, obviously. So we're expecting an update, I believe, for the MAT2A 397 and Trodelvy. So you've gotten some good data so far, and I think you've arrived at a dose. So can you just talk about what the -- what you envision seeing there with this combo in the next update?

Yes. So just from a high-level point of view, as everyone knows, we've been working on this Trodelvy 397 combination in MTAP deficient bladder cancer. We've presented that data previously. So essentially, that data set has grown since the last you've heard and the data continues to look quite promising with a high response rate and the durability continues to mature.

I think what it's done for us is it's really helped us prove the principle of if you get in there and you inhibit -- you get in there with a MAT2A inhibitor and you add in a toxin like Trodelvy carries, you see some special activity. We think we're clearly doing better than Trodelvy could do in this patient population by itself.

And so from that perspective, we think we've generated some proof-of-concept data that's exciting about other -- that raises the potential about other ADCs that could be used with a similar toxin.

Again, as you know, we're expanding out into lung also. So in lung cancer, that data is still evolving. We're still early days needs more data maturity. But suffice it to say, I think we've kind of proven the point that we have an active regimen here, clearly in bladder cancer, still evolving in lung and we're still discussing exactly how to proceed going forward. But we're really, really encouraged by what we've seen so far. I don't know, Mike, if you want to speak anything to just sort of the proof of principle of the biology here.

Yes. I think I'm right with Darrin on this one. I think it's very exciting that we essentially have proof of concept of the notion that we can amplify replication stress with a combination like this one and do something special.

This is something that we've been looking at from a mechanistic perspective for quite some time. alternative splicing, you mess that up, you cause pausing of RNA polymerase that gives you transcription replication conflict, replication stress and then IDE397 because of its role in the methionine cycle is reducing the capacity of these tumors to be able to produce the nucleic acids by the de novo synthesis and salvage pathway that they need to be able to deal with repair.

So we're increasing damage, we're reducing the ability to repair and we're seeing that work in patients. So very excited about that. And don't forget the magic here is the ADC with the Topo-I payload. We've got proof of concept with urothelial with Trodelvy. I think there's no reason for us to think that this would not work with other ADCs and other indications. So a lot of room here for us to think about additional opportunities with this combination in MTA all tumors.

Okay. And the thinking with the other combo with 892 and PRMT5 is totally different combo, but what's -- how is that -- what are the advantages of that one versus Trodelvy? It's obviously a totally different thesis biologically.

Yes, totally different mechanism of action. And this one is also very important, very exciting, particularly, we think in the context of lung cancer.

Lung cancer is a very mechanistically heterogeneous disease. It has lots of adaptive bypass mechanisms. We know that tumors on PRMT5 inhibitors have acquired resistance. We know that PRMT5 inhibitors cause alterations in chromatin architecture that enhance phenotypic plasticity that leads to resistance.

And we know that IDE397, an MTAP inhibitor -- sorry, an MTA, a MAT2A inhibitor will intercept that modulation of chromatin in order to be able to give us a durable response. So that combination, we can inhibit bypass mechanisms of PRMT5 inhibitors, but we can also maximize the ability of perturbation of alternative splicing to work in MTAP null cells because the whole synthetic lethal principle for MTAP loss is MTA accumulation. MTA accumulation allows MTA cooperative PRMT5 inhibitors to work.

They allow MAT2A inhibitors to work, but MTA accumulation in tumors is variable. It depends on the extent of polyamine synthesis. It's a byproduct of the production of polyamines. And that combination we have shown can maximize the MTA/SAM ratio to be able to maximize the synthetic lethal effect. So we think we will get deeper responses in the combination setting because we extinguish the pathway in the MTAP in all cells, and we think we'll get more durable responses because a MAT2A inhibitor intercepts adaptive bypass mechanisms that otherwise occur with PRMT5 inhibitors.

Okay. And then there was a third one you just nominated, the CDKN2A candidate. How -- that's also sort of in this pathway broadly. How does that play into the biology? And what additional tumor types could you access by attacking that?

Yes, that's a great question, Yigal, because the 15% of the tumors have MTAP loss, maybe 15% of lung cancer, 20% to 30% of pancreas, 25% to 40% of urothelial, 20% of esophageal, 17% head and neck, big populations.

Those get -- those happen because actually CDKN2A is lost. So CDKN2A loss is the most common co-alteration with MTAP loss because CDKN2A harbors two of the most important tumor suppressors known to mankind. You lose those things, you release cell cycle progression.

We have a way in to be able to attack that co-alteration and use that as another mechanism of action to deploy with PRMT5 inhibitor, MAT2A inhibitor or actually maybe even a triple combo to be able to maximize the insult on the tumor that has these 9p21.3 regions. So CDKN2A loss drives MTAP loss. So everywhere you have MTAP, pretty much you have loss of CDKN2A. So we're excited about this combination. And as long as we're on the topic of combos, we're really trying to do as much productive damage as we can in this MTAP space and in pancreas cancer, where the frequency of MTAP loss, CDKN2A loss is upwards of 30% CDKN2A deficiencies are even higher, perhaps the majority of pancreas cancers.

The big co-alteration there would be KRAS, right? So KRAS is mutant in pretty much all pancreas cancers. And so we have also been looking into that combination. We've been talking to some folks who are excited about doing that. We're in a unique position in pancreas cancer potentially for KRAS PRMT5/MAT2A triple combo. That's a very, very hard space to play in pancreas cancer. So you need a very effective therapy with a good therapeutic window.

Okay. Well, we're not able to get to everything because you have a lot, and we're kind of out of time. So we'll leave some of these other topics on KAT6 and Warner for the next meet up. But I appreciate all the details and the thoughts on melanoma and MTAP and the DLL3. And we're, of course, looking forward to the readout at the end of March, as you point out. So thank you again very, very much.

Thank you, Yigal.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, [ Priyanka Grover ], [ Joyce Sau ] and [ Roti Pinhe ]. Our next presenting company is IDEAYA, and presenting on behalf of the company, we have CEO, Yujiro Hata.

Well, thank you, upon for the introduction. And thank you again to JPMorgan for allowing us to present at the 44th Annual Healthcare Conference at JPMorgan.

Please note, we'll be making forward-looking statements today and please refer to our SEC filings as appropriate.

Since IDEAYA's founding 10 years ago, we've had several strategic guideposts that have led our organization, including first-in-class targets, predictive biomarkers, rational combinations and early-stage disease. Those strategic focus areas has led us today to have 4 clinical pipeline focus areas that we'll cover during today's presentation.

The first is darovasertib. This program is now in a registrational study and we are guiding towards top line results this quarter to enable our potential first accelerated approval filing in the United States. We believe darovasertib is truly a unique molecule and has the opportunity to potentially define this indication up melanoma across both the neoadjuvant, adjuvant and metastatic settings.

Next is our focus in the area of ADCs and damage repair. For many of you that have known us for the last 10 years, know that DNA damage repair has been one of the core scientific focus areas for the company. And we believe one of the greatest opportunities in antibody reconjugate space is to identify combination opportunities to extend durability and ultimately, survival.

Next. Third is our focus in the area of MTAP deletion. For those that you may know, MTAP deletion is often co-deleted with another key tumor pressure gene called CDKN2A, which is on the 6 P12 chromosome. Unfortunately, today, there are no currently approved therapies for this biomarker-defined patient population, which represents roughly 15% of solid tumors. And I would say, alongside RAS, MTAP perhaps represents one of the largest patient selection biomarkers being pursued by the industry today.

Lastly is our focus to address what we believe is one of the greatest scientific challenges in the area of cancer, which is the challenge of tumor heterogeneity. If I were to highlight one program that really highlights our commitment to address tumor heterogeneity, it's our recent Phase I molecule IDE574, our dual CAT 67 inhibitor, which, alongside another major, pharma company, we are -- have the opportunity to have another potential first-in-class agent in the clinic.

What has fueled this productive pipeline and engine is a proven drug discovery engine. And I'll highlight just several key points on this slide. First is that we have internally discovered 6 clinical-stage molecules across 6 potential first-in-class targets, including very difficult target classes such as helicases, polymerases and glycohydrolases. In addition, we've also pioneered key select selectivity profiles across very key parallels and protein families, including kinases and lysine acetyltransferase, as an example of KAT6/7.

What this has resulted in is what we believe is 1 of the deepest clinical precision medicine oncology pipelines in the biotech industry. We have currently 9 clinical stage molecules that are advancing. As noted earlier, darovasertib, our most advanced program. And really, the strategic promise of building this type of deep pipeline is really in 2 areas. First, as this will enable us to have wholly owned combinations across critical nodes of key pathways. Second is the ability to address multiple solid tumor indications of high unmet need including uveal melanoma, small cell lung cancer, colorectal cancer, breast cancer, among many others.

Our lead indication is uveal melanoma. Uveal melanoma, unfortunately, is a rare but very aggressive form of cancer. And unfortunately, for patients, this indication has 1 of the worst prognosis in terms of solid tumor indications. Survival typically ranges roughly 10 to 12 months. And as you can see here, the 5-year survival rate, this 15% to 20%. And unfortunately, for these patients, there are limited treatment options. Majority of these patients have no approved therapies available to them in the metastatic setting. There are no approved systemic therapies in either the neoadjuvant or adjuvant setting.

The mechanism that our lead molecule, darovasertib, is targeting is in the G-coupled receptor protein family, specifically a key activating mutation of GNAQ and GNA11. What makes this indication quite fascinating scientifically is that essentially 95-plus percent of these patients have either a GNAQ or GNA11 activating mutation. So in this instance, the indication is the diagnostic. Darovasertib was specifically designed to block this PKC activation pathway that is turned on by this mutation of GNAQ and 11.

As I noted in my introduction, our strategy for darovasertib is to position this molecule to be the new standard of care across the entire uveal melanoma patient journey, including neoadjuvant, adjuvant and the metastatic first-line metastatic uveal melanoma setting. Alongside our strategy here, as we noted in our JPMorgan guidance on Sunday, we are targeting to have 3 randomized Phase III trials initiated in the first half of this year.

So why are we so excited about this compound, the opportunity that we have in front of us at metastatic uveal melanoma? We presented data last fall at the Society of Melanoma Research in Amsterdam and we recorded an overall response rate of approximately 35%. And as you can see here, a median duration response of 9 months. To provide context, historical response rate has been reported at roughly mid-single-digit percent. So clearly, a market improvement from what patients currently have available to them today.

Beyond response rate, PFS and OS are obviously critical endpoints. And for those that are aware, PFS is the prime endpoint for accelerated approval and OS is the primary endpoint for full approval. At SMR, we reported a PFS of 7 months. Historical PFS based on large meta-analysis has ranged from 2 to 3 months. And overall survival, we reported an OS of over 21 months and historical OS has sadly been in the 10- to 12-month range.

So this is the high-level design of our current randomized Phase III study. Several pieces that I'll highlight here. First, the 437 patients we need for full enrollment is now fully enrolled as of December. And as noted earlier, we are now on the precipice of being able to provide our top line results to hopefully enable our first approval filing here in the U.S. In terms of investigators choice, there's several therapies that will be on that arm, including checkpoint, PD-1 plus CTLA-4 and the chemo DTIC.

Beyond the metastatic uveal melanoma setting, we're very excited about the indication expansion opportunities that are in front of us that we believe will enable darovasertib to be a bona fide blockbuster opportunity. In front and center as part of that indication expansion opportunity is in the neoadjuvant uveal melanoma setting. For those I may have not followed this program very closely, we did receive breakthrough therapy designation from the FDA in the spring of last year. We believe we're the only second company to receive breakthrough therapy designation in the neoadjuvant setting in the area of oncology. So I think really punctuates the importance of the data that I'm going to share with you on this slide.

As you can see on the left, the primary endpoint, there's 2 cohorts here, is enucleation. And as you can see to the bottom, over half of these patients that were scheduled to get their eye removed due to the ocular tumor, we were able to preserve their eye. Quite a remarkable result. And we believe the key data that really convinced the FDA to give us BTD designation in the enucleation setting in specific.

Second, as you can see, over half of the patients, we saw a 14-letter vision gain during the neoadjuvant treatment before the plot procedure. Again, remarkable data that gives us confidence, not just in the integration cohort of the plaque therapy quarter as well. This is the high-level design of the randomized Phase III study that we've launched in neoadjuvant melanoma. We launched this trial in the middle of last year. So now this study is fully up and running. We're going to be targeting to enroll a total of 450 patients, roughly 120 and the inoculation cohort 330 in the plot therapy cohort.

As I noted earlier, the primary endpoint in the enucleation with eye preservation and the plaque therapy cohort will be a 15-letter BCVA vision test, and there will be a pooled analysis across both cohorts on event-free survival, where we need to demonstrate new detriment. So this study, we also did recently guide as part of our JPMorgan working guidance that we will target to complete enrollment of the study in the first half of 2027. So our hope here is assuming we have the ability to get accelerated approval in the metastatic setting. By the time we are in that phase of hopefully commercialization that the neoadjuvant Phase III randomized study has the opportunity to hopefully be fully enrolled.

So now we're going to transition from darovasertib to our next program that we've now guided our goal to have in a registrational study this year. And that's our DLL3 TOP1 ADC program, IDE849. As we know, the antibody drug conjugate field has drawn significant intention in the oncology community. And we believe one of the greatest areas of unmet need that needs to be filled is how do we make ADCs more durable. And we believe there are several key opportunities here, and we believe in center as part of this is clinical combination opportunities with DNA damage repair small molecules. Within that, Idea has been a research pioneer, has evaluated multiple mechanisms to achieve this goal, and we believe PARG and specific PARG with our clinical molecule IDE161, has the opportunity to be tested in the clinic and test this hypothesis of enhancing the durability of the TOP1 ADC class.

And through that, about 1.5 years ago, we've been executing on a strategy to also bring internal potential first-in-class TOP1 ADCs with into IDEAYA. And through that, we in-licensed IDE849, the DLL3 TOP1 ADC and also another potential first-in-class bispecific B7H3/PTK7. And as you can see below in 2 models, one with our DLL3 ADC, the second, whether bispecific ADC, we see very robust combination results. That makes us very excited and confident about this opportunity to bring these 2 agents together to test this hypothesis about extending durability of this important class of therapy.

So this provides more details scientifically. I will truncate this summary to the top right. But essentially, we know that PARG enzyme specifically play a key role in the resolution of the DNA damage that's elicited by 2-point summaries. So we are essentially directly targeting this mechanism through PARG inhibition. And as we showed earlier, we not only have we generated in vitro data, we will also generated in vivo data across multiple preclinical models with multiple TOP1 ADCs, including approved ADCs. And the result is consistent. We've been able to enhance the durability of multiple TOP1 ADCs in combination with IDE161.

So now with DLL3, why are we and many companies focus in this area of DLL3. One of the main reasons is because one of the key applications in the area of small cell lung cancer. For those I may not be aware, small cell lung cancer represents roughly 15% of all lung cancers and perhaps continues to be one of the highest unmet need areas within lung cancer specifically. Unfortunately, survival is very short, and there are very few available therapies to the patients. And this is one of the key holes that we're targeting to build beyond small cell lung cancer, we believe there will be broader opportunities, including within the neuroendocrine space as well as indications such as melanoma..

So this is data that we presented at the World Cancer Lung Conference last September. I think this waterfall speaks for itself. This molecule is quite active. We reported a confirmed response rate in the second-line setting of roughly 70%. And as you can see, most of these bars are going down, and we also are seeing very deep responses as well. We also reported preliminary progression-free survival. And here, we're reporting PFS just north of 6 months. And just to provide context, obviously, cross-trial comparisons, a DLL3 T cell engager that has been improved in the small cell lung cancer space has reported a response rate roughly in the 40s and a PFS roughly 4 months. So we believe based on each of those measures, IDE849 is well positioned not only to be a potential first-in-class asset, but a leading asset in the broader DLL3 space.

So this slide summarizes our broad clinical development strategy. So there are essentially several strategies that we're pursuing. One is on the small cell lung cancer as another is more broadly in the neuroendocrine tumor space. We did provide guidance on Sunday that our goal is to initiate our first registrational study for this program that we would target to be a monotherapy accelerated approval study in addition. We'll be evaluating combinations, including with standard of care, which would largely include chemotherapy such as platinums, PD-L1 and of course, as I mentioned earlier, the PARG combination. And based on that data, we will also, in the future, look to pursue a line study in small cell lung cancer.

So our first thing -- potential first-in-class TOP1 ADC pipeline has been growing. So now we have another Phase I asset in IDE834 which is a first-in-class that we know the first of its kind, bispecific that's not enter the clinic, which is a B-cell H3 PTK7. And why is this important? This is important for several reasons. First, the co-expression of these 2 antigens is very high in several key indications, including lung, CRC, breast as well as several other solid tumor indications. A second, as you can see below, based on this specific bispecific antibody we've seen superior efficacy versus the mono TOP1 EDC, specifically versus the B7-H3 and PTK7. And we believe that's based on enhanced internalization of this bispecific ADC versus the monos. And as you can see below, we're seeing very robust regressions across each of these models. In addition, we will also be evaluating our IDE161 PARG combination as we will with DLL3 to build a portfolio of asset opportunities across this area.

So we'll now shift gears to the third area of focus for us is in the area of MTAP deletion. And as I noted in the introduction, why we're so excited and focused in this area of MTAP deletion, as I noted earlier, which is around this biology around chromosome 9p. And as we know, one of the most common deletions of the tumor pressure genes that are their most common in cancer is both MOP and CDKN2A. These 2 tumor suppressor genes are roughly 20,000 base pairs apart. Because of that, when MTAP is deleted, CDKN2A is almost always co-deleted.

So why is this important? It's important for several reasons. First, this is very common in cancer, unfortunately. This occurs in roughly 15% to 20% of lung cancer, roughly 20% of pancreatic cancer. And unfortunately, for patients there are no FDA-approved therapies for these MTAP deletion patients. There are 3 core strategies that we'll be pursuing here. First is around pursuing this interplay between the period and per median pathway in folate, and this is what we're pursuing with Gilead around leveraging the topoisomerase DNA damage in connection with MAT2A. We're guiding with Gilead to provide a clinical data update at a major medical conference this year.

Second is this combination with MAT2A and PRMT5. We are one of only 2 companies in the industry that have clinical stage molecules. This is continuing to leverage the biology and our expertise on the MTAP pathway. And here, the primary focus will be in non-small cell lung cancer. And then finally, I would say, is an area that has become a growing focus and importance in the industry, which is the key question of what else is co-authored with MTAP.

I highlighted CDKN2A is the most common call duration MTAP and the other most common alteration is RAS. And we obviously know the focus of a specifically in indications such as pancreatic cancer, and roughly 90% of patients that have MTAP-deletion in pancreatic cancer would also have a RAS alteration. And because of that, it creates a rational combination specifically in pancreatic cancer. So as you can imagine, if you're a pancreatic cancer patient, you have a RAS alteration and you have an MTAP alteration, both alterations are known to cause cancer, unless you're addressing both sets of biology will you be able to deliver maximal response to those patients. So we believe this is going to be continuing to be a very exciting field for the whole industry and definitely an area to watch for over the next several years.

I covered most of this slide, I would just highlight here our focus with an MTAP deletion currently is in the area of urothelial cancer, lung cancer and pancreatic cancer.

This waterfall is data that we presented at R&D Day last September. And really, the takeaway message here is we're seeing a response rate of roughly 40% in aggregate. The durability data is still immature. However, we can see we have several patients at the dose level 2 now that have extended beyond 200 days. In addition, as part of this in terms of a go/no-go decision, what we publicly communicated is we'd like to see a result rate north of 40%. We're still doing dose evaluation in non-small cell lung cancer and we hope to be able to select an expansion dose in that indication over the next couple of quarters.

Next is our Phase I PRMT5 inhibitor, 892 a Obviously, there are several molecules in the clinic against this target class, as I mentioned earlier, what differentiates us is we are 1 of very few companies that have wholly owned clinical assets that target both PRMT5 and MAT2A. And we believe both of these targets are foundational assets to hopefully deliver maximum value to patients with MTAP deletion solid tumors. As you can see, the monotherapy data preclinically demonstrates strong tumor regressions. And really what gets us excited about this is the ability for MAT2A to help address specifically acquired resistance mechanisms in the PRMT5 pathway. And as you can see, deep durable regressions we've been able to deliver through this combination.

The last section that I'll walk through is our next-generation molecules that are now both in Phase I, which is and 1 is in Werner Hillecase with ID-275and the second is ID our dual KAT6/7 inhibitor. And due to time for now, I'll focus on the KAT6/7 program, which has recently entered Phase I -- for those that may have seen Pfizer just several days ago, announced their first KAT6/7 7 molecule just entered Phase I this past Friday. Those may know Pfizer recently started a registrational study on the KAT 6 selective molecule. We believe KAT 7, which is specifically in the lysenacetal transfer area of biology, specifically targeting a very important area of cancer biology called chromatin remodeling.

We believe this target pathway has now been clinically validated, and we believe here the opportunity is to drive greater efficacy from what KAT 6 has delivered through this dual inhibition of these paralogs of both KAT 6 and KAT 7. As you can see to the bottom right, we see significantly greater efficacy versus the KAT 6 selective molecules here. we will most likely be focused clinically on the hormone receptor positive setting of breast cancer as well as prostate cancer and other indications, including CRC and lung cancer. Within all of the assets that we're working on in the clinic, which now amazingly represents 9 clinical stage programs, we believe 7 perhaps represents 1 of the largest clinical opportunities in terms of addressable patient population.

So we just covered, I think, quite a lot, and I hope my clock is correct that I have 15 minutes left here. So maybe that's with the Q&A portion. But we're here to the last slide. So Hopefully, you get a sense that Idea is really now at a key precipice as we are getting very close to having our top line results as I noted earlier, to hopefully enable our first accelerated approval filing in the U.S. with darovasertib.

Next, we're investing heavily on the next wave of growth. And here, as we talked about earlier, is our focus on extending the durability of TOP1 DCs, our deep commitment in the area of MTAP deletion biology. And then lastly, with KAT6/7, we think one of the most exciting opportunities to address one of the key challenges, which is tumor heterogeneity.

So with that, Anupam, thank you very much, and we're done with the prepared remarks.

Thanks, Yujiro. Yes, I'll ask the first couple of questions, but if anybody in the audience has questions, feel free to raise your hand, and I can get help -- get your question in. So I just wanted to quickly ask about the metastatic uveal melanoma study. Data is in 1Q. I'm assuming that you're looking at sort of blinded events and you've looked at it recently enough to reiterate your guidance that the data will be in 1Q. Is that a fair statement?

Yes. So yes, we're not providing specifics sort of where we are within that continue on a pump as you appreciate, there are sort of several steps in the process. But really for now, our public guidance is around being able to provide those top line results this quarter.

And I wanted to ask a bit of a broader market question. What have you learned from the Kemtrak launch here in the U.S. about uveal melanoma that you can apply to daro up here?

Yes. So are those two mics active?

Yes.

Can I bring maybe Darrin and Stu to join me at the front? I think it's much better the are functional leaders or in strain. .

Obviously, you're going in a different subtype.

Yes. Go ahead, Stu.

Stu Dorman, I'm the Chief Commercial Officer at IDEAYA. And with regard to Kemtrak and Immunocore, I mean, obviously, they've done very well in this market. What we've seen from them though is a market share that has really plateaued. And they've spoken openly about getting into the community and their challenges there, their continued efforts to do that. We feel that we have a plan in place to be able to action on that ourselves in a way that will allow us with the oral nature of the darovasertib and crizotinib combination to enter that market quite a bit faster.

Questions from the audience?

Yes. Thank you so much for your wonderful presentation. It's a multi combo story and I'm just curious about the -- how about the single agent access site and what about the monotherapy data such as IDE161?

Yes. So for us, we're going to really follow the science and the biology. So we have several programs where monotherapy is going to be a focus, including for DLL3 IDE849, in addition, the KAT6/7 molecule. But for several programs, as you highlighted, combination is really front and center, including the MTAP readout.

Additional questions from the audience? Yujiro, you talked a lot about the combination potential right now, right and having the science drive you. What led you to 161 kind of reemerging back into the pipeline here is now potentially a backbone combination product for the company?

So when you look at the ADC arena, as we know, there's been several key mechanisms that have been pursued, including microtubule mechanisms, obviously, topoisomerase, which would land you in the area of biology, around DNA damage repair. And so for us, our view is topoisomerase obviously is a critical payload mechanism. And so if you're really trying to think through what are the right combinations from a scientific perspective, ideally, you're focusing in the general biology area of DNA damage repair.

So then that leads you down a pathway of several different targets, including PARG, PARG theta, we know PARP1 is also another that people are interrogating. And that's really what led us to this area. Within those set of targets, based on the data that we've generated, we believe PARG is one of the most promising to extend the durability. And hopefully, we'll now be the first company in the industry to this hypothesis in patients and we anticipate we'll be able to test this hypothesis across multiple clinical stage topo ADCs.

How much myeloid toxicity do you see with these DNA damage inhibitors on their own? I ask because, obviously, the main issue with the topoisomerase payload that you have for Trodelvy is significant neutropenia. Do you risk making that neutropenia significantly worse by adding another drug that has hematological toxicity in its profile?

Yes. Obviously, there -- it's all going to be about what you do in the clinic, and that's the whole point of dose optimization. I don't know, Darrin, if you have anything to add.

The only the other thing I'd add is it depends on your schedule, too. If you can deliver your DNA damaging agent in a way that's less myelotoxic, then putting the 2 together may not be as problematic as you think. And then we think we've been able to do that with 161.

And I would also just remind folks, I think there is obviously also an opportunity, you may not need full dose for both agents, right? And so that's something that we'll have to test in the clinic ultimately.

Could you just repeat that for the audience?

Yes. I think the only point our CSO in the back is making, not every ADC is created equal, right? So that's sort of a general question. You obviously have quite a wide range of myelosuppression even across the ADC class, whether it's the linker, whether it's the payload, whether it's the antigen

But for Trodelvy, since this is the combination you're exploring?

Trodelvy, it's with 397.

Maybe while we're on 397 and Trodelvy, I think in your comments, you said you wanted a certain response rate to kind of move forward. Is that right?

Yes, I would say for the Trodelvy IDE397, I would say, ideally, we're seeing a response rate that's north of 40%. Obviously, equally important, perhaps more important, will be around durability I think good news is 2 things. We're seeing this phenomena where we're seeing the drop in that spare plot fairly quickly and dramatically that we haven't seen before. So I think that's encouraging. And second, we're now starting to see these patients followed up. And that's why I mentioned we've now have several that are at the 200 days that I've heard recent now, we even have a patient pass 500 days. So I think that's encouraging. And so we just need more data, more follow-up. But obviously, we can live with that kind of response rate with good durability. We should have some path forward.

And then on the safety side for that combination of 397 and Trodelvy, you are -- remind us, you are testing different doses and lower doses of Trodelvy, hoping to get -- navigate that therapeutic window?

Yes. So for the combination, I think we're in good shape. I mean -- and maybe, Darrin, once you answer this question?

Well, we are testing have been testing more than 1 dose level, but we think we found an optimal opportunity with the full dose of 397 and a reduced dose of Trodelvy of 7.5 milligrams per kilogram, it seems to have the best safety profile. It seems to have the best efficacy profile. That's where we sit today. We feel very comfortable with that. We still have to do some more within non-small cell lung cancer, there's the potential to maybe increase the dose there. We'll have to look at that. But we think we have a dose that's well tolerated.

And I think the efficacy is very promising especially if you think about the patients in that cohort that we've studied that have had EVP in the fast and fortumab pembro, they tend to not do as well with Trodelvy or other agents after that kind of therapy, and we think we're showing a highly respectable response rate in the patient population like that. So we're really excited about the opportunity here. But as Gerald points out, we just need a bigger end and we need more time to see how durable it is. And so far, the ability looks encouraging, but we just need more time.

Questions from the audience? Yes, right there.

We see a lot of companies now moving in the direction of the dual payload approaches. And here, obviously, you're focusing on a systemic DDR rather than as a payload in combination with the topo 1 and a dual payload. Could you speak perhaps to a little bit of the advantages of using it as a systemic therapy combination rather than as a dual payload?

Yes. No, thanks for the question. At the end of the day, the concepts are the same, right? You're essentially trying to deliver 2 mechanisms to enhance durability. I would say kind of the pros and cons, I'll give the very short end version. I think with dual payloads, a lot of it is, at least, I believe, around -- can you drive additivity versus synergy, right? And a lot of that is going to be driven by the art of the DAR of each payload. Unfortunately, once you set that DAR, it's fixed in the clinic right that the advantage I believe you have with a systemic agent, right?

Because ultimately, you're delivering 2 ultimately not different payloads and essentially trying to deliver that same result, but you don't have a set DAR, right? So obviously, both of the payloads and the incident of the dual payload is being delivered by an antibody. So I think that's probably the advantage there. So it's an area, obviously, we would have interest in because we have, obviously, already 2 novel small molecule mechanisms part would be an obvious second payload to consider.

Any final questions from the audience? Thank you, Yujiro and team.

Great. Thank you all so much.

Welcome, everyone, to day 1 of Citi's Global Healthcare Conference here in sunny and hopefully very warm Miami. I'm Dov Nochomovitz, one of the biotech analysts at Citi. So the first session, it's my pleasure to have with me the management of IDEAYA Biosciences. We've been covering them for quite a long time. I think since the first day they were public, if I'm not mistaken. And I have Yujiro Hata, the CEO; and Joshua Bleharski, who is the CFO. So welcome. Thank you both very, very much. And I was just saying to Yujiro, that time is flying. They just had their big R&D Day in New York just a few months ago.

So Yujiro, a lot's happened. You have a lot of updates over the last several months. You have a big catalyst coming as we know. But maybe just to start out, if you could provide just a quick overview of IDEAYA, what the generating thesis was for the company? What are the big programs, and we can move into some of the big updates coming.

Yes, for sure. So thank you so much, Yigal, for inviting us again this year to your annual Healthcare Conference at Citi. So IDEAYA Biosciences, we're a leading precision medicine oncology company. We have now 8 programs in clinical development. Yigal, as you know, our lead program, darovasertib, is in our first-line registrational trial in metastatic uveal melanoma. We are moving closer towards our top line results to hopefully enable our first accelerated approval filing here in the U.S., which is soon approaching. Our guidance is year-end this year to Q1 next year.

In addition to the metastatic uveal melanoma, we have 2 Phase III registrational trials that are either ongoing or we're preparing to launch in the next quarter or two. And that's also in the neoadjuvant uveal melanoma setting as well as an adjuvant. Earlier this spring, we did receive breakthrough therapy designation for this program in the neoadjuvant setting specifically. Beyond that, as you know, we have a very broad and diversified pipeline. I would probably say the next program and area of focus is on DLL3, our TOP1i ADC, IDE849.

We had recent data that was presented at the World Cancer Lung Conference in Barcelona. And then we also have 2 clinical stage assets in the MTAP-deletion space with IDE397 MAT2A and also a Phase I PRMT5 inhibitor. So I think we have a lot to talk about today, but those will really be the 3 key highlights.

So maybe we could start with the first-line MUM setting. As you pointed out, the data is imminent essentially. But you had some important updates recently, I believe, at the Society of Melanoma Research, where you talked about some of the prior data supporting the current Phase III trial. So if you could kind of walk through what we know about the efficacy of Daro-Crizo in this setting, what the Phase II data look like and how that points to success as we get close to this PFS readout?

Yes. So maybe just quickly, you got the table set. In the indication of metastatic uveal melanoma in the frontline setting, we believe the median PFS is about in that 2- to 3-month range, very likely more in the 2.5-month range. And historically, what we presented, including at SMR, which we had an oral presentation in Amsterdam fairly recently, we noted a PFS of about 7 months. So we think a very meaningful improvement based on historical. Second, when you look at response rates as well here, historical response rates have been in that single-digit percent ORR. As you know, we've reported response rates north of 30%. We think a very robust median duration of response as well. So with those two together, we feel good as we go into these top line results.

And as far as the -- you also had some data on preliminary OS data in the Phase II. So I know we're not necessarily going to get that at this update, but how does that impact your overall thinking in terms of the potential of the program?

Yes. No, thanks for bringing that up, Yigal. So that's correct. So historical OS here, we believe, will be in roughly that 12-month range. The data that we reported at SMR was just north of 21 months. And as you know, that data could continue to mature where that number could continue to go up. So we think based on that, we think a meaningful delta based on historicals. And obviously, we have our randomized readout that will also be following the median PFS, and that enrollment for full approval should be done here very soon.

And as far as what specifically we're going to get in this update, obviously, the PFS data, anything on OS or that would be a later look? How much are you going to be able to tell the markets about that?

Yes. We'll try to provide as much data and information that we're able to you. So of course, response rate, DOR, PFS. Is there a trend in OS, I think it's going to be the sort of the key question and whether OS will be sufficiently mature by the time of the PFS readout.

And maybe just talk a little bit about the market. I mean, obviously, there's one drug approved, but it's not approved for everyone. You have a potentially label that's not genetically determined. So could you just talk about what that implies as far as size of the market and how you could be competitively positioned versus the player that's already out there?

Josh, do you want to take that?

Yes. So as you pointed out, there is a competing drug on the market in the HLA-positive setting. Of course, we're going after the HLA negative population, at least as a primary priority. We think there's about 4,000 to 5,000 patients in that market broadly. We think the split between the positive and negatives is roughly 60-40, 2/3, 1/3 in favor of the negatives. So it's quite significant. And so I think initially, as I said and as Yujiro said, the goal is to get in -- get the negatives on the label, but we do think there is a path to darovasertib being used as the standard of care across the patient spectrum regardless of HLA status.

And anything else you want to say about just the baseline demographics of the study or any other factors that point to or position you for a successful outcome? Obviously, what you cited on the PFS is quite a wide margin and it puts you in good standing for a positive outcome. But is there anything else that's engineered into the trial that's going to help result in a positive outcome?

Yes. Yigal for us, when you look at the patient baseline characteristics from the Phase II data we presented at SMR recently are relative to our registrational trial and compared to other registrational trials that have been done in the frontline setting, we do feel the baseline characteristics are fairly comfortable with the exception of ECOG performance status. And so here, in the Phase II study, we saw roughly 40% of patients ECOG 1, 60% were ECOG 0. And the sort of peer company registrational study that was done both in the treatment and control arm, the ECOG performance 1 percentage was half of that, roughly 20% versus 40%.

We have looked at the data cut based on ECOG 1 versus 0, and we do see a correlation across all of those efficacy parameters that I mentioned. So we do think there could be the potential for further upside, which is why I'm mentioning sort of the 7- to 8-month PFS as obviously a potential scenario, but we'll have to see for that what the readout.

And you briefly mentioned neoadjuvant, and we can also talk about adjuvant. Just can you outline the development strategy in neoadjuvant? What are the pieces of the puzzle there? Because just so we understand clearly what the cohorts are and what are the endpoints and signals that you're looking for in each of those to determine a label?

Yes. So look, first, we'll see neoadjuvant uveal melanoma, we think an extraordinarily exciting space for this program, an extremely high unmet need. Some of the numbers Josh just mentioned, now annual incidence goes up to 10,000 to 12,000 patients. We believe prevalence would likely be multiples of that. There's nothing approved, no systemic therapy is approved here, and this would be agnostic of HLA-A2 status.

In terms of the cohorts, there's two patient cohorts here in consideration. One is the Enucleation Cohort. These are patients that otherwise would get their eye removed to their primary tumor. Second is the Plaque Brachytherapy Cohort. So these are -- majority of these patients are getting these radiation plaques that are exposed to the eye to the shrink the tumor. So those are the two cohorts. Primary endpoint for enucleation is eye preservation rate. We talked about that, which is where we believe we got the breakthrough therapy designation based on that very robust number we saw and we shared with the FDA.

For the Plaque Brachytherapy, it's a visual acuity readout based on a 15-letter BBCA test. For both cohorts, we need to hit a no detriment threshold for event-free survival. And as we've mentioned in the past, based on single-arm data so far in the Phase II study, we've seen very few events. So we do feel that we should have a good shot at hitting also that no detriment threshold for EFS. So that's neoadjuvant. I'm also happy to go through adjuvant as well.

What else? Who are you competing with in neoadjuvant? It doesn't seem like there's a whole lot.

That's exactly right. Yes. So unfortunately, for these patients, we think really the competition here is extremely limited. In terms of systemic therapy, we think we're really the main company that's pushing ahead here in a registrational study. So -- and obviously, based on the patient unmet need and the fact that, unfortunately, these alternatives are really not great alternatives.

Is there a thinking as to why there's been just sort of a dearth of innovation in this specific area? I mean, given the severity and the lack of going blind, I mean, these would be seem to be high areas of interest for drug developers, but you seem to be the first that I'm aware of to do any kind of late-stage work here.

Yes. So I think there's probably 2 parts to that, Yigal. So first is here, it's a unique situation, right, where the tumor is located in the eye. So as you can imagine, would a systemic therapy really able to successfully and consistently shrink these tumors in the eye. I think we're fortunate. It's based on empirical data where we believe we're clearly delivering that value. And then second, as a reminder, most of these patients are getting those ocular tumors because of an activating mutation at GNAQ or 11. And our drug is directly hitting that activation mutation through the PKC pathway. So we think based on those two unique aspects, we were, I think, very fortunate. And hopefully, we can bring this to patients as quickly as possible.

Are you able or in a position to give some time lines on these because everyone is super interested. As you pointed out, it's a bigger market. It's an untapped market. What can you say about the time lines with those -- how are those cohorts tracking too, by the way, that kind of tumor?

Yes. So basically, we're going to try to enroll this study in roughly 5 quarters. It's 120 patients in the Enucleation Cohort, 330 in the Plaque Therapy. The Plaque Therapy Cohort, you know Yigal got reduced by 70 patients based on statistical modifications we made related to alpha usage. In terms of the readouts timing, the first we'll get is the eye preservation data. We get that data roughly in about 6 months. Second, we anticipate will likely be the no detriment EFS threshold. And then the last would be around visual acuity, which the first interim analysis would be 18 months from last patient enrolled. So that's the sequence of the event readouts.

So just to be clear, that's 6 months from today or 6 months from a future point, just…

So the 120 patients for the enucleation, let's say, that last patient by 6 months, we should know that last patient's answer. But again, because the threshold is only 10%, right, and the 2:1 randomization here, we should know if we exceeded that 10% threshold, we think relatively quickly.

So there, you have -- I mean, what we've seen in the early data just...

It could be very quick.

Very significant cushion there. And then for the vision, I mean, you talked about at the R&D Day, you talked about the predictive tool. But what other data points or clues do you have that you're going to see that visual benefit because that also is a novel endpoint, is it not for this disease?

Yes. It's a very novel endpoint also as the primary endpoint for an oncology indication. It is, we think, quite unique. In terms of the key data for the plaque therapy cohort and related to vision, one would be the simulation data, both in terms of radiation reduction, predictive future vision. But the data that we shared at ESMO that I do think got people more enthusiastic about this cohort was specifically the actual vision impact we saw during the neoadjuvant treatment before the plaque procedure.

And there, Yigal, as you know, we noted on average across both of the enucleation of the plaque therapy cohorts, we saw a median letter vision gain of 14 letters. That's significant because the endpoint is connected to a 15-letter BBCA vision letter improvement. So if you have a cohort, which would be on treatment, where you're seeing this very meaningful letter gain, but you would obviously not see that. We don't anticipate you would see that in the control arm. We would hope that, that would stack in the favor of the treatment arm versus the control arm. In addition, you would have this dramatically -- at least dramatic effects we're seeing to ocular shrinkage, which should also lead to less radiation.

Yes. And knowing the retina space pretty well, if you get -- I mean, 3 lines, 14, 15 is 3 lines, that's quite significant. That's more than what you see in some of the anti-VEGF trials in the old approval trials for the anti-VEGF. So it's a big -- it's a good number. And then let's talk about adjuvant because that's a newer topic. So what is the structure of that study? And what can you say about how you're going to do that one?

Yes. So we're going to be doing this with our partner, Servier, which is our ex-U.S. partner. We're guiding with Servier to initiate the study first half of next year. We're still finalizing the protocol, but I can help at a high level here. It will likely be roughly about 450 patients. We will most likely target the high and high medium metastatic risk population. Here, most likely randomized 2:1 and here, the primary endpoint being superiority for relapse-free survival. So we're excited to get that study going. This will be irrespective of HLA-A2 status. And at least right now, our view is we think that should be a high probability study based on the fact that we're seeing strong activity in the metastatic setting. Here, I should also mention, we will do this as a Daro-Crizo combo. And then second, we anticipate the treatment duration will be a year.

And Josh, do you -- what about the market size for adjuvant? I mean, is it sort of in between the two you mentioned already? Or how does it shake out?

Yes, it could potentially even be the largest of the three. I think clearly, the goal here is to get patients on therapy earlier, right, so that we can really intervene in disease before it metastasizes to the liver and elsewhere in the body. So I think the combination of the prevalent pool, the incident pool and then the duration that we think we can have these patients on therapy really, when you add these three indications up, it starts to get into the $1 billion [ZIP] code, right? So we think there is a path to this being a blockbuster opportunity.

And so these are patients that had some form of surgical intervention. Could it also be the plaque brachytherapy or not necessarily? Or who -- what is the defined patient population in the adjuvant? Is that correct, that group of patients?

Yes. So the adjuvant patients would be all essentially postoperative. So either post-enucleation procedure or post-plaque procedure. Some may have gotten proton beam radiation, although we anticipate that would be a small [indiscernible].

So they could have had enucleation as well.

It could have, correct.

Okay. Interesting. Just so to prevent the metastatic spread.

Exactly.

So switching topics then over to MTAP and MAT2A. So that's a space which is obviously getting a lot of attention from you, obviously, as well as larger players. So just kind of -- could you just summarize the thinking there as far as what are you doing with MTAP and MAT2A, what's the therapeutic goal? It's, again, a potentially very large market segment? And how are you positioned competitively given it is becoming more of an intensely competitive area.

Yes. So look, we think MTAP-deletion is an exciting opportunity for several reasons. One, Yigal, as you noted, it represents a large patient population, roughly about 10% of all solid tumors, including double-digit prevalence in important indications like lung cancer, tDAC as well as urothelial cancer. We believe this area the core aspect in terms of, we think, success in terms of clinical strategy, we believe will be about implementing rational combinations as well as who can wholly own the key components of those combinations.

And that's where we believe, based on that criteria, we believe we're one of the industry leaders in the MTAP-deletion area with a Phase II MAT2A inhibitor IDE397, a Phase I MTA-Cooperative PRMT5 inhibitor IDE892. And Yigal, as you know, we have a third MTAP program that's now approaching development candidate nomination that we believe is targeting a major co-alteration of MTAP-deletion, which we'll note here at the conference here today, which is around CDKN2A co-alteration. So the co-alteration of MTAP and CDKN2A is the most common, more common than RAS.

And so we think would be relevant not just for combination studies for indications like tDAC, but as well as lung cancer as well as others. So we don't believe there's another company out there that has that diversity of assets. Now we have 2 clinical stage and now our objective in the next couple of quarters will have 3, and we think that will put us in a very unique position within the broader sector.

So this is -- just so we're clear, this is a new statement today. This is we've heard of the CDKN2A program. And how close are you to the filing -- you're close to a development candidate and then the IND would be sometime down the road?

Correct. Yes. So the development candidate, I would say, is fairly imminent. We've made a huge amount of progress. So just maybe context here, we've been doing chemistry well over 4 years. The chemistry is extremely complicated. There isn't another molecule of this profile in the clinic at this time. We have data around combinations that we think are going to be quite important. And then hopefully, an IND towards the end of next year, that would be the goal.

So was this one of these super challenging chemistry exercises like what you've talked about with the Werner Helicase? Or did it not rise to that level? Or was it still tough?

No. Look, I think we have a phenomenal research organization. And it was a very big challenge. But I would say our view is that we made multiple major breakthroughs starting from last year into this year that gives us the confidence to be able to provide this communication today.

And so what would the combos be? Are you saying -- because you have three now. So how would you pair them off? Are you talking about triples or that's all to be determined?

Yes. So I think those are the questions that we'll continue to answer here. But let's just say at a more high-level summary for lung cancer, for example, we think the MAT2A-PRMT5 perhaps checkpoint would be the most exciting, especially when you think about a frontline type study. For tDAC, as we mentioned, the co-alteration strategy, we think could be an interesting one. Obviously, there are PRMT5 perhaps, this third program. There's also obviously thinking about RAS as well. There's different conversations ongoing on that front. Urothelial cancer, obviously, we're doing the TROP-2 combination around this pyrimidine folate pathway. So I think we have several shots on goal here. And depending on the indication, we may prioritize different combinations. But essentially, with these three targets, we feel we've covered our full basis in this whole [indiscernible] area.

And then for -- just can we just run through some of the clinical progress? I mean you've talked about the cohorts for urothelial and non-small cell lung cancer. What's the next tranche that we're going to get out of those studies?

Yes. So we're planning to submit an abstract for presentation at a major medical conference in the first half of next year with Gilead on the Trodelvy combination with our MAT2A inhibitor, IDE397 that will likely be focused in MTAP-deletion urothelial cancer. We may follow that with a second medical conference update in the second half that would focus on non-small cell lung cancer. So that's our I would say, more near-term focus and guidance.

Now here, we're also now in the clinic with our, we think, a potential best-in-class PRMT5 inhibitor. Obviously, there, we could think about monotherapy data. But of course, for us, as you know, Yigal, we're very focused on the MAT2A combo. So can we generate that data quick enough to be able to present data next year. So we'll likely give more visibility on that in January, but we're going to do our best.

So for there, you're still ramping on the dose escalation. What's the -- what can you say that at this point?

Yes. So for PRMT5, basically, our strategy is the following. Once we clear the first cohort, and this has already been okay based on what was in our clinical protocol with the FDA. Once we clear the first cohort, we can start the combination work with MAT2A in the second cohort. We believe in that second cohort based on our preclinical modeling. We should already be at a very efficacious combination dose. So we think we'll be at an active dose quite quickly. We know exactly what dose to use for our MAT2A inhibitor IDE397. So that should also expedite the speed of that data generation. So our view is we should be able to move quite quickly. So -- and we're also cognizant, you may know, Yigal, there's a peer company that's already also guiding to their first MAT2A-PRMT5 combo data in the second half of next year.

And what -- and this is in -- just remind us in which tumors or how broadly are you looking?

So in the escalation, we will look at multiple tumor types. In the combination, we'd like to be as focused as possible in non-small cell lung cancer, which based on our preclinical data, we believe should be the most sensitive tumor type for this compound. And the largest market, we think in MTAP is in non-small cell lung.

Do you have sort of internal thresholds for what's going to be your good enough, go, no go -- I'm not going to tell us that today.

Look, I think we've seen the data from the PRMT5 side and MAT2A, right? So let's just say, roughly in that 20% to 30% response rate, I think durability has ranged. We clearly want to see more than that and to beat the doubling of that, hopefully fairly readily and can we also make a meaningful improvement in durability. I think if you do that, then you got a real shot in a first-line type study with something like a checkpoint inhibitor. And that's the goal here.

Did we ever see the preclinical with your proprietary PRMT5? I mean, we saw the [indiscernible] looked amazing, obviously, but you have your own now. But I don't know -- I don't remember, do we ever see that?

We did publish some data at R&D Day. We will publish more data in the first half of next year at a medical conference. I know abstracts have already been submitted. No, look, it's a great molecule. It was a molecule that was made fit for purpose to be combined with IDE397. And that's the advantage that we have now is that versus sort of just assembling different molecules together, we picked this molecule to be combined with IDE397.

Another -- let's go to another big topic, the Delta-Like Ligand, the DLL3. Again, another space which the competition is ramping quickly. You have a very competitive molecule. So tell us more about it. What makes it competitive? What are the differentiating features? How is it designed? And what's the next step?

Josh?

Yes, we're pretty excited about the DLL3. I mean, we obviously have published data on it at the World Cancer Lung Conference earlier this year. It's obviously focused on small cell lung cancer right now. We think we're seeing really compelling response rates and importantly, durability, at least early days. We looked at data, almost 100 patients worth of data from doses that we think are going to be pretty active, expansion doses well north of where some of our competitors have been. So we think there's a chance to differentiate on efficacy and durability.

And I think a lot of what's driving that is the differentiation between our linker system and those of some of our competitors. So we think we have an ability to dose a little bit higher because of that linker and avoid some of the common tox that you might see otherwise as associated with that. And really, the difference is where that payload is cleaved off, right? [RS] is intracellularly cleaved, whereas our competitor linkers are more tumor microenvironment linkers. So there's a higher chance for some of those off-target tox profiles that you see.

And the types of tox that you're trying to avoid or that you've seen less of or what sorts of things are you seeing less of so far? Or is it too early to make a definitive statement yet?

Look, I think for the ADC side, I mean, it's really around heme tox and blood-related heme tox. So that's been really the primary area of focus. I would say there, we're observing an AE profile that looks very comparable to other approved Topo-ADCs. So I think we're in a really good position from that perspective. And so I think for us now, it's really about optimizing dose and ensuring, especially around where do we get the maximal both confirmed response rate, in particular, in this indication, we think really the core focus is going to be around durability.

And you mentioned going beyond small cell potentially. What like -- I guess, neuroendocrine tumors, right? Would that be a possibility? Or where else could you see the supply?

Neuroendocrine tumors for sure, which is going to be a compilation of different types of neuroendocrine transformations, including pancreatic, colorectal, obviously, components of lung as well, of course, small cell lung cancer. We do think there is meaningful DLL3 upregulation based on several recent papers and publications in melanoma as well. We think that could be interesting. So I think we would like to do sort of an exploratory basket in DLL3 upregulated tumors. So -- but we do think this is an opportunity that extends well beyond small cell lung cancer.

And how close might you be -- I mean, if you keep getting good data here, how close are you going to just go into a pivotal right away? Like what's the -- and you have a dose you've identified, as I understand. So how close are you to starting such a registrational study?

Yes. So we're going to give more guidance on this most likely early next year. In our mind, Yigal, there's really two registrational trials that are of focus for us. So one will be where do we focus a potential monotherapy accelerated approval study. And there, your options include extensive stage small cell lung cancer, possibly in the neuroendocrine tumor space. And we're thinking through that carefully. I think we have been developing that strategy over the last several months, and we'll be prepared to communicate that here shortly.

The second will be where do you focus in small cell, in particular, what does that study look like in frontline small cell. So I think those are really the two focus areas for us. Within that, and especially that frontline small cell, I think it's also going to be about the data we generated on the key components, including standard of care agents like chemo, checkpoint and as you know, Yigal, we're very focused on this IDE161-PARG combination, a, because it's a proprietary combination to IDEAYA. Second, we believe it may have the ability to extend durability, which would position us very uniquely in potentially several indication settings.

And the idea there is to offset or prevent the DNA damage repair along with the ADC. Is that the idea?

Yes, so -- yes, I think that the quick summary there, Yigal, that's essentially correct. So -- but it's really around the topoisomerase payload, as we know, that mechanism is specifically linked to DNA damage repair, unlike other payloads that might be based on mitotic mechanisms. This is specifically around DNA damage repair. So as you know, Yigal, one of the areas that the company has built deep expertise is in the area of DNA damage repair, and we're essentially leveraging that biology expertise.

So we've been looking at various targets in the DDR space that we think can amplify essentially the DNA damage that's delivered by topoisomerase. So we think one of the key targets that can do that is PARG. And now we've validated that preclinically, both in vitro and in vivo in multiple models, multiple cell lines across multiple ADCs. And now we're getting prepared to enable that clinically. So we do think this is going to be a very exciting strategy and also one that can really differentiate us, which is, as you know, becoming a crowded ADC space.

So that's where the PARG is going as this combination. It's not going to do the -- we're not going to do a monotherapy approach. I mean originally, that wasn't clear what was going to happen, right? But now that seems to have been clarified.

Yes, that's correct. And where we've been spending the time in the clinic is really thinking through what is that really optimal dosing approach to maximize the PD while having the most favorable AE profile. Now we believe we've optimized that, and now we're prepared to enable that combination for the clinic.

And you had another announcement. I'm losing track of time, but I think it was yesterday, where you announced a new -- another ADC, the B7H3-PTK7. So tell us a little bit more about that. That target, the PTK7 is less familiar to probably a lot of people. So if you could expand a little bit on the significance of that. B7H3, most people are familiar with. So what is that doing that bispecific? Is it the same linker because you mentioned the linker ability tell us about the design?

Yes. So it's a tetrapeptide cleavable linker. So that's the same. It's a topoisomerase payload, so that's similar as well. I would say what makes this program unique, one, it is first-in-class. So it's the first clinical stage bispecific with the format of B7 targeting both B7H3-PTK7. Second, it's unique in that it's an AND format. So you may know bispecifics either come in an AND format or an OR format, and means it needs to bind to expressing both versus either OR, OR becomes broader activity. Here, what we're really focusing on is amplify the efficacy in the dual expression population. Therefore, you can have a wider therapeutic window and drive greater efficacy in that dual expression population.

And the reason why we picked this program over many other bispecifics that we have evaluated was because the co-expression of these 2 antigens are actually very high in the key priority tumor types for us, including non-small cell and colorectal cancer. This molecule is very active preclinically, and we do see greater efficacy versus those mono formats, B73 or PTK7. So we do anticipate we should see more efficacy versus those mono ADCs in those dual expression areas. And again, here, absolutely one of the core reasons why we brought this in as well because of the ability to do this combination with PARG IDE161.

And you would expect sort of a similar benefit to adding the PARG, whether it's with 161 or with 034. It's the same rationale?

It's the same exact rationale.

Right, right. Okay. You have more. There's a lot.

We do.

So we can try to get 5 minutes in 20 seconds. But I have -- so there's IDE574. This is the KAT6/7 inhibitor. Give us a quick status update on where that is, and it's a dual. So that has some advantages, as I understand, relative to picking just one of those isoforms.

Yes. This is another exciting program. And it's interesting. I was just thinking about this recently. But when you look at the last couple of years, some of these programs that have been hitting kind of multiple targets within the pathway or paralogs have shown some actually quite exciting clinical data, which I think for us, at least further reinforces the strategy that we're taking both in the MTAP space as well as in this area, KAT6/7, which is the mechanism specifically around lysine acetyl transferases, which directly impact a very important area of biology called chromatin remodeling, which we know impacts specifically gene modifiers, which if they're disruptive, unfortunately cause cancer.

Next, we know KAT6 specifically has now been clinically validated by Pfizer. And our view that by having this more broader dual inhibition of KAT6/7, we should be able to enhance the activity, drive greater durability and even a scenario where we may be able to drive efficacy without combining with agents like fulvestrant. And if we're able to do that, clearly, we would widen the opportunity for where KAT6 and Pfizer has really paid the groundwork for. Just quickly here, they did report data in the past, including a median duration response of over a year. So clearly seeing exciting durability, and that was with fulvestrant. So can we show greater efficacy? Can we expand this to other indications beyond breast cancer into indications like non-small cell?

So where would you start with the development, which setting, which breast cancer setting, like you go post-CDK 4/6? Or what do you -- there's a lot of options there.

Yes. I think we would likely -- so the answer is yes, I think there. And also, we would likely mimic what Pfizer has done with KAT6. Here, we would look at it likely with an agent like fulvestrant, but as well as without and try to answer that question directly.

So breast cancer would be the primary focus, and then we would then extend into other indications depending on if we can confirm and validate that data in that setting into areas like lung cancer.

I briefly mentioned the Werner Helicase program, and there's also the Pol Theta program. So let's try to squeeze those in quickly. I think there's been a lot of -- I've been anticipating seeing the first clinical data for the Werner program for a while. I know you had some biomarker data earlier there. What is the latest timing on seeing that? Because that's considered a really interesting pan-tumor target.

Yes. So Werner Helicase for those that may not be as familiar with the target. So this is synthetic lethal with a genetic biomarker setting called MSI-High. We think one of the most important targets in synthetic lethality in terms of the robustness of that synthetic lethal interaction. Here, indications of relevance include gynecological cancers like endometrial cancer, ovarian cancer, and also colorectal cancer.

I would say where some of the past published data on this area, which has not been so great has been in colorectal cancer. And that's where can we drive greater activity in CRC because, as you know, we have a different binding domain and interaction when we don't believe we have that susceptibility with that cysteine 727 binding interaction, which the other molecules do. So that's the question we'd like to answer…

That's in Novartis...

That's both the Novartis and Roche molecule, we believe, has that interaction with that cysteine that our molecule doesn't. And as you may know, point mutations around cysteine is very common and the MSI-High setting, in particular, you have to very carefully monitor around these point mutations because that's really the key liability, we believe, which is why it's hard to treat those patients with targeted therapy. So here, we'll be in coordination with GSK on that disclosure. I would hope we would have some ability to share data on that sometime next year. Here, you would also, at some point, likely consider a checkpoint combination.

And then the other one, the Pol Theta program, we hear less about that one?

Yes. So Pol Theta Helicase, another first-in-class asset. This is all about combining with the PARP mechanism. So just as kind of maybe take 2 steps back. We know when you see PARP acquired resistance in BRCA2 breast cancer, there have been published papers where we've seen the majority of acquired resistance is connected to a backup DNA repair mechanism called microhomology end joining. And within that, we know Pol Theta is Achilles heel.

So here, what you're essentially trying to do is to directly target the main mode of acquired resistance to PARP inhibitors, specifically in indications like breast cancer. So if you can do that, can you enhance the durability? We don't anticipate this program will have monotherapy activity. So we've been in escalation, combination studies have started with GSK's PARP inhibitor. So that's the current status.

Niraparib.

Niraparib. Correct.

And that's under the -- they're going to control those.

They're driving that forward correctly.

Well, we will keep going, but unfortunately, we have to call it there. So thank you very much. I think we covered a lot of ground. So looking forward to the top line readout soon.

Yes. Well, thanks so much, Yigal. Great to see you, and good luck for the rest of your conference. Thank you.

Thank you very much.

Thank you, Yigal.

All right. Great. Hopefully, everyone is connected. Well, I'm Yigal Nochomovitz, biotech analyst here at Citi in New York City. It is my pleasure to introduce the next iteration in our virtual C-suite fireside chat series with Yujiro Hata, who, of course, needs no introduction, the CEO of IDEAYA.

If you guys have questions for Yujiro during the course of the conversation, please e-mail me, [email protected], and I will hopefully see those and relay them over to Yujiro.

So Yujiro, welcome. Thank you. A lot has been happening. You had a great R&D Day at the -- right after Labor Day. A lot of activity at several medical meetings as we well know. So maybe it would be helpful if you could just kind of review maybe some of those key milestone markers with the pipeline. And then we'll move into a discussion across all of the programs, but just that would be a good place to start, I think.

Yes. So first, Yigal, thank you so much for hosting this fireside chat, and thank you to Citi as well. So Yigal, as you mentioned, this past quarter, it probably has been one of our most productive quarters that we've had since the company's founding. As you noted, we had several updates at major medical conferences, including at the World Cancer Lung Conference for DLL3 in Barcelona. We also had an oral presentation at ESMO for darovasertib in neoadjuvant. We also had the Society for Melanoma Research oral presentation at Amsterdam, where we reported our first survival results.

And as you know, our lead program is getting closer to our objective around the randomized PFS results to hopefully enable our first accelerated approval filing in the U.S., which right now is guided from year-end. So we're getting about a month to December to Q1. So we are getting closer and closer to that.

Enrollment is going great. We're almost finished with full enrollment. So that study is also in the process of getting wound down. So I would say we're probably going to be done with full enrollment for the OS, randomized OS as well portion in about a week or so.

Beyond that, we're firing on all cylinders on -- which is continuing to be a growing pipeline, DLL3. We did dose our first patient in the U.S. We're ramping up sites globally to accelerate that. Obviously, a big focus in small cell neuroendocrine tumors as well. And MTAP as well here with our partner, Gilead, on Trodelvy. We picked an expansion dose recently in urothelial cancer. We've dosed several patients already in lung cancer, and that enrollment has been extremely robust. And just as a reminder, as part of our earnings, we did note a confirmed 57% response rate in the MTAP urothelial cancer setting.

Beyond that, our PRMT5 asset is now in Phase I. We got IND clearance. We also filed an IND on our B7H3/PTK7 bispecific ADC as well. So a lot happening and we expect hopefully a very catalyst-rich next several quarters.

Okay. That's a good start. Well, maybe if we could just kind of go big picture first and go through what you sort of see as the opportunity across the uveal melanoma landscape, because as you pointed out, we're looking at metastatic, neoadjuvant, adjuvant. And so if you could kind of just outline the scope of those opportunities and how crowded or not crowded each of those are?

Sure. Yes. One of the areas that we're very focused on is to ensure that darovasertib has the opportunity to be the standard of care across the uveal melanoma patient journey. So Yigal, as we just talked about, we're getting close to hopefully our randomized PFS results for frontline metastatic uveal melanoma. As you know, we launched a second registrational study in neoadjuvant uveal melanoma. And now we're guiding with our partner, Servier, to launch a Phase III randomized study in adjuvant in the first half of next year.

In terms of metastatic annual incidents, we believe this is about 4,000 to 5,000 patients. Prevalence would be higher than that. We're seeking approval in the A2 negative population where there is nothing approved. So we would be a frontline treatment in the scenario we make it to market. We also believe the [ agent ] is going to be equally active in the A2 positive setting. And we do believe we will capture market share in that segment.

For neoadjuvant, that number of annual incidents goes up substantially from 4,000 to 5,000 to at least double that. So we think that's more in the 10,000 to 12,000 range. Here, average treatment duration in neoadjuvant roughly in that 6-month range. And then in adjuvant same thing, 10,000 to 12,000 patients. There, treatment duration, we're anticipating -- or we're discussing with Servier is a 12-month treatment duration. And in the adjuvant setting, we anticipate we'll pursue that with our partner as a daro-crizo combination as well. And also in adjuvant, there's nothing approved, as you know, Yigal. So here, we would anticipate that we'll be randomizing against placebo in the adjuvant setting.

Okay. So I think it would be helpful if you can kind of walk through the neoadjuvant data that you showed at ESMO because there were 2 cohorts. Obviously, the enucleation and the brachytherapy. So what were the key conclusions in each of those? And did they meet or exceed your expectations as far as the endpoints that you're aiming for there?

Yes. So maybe just to table set here, Yigal. We received breakthrough therapy designation from the FDA in the spring based on a good portion of the data that we just shared at ESMO, in particular the enucleation cohort. We shared about 95 patients worth of data. Roughly 60% of that was from the enucleation cohort, the remainder in the plaque therapy.

In terms of eye preservation rate, what's in our current Phase III clinical protocol, which we had alignment with the FDA was we needed to exceed -- or we need to exceed a 10% eye preservation rate with a 95% confidence interval to receive a full approval. So that's our primary endpoint for the enucleation cohort. What we demonstrated is the majority of patients, we are preserving their eyes and getting them off of the enucleation track. So we are obviously well above that 10% threshold for full approval.

For the plaque therapy cohort, the primary endpoint here is around visual acuity, which is a 15-letter BVCA vision test. Here, I would say several pieces of information that were new. First is that we are seeing very -- what we think is a very meaningful vision improvement during neoadjuvant treatment before the plaque therapy. So Yigal, you may recall, at our R&D Day, we noted a median letter improvement during neoadjuvant treatment of 7 letters at R&D Day. And at ESMO with a larger data set, more follow-up. If you pull both of those 2 cohorts, we saw on average, roughly a 14-letter vision gain. So that's a fairly significant jump from 7 to 14 as we went into more patients with more follow-up.

And then lastly, based on the level of consistent and robust ocular tumor shrinkage we're seeing, at least based on visual radiation prediction tools and visual prediction tools, we believe the amount of predicted vision loss is going to be substantially less in the treatment arm versus the control arm. So that's the setup.

As you know, there's also a no detriment requirement of event-free survival, which is going to be a pooled analysis across both cohorts. There's no specific hazard ratio we need to hit. All we've said with the FDA is that they need to be overlapping confidence intervals that we're not doing harm to the patient. And we have publicly noted, Yigal, here that so far, we've seen very few events in the single-arm Phase II study. So we feel good about that no detriment to EFS requirement as well.

Okay. And then given the 10% level that you mentioned with regard to eye preservation and then the 10% to 17% range on the improvement in letters. How are your -- the Phase IIIs, the pivotal structured such that you're well positioned to be better than those or at least in that range for the vision and I presume much better on the eye preservation? Just -- if you could just review the cushion you have on the Phase III to get to those -- that type of efficacy.

Yes. So on the eye preservation one, Yigal, I think that one is pretty straightforward, right? Where it's a 10% threshold, 95% confidence interval, which means you want to ideally be at a 15% eye preservation rate or higher. Here, we're already multiples north of that. So I think that one should be relatively straightforward.

For the plaque therapy, so the way this is going to work is the treatment versus the control arm. We wanted to be able to demonstrate 20% of patients or greater are passing that 15-letter BVCA vision test in the treatment arm versus the control arm. So that's what we need to show to hit our primary endpoint.

So the reason why we feel good about this endpoint is because, as I just noted, Yigal, during the neoadjuvant treatment, the treatment arm patients should have better vision because during neoadjuvant treatment, we're seeing this vision gain that's occurring, which in the control arm, that shouldn't occur. And then second, the patients of the treatment arm should have much smaller ocular tumors because daro is shrinking those tumors and therefore, getting less radiation to the critical eye structures and therefore, less vision loss. So now you have 2 stacking events, right, that should hopefully push it in our favor to be able to hit that primary endpoint.

Okay. And are you -- I mean visual acuity is obviously kind of a gold standard measure. Are you looking at anything else in terms of position of the tumor in the eye or anything related to center versus noncenter lesions looking at retinal imaging, for example? Or is that all secondary?

Yes, those are secondary. So the primary endpoint is around this BVCA 15-letter vision test. We have other secondary endpoints, including response, prevention of macular edema as well as others. So -- but the primary endpoint is this 15-letter BVCA test.

Okay. And then you also reported that apparently a certain percentage of patients had gained over 5 letters consecutively at consecutive visits. Why is that important for people to understand as opposed to not consecutive or over a longer period of time?

Yes. Great question, Yigal. So I know you also track the ocular space. So at least from what we understand, the consecutive visit readout is actually quite important in that -- in the setting of just sort of a visual improvement that it's not just at one time point, but through multiple consecutive visits, they're seeing the sort of consistent maintained visual improvement. So I think that data also improved since our R&D Day. So we're excited to see that as well.

Okay. And just again, on neoadjuvant, the time lines are for data. When is the -- what is the latest statement on that?

Yes. So the way -- yes. So you may have seen that the plaque therapy cohort, we reduced the number of patients we need to enroll from 400 to 330, and that was based on FDA feedback around the statistical plan, and we didn't need to split the alpha between the 2 cohorts. So that's great for us. It makes trial size smaller, which means we can enroll it faster.

So right now, what we've said is that we -- our target at least is to try to enroll this study in roughly 5 quarters. The first data we'll likely see will be the eye preservation data from the enucleation cohort. The second data set would most likely be the no detriment to EFS. And because of that no detriment threshold, we believe with about 35% to 40% of the events, we'll know that answer.

And then the last one is the visual acuity results from the plaque therapy cohort. And that first analysis will be approximately 18 months from the last patient enrolled. So that's the sequence.

And when did this clock start on these 5 quarters?

So we are right now in that process of -- the study has just launched. So essentially right around now.

Okay. All right. Got it. So then usually, when companies talk about changes to power, usually the press release says that they had to raise things, right? In this case, interestingly, it could go in the other direction. So was that -- clearly, you had the buy-in from FDA and you did it. I just -- was that controversial or not? I mean you could have kept it, I suppose, and had more of a cushion, but it sounds like in this case, it simply was not necessary and not a wise use of R&D capital.

Yes, exactly. No, look, I think the FDA collaboration has been great. We're obviously very grateful for them to provide us that feedback that we didn't need to split the alpha between those 2 endpoints. And yes, sort of simple statistics, not needing to split that alpha enabled us to reduce the patient enrollment number.

Okay. So then -- so that's neoadjuvant. And then adjuvant, anything else you want to -- you briefly mentioned the design there. Can you just go into a little bit more detail perhaps on the timelines? And then...

Yes. So here, Yigal, it's going to likely be in that 400 to 450 patient enrollment range. We want to ensure that this study has sufficient power. Second, with our partner, Servier, we did discuss, do we do it as a company sponsor versus a cooperative group? We decided we're going to be able to move a lot faster to do it as a company-sponsored study with Servier. Second, our partner will be side-by-side with us in terms of to ensure rapid enrollment for this trial. Next is that the patient population will be HLA-A2 agnostic. So we're not going to have any kind of HLA requirement here.

In terms of the metastatic risk population, we haven't made the final decision there, but it's most likely going to be the high risk and the high medium risk group. So that's the setup.

And in terms of the control arm, as you know, Yigal, there's nothing approved here. So we believe the control arm will be essentially placebo. This will likely be a superiority endpoint around relapse-free survival.

Okay. So then sort of in the marketplace, if people get daro neoadjuvant, I assume they would not be eligible in the adjuvant to get it again? Or like how does that whole logic work?

Yes. So once commercialized -- so one is, as you know, for the neoadjuvant, it's monotherapy. There will be likely some clear out period, which there typically is anyway between neoadjuvant, you have the primary procedure before you start adjuvant care. And for adjuvant, it would be as a combination. So for the actual trial, I would assume here that we will not let patients that were on the neoadjuvant portion flow into the adjuvant, especially on the control arm side, as you can imagine.

Okay. Makes sense. And then -- so of course, the phase -- well, let's talk then about the metastatic MUM, which we're getting very close, as you pointed out. So I think everyone is very familiar, but just to remind everyone, maybe what is the expectation for control and active for PFS? You mentioned your very close to finishing on the OS enrollment. So can you just talk about when that might potentially be available and whether there be any commentary on OS towards the end of the year? Or that would be a future update?

Yes. So for the PFS here, at least we feel based on historical data, the control arm is going to come in somewhere between 2 to 3 months. We feel the treatment arm, as we reported, most recently at ESMO -- sorry, at SMR as well as ESMO earlier, it was a 7-month PFS. I would hope that it's going to land in that 7- to 8-month range, which would put us in a solid position to hit stat sig for accelerated approval.

In terms of OS, Yigal, as you know, there, we feel the historical data in treatment-naive has been in that 12- to 13-month range. At SMR, we reported a 21-plus month OS. So I think as long as we're in that range or obviously above, we should be in good shape for the full approval OS as well.

Okay. And at this point, are you -- I mean it's November 6. So are you kind of getting -- are you in the database lock portion of this right now? Or are you still -- that is yet to occur?

That has yet to occur. So the events are continuing. So yes, that's still ongoing in terms of the collection of the event. So the database lock has not occurred.

Okay. And the data from Society of Melanoma Research, which was a very good number, the 2021 and change, how does that -- in terms of thinking about how that would work in translating to the Phase III of those patient populations very similar that, that's a good translatability. Can you make that statement with high confidence that, that over 20 months is a good a good proxy for what could occur in the Phase III?

Yes. Look, it's a frontline patient population. I think, Yigal, if I were to sort of highlight one patient baseline characteristics where maybe we might see some improvement was around the ECOG performance status. So as you may recall, from the SMR data we presented, the ECOG performance 1 percentage of patients was about 40%. ECOG 0 was 60%. And the peer company of ours, randomized Phase III, both in their treatment and control arm, the ECOG performance status percent was about half of that. So ECOG 1 was 20% versus 40%.

So I think there, the question is if we had that type of population, might we see some additional benefit in survival? And as you know, Yigal, there is published data on how ECOG performance status does impact things like survival. So that's one for us to watch. But yes, so otherwise, it's a frontline patient population. And otherwise, I would say the patient baseline characteristics are going to be similar.

Okay. And then it sounds like you're not speaking about OS for the myeloma -- for the MUM study, that's not going to be something you're ready to talk about until sometime in 2026. Is that a fair statement?

Yes, when the IDMC looks at the PFS, randomized PFS, Yigal, they will look at OS, but our anticipation is that it's going to be too early.

Okay. Okay. That makes sense. All right. Well, let's move on then to talk about some of the other topics. So IDE397, maybe to start out with just that MTAP deletion market is a very interesting market. What is the commentary there in terms of the opportunity set?

Yes. So for MTAP deletion, this is an indication where there is multiple tumor types that are relevant here. I would say, for us, the tumor types of greater priority for us is lung cancer is one, urothelial cancer, and I would say, PDAC. There are other tumor types as well that we're evaluating. But I would say those are going to be the highest 3 priorities.

And obviously, here, Yigal, as you know, we're 1 of only 2 companies that we're aware of that have 2 clinical assets in the MTAP space, obviously, MAT2A and our MTA-cooperative PRMT5 is now in Phase I as well.

Okay. And what -- if you could just kind of give us a quick synopsis of what you've seen so far with 397 in both the monotherapy and you've shown some combo data as well. And then what is the go-forward strategy there for both monotherapy and combo?

Yes. So for IDE397 monotherapy, we've seen a confirmed response rate in that 25% to 30% range. The expansion initiatives have been largely focused on the lung cancer and urothelial cancer. And now we've shifted the focus to the Trodelvy combination, which is data that we shared at our R&D Day recently. And there, as I noted, at the expansion dose that was selected for urothelial cancer, which is 30 mg once a day with IDE397, that's our monotherapy expansion dose. And Trodelvy at 7.5 mg per kg. And so that's an infusion once every 3 weeks.

And as you know, Yigal, Trodelvy is approved at 10 mg per kg. So it's below the approved dose. And that dose in urothelial cancer, at least right now, it's a small data set, but we're observing a confirmed response rate that's in the 50s. So that's good to see. We're still monitoring durability. But so far, I would say, we've continued to see not just confirmation scans, but continued confirmation even post the confirmation scan. So I think that's encouraging to see.

We're now expanding that work in lung cancer. So we've already dosed several patients there. And then, of course, now our PRMT5 asset is in the clinic. Our plan is to launch that combination work as fast as we can. So based on the starting dose the FDA agreed with us on our PRMT5 molecule, we believe by the second cohort, we should be at an efficacious dose. So -- and we have -- based on the protocol, have the ability to enable that combination once we're in that second dose cohort. So we'll get that moving rapidly. And there, I would say, our #1 priority for that combination will be in lung cancer.

We have other, I would just say, strategies here around coalterations without getting into too many specifics, including in our internal pipeline, which is our third MTAP program, which is targeting, we believe, the largest coalteration of MTAP and that would give us 3 potential clinical assets in MTAP, and we would be very unique in that regard. And then all I could say is we're having other conversations about enabling other coalteration combinations in the MTAP arena at this time.

Okay. So for lung cancer, what -- is it going to be the same dose with Trodelvy? Or are you going to -- is that unclear at this point?

So right now, that expansion dose should be very viable in lung cancer. So that's our focus. I think the question is, can we dose Trodelvy a bit higher in lung cancer? Yigal, you may know that urothelial cancer patients, I would say, I'm going to make a general statement here, but are sort of viewed to be typically a bit more fragile than lung cancer patients. So you may have the ability to dose a bit higher. So we may explore that, but we do feel very good about this dose that we have.

Okay. And what type of response rate would be -- would it also be in the 50s that you got for urothelial? Or what are you looking for in the lung cancer to go forward?

So I think for both urothelial and lung, Yigal, that I think as long as we're sort of 40 and above with good durability, I think we're going to be in good shape. Obviously, if we can move 50s and above, even been better, of course. But in terms of kind of a go/no-go and that's what we've publicly communicated, I would say, ideally, 40s and above. Right now in urothelial, we're north of that. Obviously, we want to build more data, a larger data set and obviously more follow-up.

You're keeping the 397 dose the same in long end. It's just Trodelvy that you think you can go higher with in lung. Is that correct?

Potentially, yes. That we may interrogate to see if we might even drive greater efficacy. But obviously, the balance between safety and efficacy is obviously important any time we're doing ADC combination. So we know at that 37.5% at least right now, based on the data we have, which is growing, we feel really good about what we're seeing from a safety perspective. So -- but yes, could we go higher in lung and move that to 10%? I think that's still an open question.

Okay. And then what's the next -- so if these look good, what's the decision point after this? Is it -- do you do -- you go into late-stage studies in one or both of these? Or are you going to sort of determine which is the better place to start a pivotal urothelial or lung with your partner?

Yes. That is the next step. Yigal. Once we have a larger data set, more follow-up, we'll likely give that guidance perhaps in January for next year. But at least in my mind, the next step is a registrational study. And here, yes, that's going to be the decision matrix. Do you go forward in lung only? Do you do both lung and urothelial? Obviously, lung is a larger market.

I think the part on urothelial that we're monitoring that we think could actually expand this market quite significantly, Yigal, I'm sure you saw the PADCEV PD-1 data in urothelial that's moving -- potentially moving even before metastatic into the pre-metastatic setting, and that data looks quite encouraging. So if that happens, we believe the frontline metastatic setting in urothelial could really open up. And if we can capture that portion, this market would get much larger.

Okay. And then for the combo with PRMT5, now it's your -- obviously, it's your own molecule. How are you feeling about this combo given some of the past attempts with other partners with PRMT5? How is this looking?

Look, Yigal, for us, to really make a run at frontline lung cancer for MTAP, this is our focus. Based on all the data we have, the preclinical data, we feel that's the best opportunity to really deliver hopefully an exciting result. We know others have launched a PRMT5 combo with chemo. I think that's with a checkpoint inhibitor. We think that's fine. That wouldn't be our preference. We think if we can deliver something exciting with a chemo-free regimen with a checkpoint inhibitor, would really position us in a unique way in frontline lung. So that's going to be our focus.

We obviously have to start generating data now, but we feel very good about our MTA-cooperative PRMT5 molecule. We do believe that has a potential best-in-class profile. I'm sure we want to have time to go through that now. This molecule was made fit for purpose to combine with IDE397. So that's going to be our strategy and focus in lung cancer for frontline.

Okay. Right. And then have you talked about the doses? You said you're in the -- the second cohort looks like a good place to be. So what -- can you be more specific there about what the doses are? That's...

Yes, so for IDE397, we're fairly confident we know what that dose needs to be in combination with the clinical stage PRMT5 inhibitor. So we have that data. So we know what that dose should be. And then it's about as we dose escalate with the MTA-cooperative PRMT5 inhibitor. But based on our preclinical evaluation, we believe by the time we've cleared that first cohort in combo with a set dose we know with IDE397, we should be at an efficacious range. So we should be at an efficacious range essentially right out of the gates because we're not going to start the combo work until we get to the second cohort.

Right. Okay. And then in terms -- what would you be watching for in terms of possible like combo talks that needs to be monitored? Is there anything specific that just needs to be kept in mind? Or you wouldn't expect any additional tox on combo -- because of the combo?

Well, I think in this pathway in general, right, for PRMT5, I think probably the main one people have been looking at in terms of target related is around myelosuppression. So I think that's what we'll be looking at. Based on prior work we've done here, at least our perspective is we should have several cohorts hopefully available to us that we could move forward with. That should be efficacious. So -- and that's what we'll prosecute in the clinic and make that determination.

Okay. And someone was just asking me if you could expand a little bit on -- you mentioned these coalterations in MTAP. Can you just expand on that so everyone is clear on what you mean?.

Yes. So we know that MTAP is genetically -- has genetic alterations with other key mutations, including RAS, right? So in PDAC, for example, if you said pan-RAS, RAS more broadly, so KRAS, HRAS, NRAS, you're going to have most of those patients will overlap with MTAP and at least in certain tumors like PDAC. Depends on the tumor type they vary.

The other beyond RAS, I would say, people have been looking at, which is CDKN2A. So you may know that CDKN2A MTAP are very often co-deleted because the proximity of those genes are very actually close. So when MTAP is deleted, CDKN2A is often co-deleted.

So we've been having a drug discovery program on this for 5 years now. So we've been kind of over this for a long time that this could be a great combination opportunity. But for us, we are very focused, and we wanted to wholly own this. So what we're doing, I can tell you is the chemistry has been very, very complicated, but we're very much nearing a candidate now. And so if we can deliver that, that would be our wholly owned strategy around taking that coalteration approach. So hopefully, with that, we would sort of cover our full basis on what's at least what we think are the most exciting rational combinations. And then in that case, we would wholly own 3 sort of pieces of this lever that would position us very uniquely in the market.

Okay. So that's -- you're not ready to talk about an IND on that yet, I guess.

Candidate this year, yes, I would hope sometime next year, maybe towards the end of the year. And for coalterations, PDAC is one, an obvious one, maybe lung cancer, although I think we will prioritize the MAT2A, PRMT5. But probably for the PDAC 1, the coalteration strategy for us is one we want to consider and ideally with an internal asset as well.

Okay. I want to make sure we get to DLL3. So 849, obviously, a lot of interest in this asset you've got from Hungry. Well, so just essentially tell us what is the thesis on your construct? You've got competitors, as you know, but what makes yours stand out?

Look, we feel that our ADC DLL3 with Topo-1, it's from a very battle-tested platform from Hungary. They've been in several thousand patients across multiple clinical stage programs that have been presented in many major medical conferences. And so we know that this platform, in particular, around the payload linker system, which is a tetrapeptide cleavable linker, which is sort of your classic linker system, which cleaves once it's internalized in the cell from lysosomal degradation. So here, things similar to the Daiichi platform that was developed. And so we feel really good about that platform and its level of validation in patients across many, many studies.

So we feel we are positioned to have a potential best-in-class molecule based on what was presented at the World Cancer Lung Conference recently in Barcelona. Just a quick snapshot, at least at the 2.4 mg/kg expansion dose, which is likely going to be one of our expansion doses, what we focused on. And just so you know, that's the starting dose, the FDA has let us begin our U.S. trial with. So our first patient that was dosed was at that dose. We saw a confirmed response rate by RECIST at 70% in the second-line setting. So we feel really good about that number.

We've seen a lot more data since the World Cancer Lung Conference. I would say the data continues to remain to be robust. In addition, on the PFS side, across all lines, we reported a PFS of approximately 6.7 months, which, Yigal, as you know, is a very good number in relation to other reporting of PFS, including IMDELLTRA, where they got accelerated approval. It was 4 months and change. So we're obviously north of that. We want to build that data set, build it with a global data set, and that's what we're doing right now.

So I think we're in a good spot. And now it's going to be about speed as well as what is our clinical strategy. We're not prepared to disclose at this time all the specifics for competitive reasons, but we would like to launch ideally 2 registrational trials here. One in small cell and then I would say another -- and an another tumor indication. And we do believe, based on the data we're seeing, we should have some monotherapy accelerated approval path available to us.

Interesting. So you're thinking monotherapy accelerated approval because, as you know, some of the competitors are talking about comparator arms and talking about needing to enroll in IMDELLTRA in those arms, which obviously raises the bar for a randomized trial. So is that -- any comments you want to offer on that discussion?

I mean, you can still have an accelerated approval path as a randomized study, right? So I think there, Yigal -- and that's the part we just haven't disclosed yet what our strategy is. But what I can say is we're thinking about this very deeply. I know the clinical team, I know is even going to investigator about next week to kind of dig even deeper on this and get them put on where to focus that monotherapy accelerated approval study. But hopefully, we'll be able to share that publicly here not too far in the distant future.

The only other part I should have mentioned to you, Yigal, was at that expansion dose I mentioned because I think maybe there was maybe some lack of clarity on this, we are seeing what we think is a very viable AE profile, where the Grade 3 or higher AE rate at that does, at least right now, was observed at less than 20%. We think we can go even higher than that based on that because as you know, with ADCs, it's very common to have Grade 3 or higher, that's in the 30, 40-plus percent range, including very well in ADCs like in HER2.

So that's still kind of in being determined, 2.4% is not -- you say starting dose, but it could -- there could be a potential for going higher.

We could potentially go higher. I think right now, we're very focused on that 2.4 dose, and we will be doing some dose evaluation, but we feel good about that dose. So -- and that is -- we think it's a very viable dose at this time.

Any thoughts you want to offer on activity in the CNS tissue for your construct?

So the data that was presented at the World Cancer Lung Conference is a response waterfall in patients that have brain metastasis. And what we could say is we're seeing very robust activity there. So we don't see any diminishing of response in that setting. So we feel good about that. And obviously, brain metastasis is something you have to think about in that indication specifically.

Right. Okay. Well, in the final few minutes here, you have a lot of other assets earlier stage or some that are earlier stage, some that are maybe getting close to mid-stage. So could we kind of walk through those in a little bit more rapid fire maybe? I mean which of those would you like to highlight? Pol Theta PARG. Obviously, you have the KAT6 as well. There's a B7H3/PTK7, bispecific ADC. And then there's -- well, we talked a little bit about 892. But so of those other ones, can we just kind of quickly run through those? And where do you see the most opportunities?

Sure. Yes. I can do more rapid fire here, Yigal. So maybe with -- quickly with Pol Theta, so for the listeners here, this is partnered with GSK. Focus is combination with niraparib, specifically in patients with BRCA. That escalation has been going well, has entered the combination phase with niraparib. We do anticipate an expansion dose being selected here relatively soon on that combination, which would trigger an expansion milestone payment. So I think that's all going as planned.

For Werner Helicase, as you know, Yigal, we feel we have a truly differentiated best-in-class molecule based on the way it binds to the D1/D2 domain and does not bind with that key cysteine 727 interaction, which both the Novartis and Roche molecule do. And our hypothesis on this is that, that should lead to greater efficacy. That escalation is also going well. And hopefully, we'll be able to give some disclosure update on that with GSK over the next couple of quarters. And there, we do plan to have, I would say, an important focus on gynecological cancers as well as combination with GSK's checkpoint inhibitor, dostarlimab.

The next 2 programs here, Yigal, I think that at least I'm excited about. We're quite excited about what we're seeing preclinically with our B7H3/PTK7 bispecific. It's very active preclinically. We do see enhanced efficacy versus B7H3 alone or PTK7 alone, based on the data we have. The co-expression population is large, which is why we pursued this bispecific, in particular, in indications like non-small cell lung cancer and CRC, which are 2 very high priority areas for us. So now that IND has been filed, it's essentially now a clinical stage asset.

We will be very focused, I didn't mention it, for DLL3 on the combination with PARG IDE161, which is our other Phase I asset to enhance the durability of Topo ADC. So that preclinical data, which we shared at R&D Day, looks great. And we've demonstrated this with multiple ADCs now. So that's going to be a really key strategy and lever for us for both DLL3 and the bispecific.

KAT6/7, we're tracking towards that IND next month. A first-in-class dual inhibitor. One of these have not entered in the clinic, is similar to our bispecific. No bispecific of that format has entered the clinic yet. Clearly, we believe, based on the preclinical data we're seeing, with that dual inhibitor, we should be able to drive greater efficacy. So we're going to be very focused on that asset as well. Breast cancer, lung cancer, obviously, big opportunities.

As you can imagine, Yigal, we're not going to be able to do all of this on our own. So we're having a lot of different conversations, a lot of interest across the portfolio. But we're trying to build a world-class precision oncology company, and we're thrilled to really be able to get these next set of assets in the clinic and to move them forward.

I mean there's been a lot of excitement around the Werner Helicase, and I was tracking it for a long time. Is that -- are we close to getting an initial readout there? Because I know you had -- you showed the biomarker data, I believe it was earlier this year, if I'm not mistaken. But what is the time line there? And what would be a good result that would be compelling?

Yes. So yes, we need to be in coordination with GSK, Yigal, on that and kind of the timing of that disclosure. Ideally, it's one we sort of have an expansion dose, and we have a decent amount of data there. So we'll be in coordination. In terms of response rate, I think there will be about, at least in my mind, what do you see in the setting of gynecological cancers. So here, in this case, specifically, indications like ovarian and endometrial cancer.

And then I would say the second area is most likely around CRC, which we know MSI-high is very prevalent in both of those settings. And you may see different response rates depending on which of those 2 indications or general indications that you're focused on.

So what would we like to see, I mean, Yigal, I think for a monotherapy ideally, right, you're above 30% or higher with good durability. So this will be the first time again, a molecule is going to be tested in the clinic without this cysteine binding interaction. And we know, in the MSI-high setting, in particular, you have to be very thoughtful about point mutations because it's a very rapid point mutation clinical setting.

You're doing high MSI for Werner, and I guess -- say solid tumors, but I guess, as you point out, endometrial would be important. And then you're also doing that with the PARG with KEYTRUDA. So -- but I mean that's a different partner, obviously. So when you think about those 2 programs, they could both proceed together, right? I mean how do you think about that? Is one going to win? Or is it not like that?

Yes. So with PARG IDE161, our focus here, Yigal, is around enabling the Topo ADCs. And the reason why we've been evaluating the KEYTRUDA combo, which were done with that dose evaluation is really answer the question around safety. Could we generate that safety data? And we've done that now. And the reason why we did that was as we enable the ADCs now with the ADCs with PARG, right? As you can imagine, in lung cancer or non-small cell lung cancer, in particular, you're going to likely want to do that with a checkpoint inhibitor. So that's why we have that data to enable as we think forward about the PARG checkpoint ADC combination.

So that's where our focus is for that program versus sort of competing with Werner independently in the endometrial setting. So hopefully, that makes sense. But that's our current focus right now.

Okay. And then the KAT6/7 axis is also heating up. There are several other players in the space. You have a dual or I guess, it targets both 6 and 7. What is the rationale for that versus just one of them? What does that get you in having the dual targeting?

Yes. Our CSO, Mike White, is -- we think, is one of the world experts in this arena. But really, the shortened version of it, Yigal, is we believe 7 is a key potential bypass mechanism for KAT6. And so we have a lot of preclinical data to support that statement, including data that we presented publicly. But essentially, we feel by hitting these 2 together, which I would call for now paralogs, we feel we can drive much greater efficacy and durability as well as expand the opportunity into other indications beyond breast cancer, including indications like non-small cell lung cancer.

So the chemistry was very complicated. And our team is obviously first rate, and we were able to figure that out. So we'll be in patients here shortly. I should have mentioned also the GLP tox in both species is done. Everything is behind us now. So it's really just about IND assembly, some of the final CMC pieces. But essentially, we have the data we need to file that IND.

I was always impressed with some of your more technical slides where you talked about advanced physics concepts like free energy perturbation, which doesn't come out much obviously, to say the least. But really, the question is, with the obvious acceleration in machine learning and LLMs and everything and AI and AGI, how much more is that helping you in the very early -- in the early innings when you're designing molecules? Are you leveraging that even more because you do have a platform, which I'm sure you're working on all sorts of other things you haven't talked about at all. But how much more is that technology advancement helping you?

Yes, Yigal, look, it's been an amazing voyage because we began investment in this area several years ago, and we began applying it to serval programs like KAT6/7 as well as others. And now it's essentially integrated across all of our drug discovery programs. And I would say it's been a really great surprise how much more efficient it's made us in terms of optimization of certain parameters of lead optimizations. We found that it's not great for certain areas of lead optimization. But extremely effective in others.

So I think here, it's really about knowing where to apply it. And I would say what makes us unique versus some of the other players here is that we're applying it to first-in-class targets, right? And we also have a machine learning process and system that's becoming more and more sophisticated because we're actually feeding the results into the next program. And so we probably have one of the largest Helicase databases, polymerase databases of chemistry, and we're feeding that into the machine learning system. So it's actually getting more and more effective and sophisticated in what it's doing.

So look for us to double down in that area, Yigal, and that's why we highlighted it at our R&D Day. And I know for our CSO or our Chief Technology Officer, it's definitely a very much of a high priority. So our hope longer term, it should just essentially accelerate our time to IND, right? So by how much? Right now, we're probably seeing about a 30% acceleration, which is big, right? So now the question is, can we even enhance it beyond that? So before it took us 5 years to get Werner. If you could do that in 3, that's big, right? If you could even reduce it more than that, that's a game changer for us.

And then without giving away the house secrets, so to speak, I mean, you mentioned areas where it's more effective and less effective. Just generally speaking, like how do you characterize like that? Where is it -- where are the pitfalls? Where is it -- where do you know that it's just -- it's not going to do a good job? And where is it really, really, really helping you?

Yes. That I can't tell you, Yigal. I'll get in trouble if I told you that, but I do know the answer. So -- but yes, there are definitely [indiscernible] areas. And we actually have great data on it, which I've seen just where -- how predictive AI has been for certain parameters of lead optimization and where in other parameters, it just -- it does not do a very good job. So you do need to know where to apply it effectively. And as companies get more sophisticated and build their own databases, I think companies will get better and better at this, which is great for the whole sector.

Okay. Great. Well, thank you. Very interesting, for sure. And we'll be watching for the MUM data any day now or in the next few weeks, I guess. So thank you. And congratulations on a very, very strong progress over the last 6 months.

Yes. No. Great, Yigal. Thank you so much for the time and really appreciate the chance to talk today.

Okay. Absolutely. Take care.

Bye for now.

Bye-bye.

Welcome to all of our attendees to IDEAYA's 10-year anniversary R&D Day. Today marks an important milestone in the company's history, and we want to thank each of you for sharing this special day with us. I hope everyone will walk away feeling inspired by the extraordinary R&D ongoing at IDEAYA and the strategic vision that will drive forward our growth as a global leader in precision medicine oncology in the coming decade.

Please note, we'll be making forward-looking statements today, and please refer to our SEC filings as appropriate.

To kick off our 10-year anniversary R&D Day, we wanted to first share a short video to help bring the broader IDEAYA organization and our extraordinary scientists and research labs in South San Francisco to all of you in Midtown New York City today.

Please begin the video.

[Presentation]

We will now introduce today's speakers, Dr. Arun D. Singh, Director of Ophthalmic Oncology at the Cleveland Clinic; Dr. Darrin Beaupre, Chief Medical Officer; Dr. Michael White, Chief Scientific Officer; Dr. Jasgit Sachdev, Senior Vice President, Clinical Development; and myself, CEO of IDEAYA, will also serve as your host today.

For today's agenda, we have approximately 2 hours of presentations and 30 minutes for analyst Q&A. I'll kick off to provide a brief introduction and to outline IDEAYA's strategic vision for the next decade to build a global leader in precision medicine oncology.

Next, Dr. Singh will provide a walk-through of updated clinical data for darovasertib in neoadjuvant uveal melanoma, specifically in plaque therapy-eligible patients.

Next, Dr. Darrin Beaupre will walk us through the first-in-human data that was presented yesterday in Barcelona, Spain at the World Cancer Lung Conference for IDE849, a potential first-in-class and best-in-class Phase I DLL3-TOP1 ADC for small cell lung cancer.

Next, Dr. Michael White will walk through the preclinical mechanistic combination rationale for both IDE161/PARG and TOP1 ADC and the IDE397, MAT2A and Trodelvy clinical combinations in MTAP-deletion.

Next, Dr. Jasgit Sachdev will present the first-in-human IDE397 and Trodelvy clinical combination results in MTAP-deletion urothelial cancer.

Then Dr. Mike will present the product profile of IDE892, our potential best-in-class PRMT5 inhibitor and provide a walk-through of our AI-enabled drug discovery capabilities.

I will then provide brief closing remarks, and then we will start the analyst Q&A portion of the event.

Since founding IDEAYA 10 years ago, we are now on track to have nine clinical to IND stage programs in the clinic by year-end. The key strategic priorities over the past decade have been pursuing first-in-class targets, discovering patient selection biomarkers and enabling transformative rational combinations. Through this, IDEAYA has discovered and advanced multiple first-in-class targets into the clinic, including Pol Theta Helicase, Werner Helicase, PARG and MAT2A and has been a research pioneer across multiple biomarker-defined solid tumor populations, including an MTAP deletion, BRCA and MSI-high.

As we look forward into the coming decade, we believe there are three major macro trends that will redefine the way we treat cancer, including: one, a deep molecular understanding of the drivers of cancer that will lead to new breakthrough targets that were once thought to be undruggable, including helicases to transcription factors.

Second, the continued growing intersection between therapeutics and diagnostics that has the potential to deliver better survival outcomes in early-stage disease, including in the neoadjuvant and adjuvant settings.

And finally, three, the continued transformation of the life sciences industry fueled by information technology, specifically the application of artificial intelligence and drug discovery.

These three macro trends in Oncology and Life Sciences will serve as important strategic guideposts for IDEAYA in the coming decade.

We have launched two potential registration-enabling trials for darovasertib and U.S. commercial readiness activities are ongoing. We believe darovasertib is uniquely positioned to be the potential standard of care therapy across the uveal melanoma patient journey, including in the neoadjuvant adjuvant and metastatic settings. We're excited to advance our efforts to bring darovasertib to patients worldwide with our partner, Servier.

Beyond darovasertib, we have identified our next two clinical growth drivers in our TOP1 ADC and DNA damage repair and MTAP-deletion clinical portfolios. Our TOP1 ADC and DNA damage repair clinical strategy is supported by two potential first-in-class clinical stage programs in IDE849 and IDE161 as well as a third program in bispecific B7H3, PTK7, ADC, IDE034. We are on track for an IND next month.

In MTAP-deletion, we believe IDEAYA has built the broadest pipeline in the industry with potential first-in-class MAT2 inhibitor IDE397 in Phase II, potential best-in-class PRMT5 inhibitor, IDE892 and our third MTAP program, which is on track for an IND next year.

Lastly, in the medium to long term, our strategic focus on early-stage disease in IDEAYA drug discovery will continue to drive our growth for our next-generation pipeline.

For our ADC pipeline, we have a 3-pronged strategy we are implementing, including: one, advancing potential first-in-class ADC programs into the clinic that have sufficient single-agent activity to pursue a monotherapy accelerated approval path in the later-stage metastatic setting; second, enabling ADC immunotherapy clinical combinations to pursue earlier-stage disease, including in the first-line setting. And then finally, last, enabling first-in-class clinical combinations with TOP1 ADCs and novel DNA damage repair small molecule mechanisms such as PARG to enhance the durability response of DNA damage repair mechanism-based ADC payloads.

To advance our industry-leading MTAP portfolio, we are pursuing a 3-pronged combination strategy. First, targeting multiple nodes in MTAP pathway to address key resistance and bypass mechanisms by taking a two-hit approach with MAT2A and PRMT5.

Second, targeting key genetic alterations of MTAP such as RAS, CDKN2A and EGFR, which is the strategic premise of our potential first-in-class MTAP program #3, where we are on track for an IND next year.

And then finally, third, leveraging the DNA damage repair mechanisms associated with the MTAP deletion pathway, which is the basis for Trodelvy and IDE397 clinical combination that we will present later today.

Lastly, as we look to enhance our IND engine capabilities and the next-generation pipeline, we'll continue to invest our growing capabilities in AI drug discovery. IDEAYA's differentiation in AI drug discovery lies at the intersection of first-in-class biology, AI drug discovery and structure-based drug design.

With that, we'll now advance to the clinical development update portion of the event today. And it is now my pleasure to introduce Dr. Arun Singh from the Cleveland Clinic to walk through the darovasertib data in the neoadjuvant uveal melanoma setting. Dr. Singh?

Good morning. Thank you, Yujiro. I'm here to present a background information pertaining to primary uveal melanoma and some of the emerging clinical data from the OptimUM-09 trial that test darovasertib as neoadjuvant therapy in subjects which are -- who are eligible for plaque brachytherapy.

Many medical professionals are involved in the management of a patient with uveal melanoma. Most commonly, the patient presents to a general ophthalmologist after having some difficulty with vision. The suspicious findings trigger a referral plan that can involve ocular oncologists, radiation oncologists, medical oncologists, considering any other physicians over a long-term follow-up and the management of these patients. Often in the United States, tumor biopsy samples are obtained for genetic testing to identify patients at metastatic risk.

The management of uveal melanoma and subsequent outcomes are all size dependent. If a patient has a small tumor, they may be observed for a period of time. If tumor is medium-sized, plaque brachytherapy is undertaken to deliver radiation to achieve local control.

If the tumor is large, an enucleation procedure will be required. That is where the eye is removed. Fortunately, based on these two procedures, local relapses are relatively uncommon. However, in the process of this therapy, the patients may either lose an eye or lose their vision from radiation complications. About 40% of patients go on to develop metastatic disease, which has limited treatment options.

The current treatment paradigm for localized melanoma, therefore, opens the door for novel therapies that could be implemented in the neoadjuvant setting that can protect vision, preserve eye and may even save lives. This takes us to the OptimUM-09 trial, that tests darovasertib in the neoadjuvant setting. This would be the first of its kind.

The vast majority of uveal melanoma tumors have mutations in GNAQ or GNA11 that activate protein kinase C, a key driver of tumor growth. Darovasertib is an oral potent PKC inhibitor, which shows -- which has shown promise, particularly in combination with crizotinib in metastatic melanoma.

In this study, darovasertib provided as a single agent at the dose of 300 milligrams twice a day prior to primary local therapy was evaluated to determine its effect on tumor shrinkage, radiation reduction, visual outcome and eye preservation.

In this presentation, we will focus our attention on plaque brachytherapy cohort, which included 39 subjects that were evaluable for safety and 21 for efficacy. Herein, subjects received up to 12 months of neoadjuvant therapy with darovasertib and then were transitioned to plaque brachytherapy. For those subjects who received benefit from the neoadjuvant therapy, adjuvant therapy was planned for additional 6 months -- up to 6 months.

Primary endpoint for this cohort included safety and radiation dose reduction and secondary endpoints included vision and relapse-free survival. In the 39 subjects evaluated for safety, the majority of treatment-related adverse events were Grade 1 or Grade 2 with a low frequency of high-grade adverse events. The most common adverse events included diarrhea, nausea and vomiting, rash and fatigue.

Dose reductions and discontinuations due to treatment-related adverse events were uncommon and as was the frequency of serious side effects. Therefore, darovasertib was well tolerated in this setting.

In the 21 efficacy evaluable subjects who had received at least three cycles of the therapy, the baseline characteristics revealed a median age of 56 years, median tumor height of 7 millimeters and a median basal diameter of 14 millimeters. Overall response criteria required 20% or greater decrease in tumor reduction.

As shown in this waterfall plot, majority of patients experienced tumor shrinkage and a large proportion reached a 20% reduction threshold for partial response, providing an overall response rate of 76% in this patient population.

Let us review a few case examples. The first case was presented at the International Society of Ocular Oncology meeting in July of this year. The subject is a 62-year-old male who experienced vision changes and were diagnosed with uveal melanoma involving the right eye. The tumor height was 6.2 millimeters and the basal diameter was 13 millimeters. The patient had evidence of retinal detachment as shown on the ultrasound. And after 12 cycles of darovasertib treatment, the subject experienced 60% -- 63% reduction in tumor height and 71% reduction in the basal diameter. And the retinal detachment also resolved.

This led to improvement in vision, while patient was receiving neoadjuvant, darovasertib. Also, you can see the change in tumor intrinsic characteristics where it goes from a hollow echogenic appearance to one that's more dense. That's typical of tumors that are undergoing cell death and necrosis. Furthermore, the radiation dose to the optic disc and fovea were reduced.

Based on our vision prognostication tool, his risk of 20/200 or worse vision at 3 years, that is same as legal blindness was also reduced.

The second case is a 56-year-old female with a tumor that was 4.9 millimeter in height and 14.7 in basal diameter. After 10 cycles of neoadjuvant darovasertib, there was remarkable flattening of the tumor. 77% reduction in the productive tumor dimensions. It's remarkable.

Radiation reduction to the key visual structures such as optic disc and fovea was near 40%. Because of distancing of the tumor from these structures, the probability of having 20/200 or worse vision at 3 years was also reduced.

So darovasertib seems to have significant potential in the neoadjuvant setting. But before we transition to additional data from OptimUM-09 trial, that Darrin will present, I want to briefly describe two tools that we used in this analysis, and they will be included in the registration trial to support some of the relevant endpoints.

In this slide, on the left, you can see an example of an eye using Eye Physics software where the tumor is simulated for radiation treatment prior to neoadjuvant darovasertib. Once neoadjuvant therapy was completed, a repeat simulation is performed to identify the radiation distribution after tumor reduction.

In this example, a reduction in radiation dose to the key eye structures that is fovea and optic disc is evident. And by comparing pre- and post-darovasertib treatment simulations, one can measure the benefit with respect to radiation dose reduction.

On the right is the vision prognostication tool that my team developed. The tool predicts the risk of severe vision loss that is 20/200 or worse that is same as legal blindness at 3 years in subjects who received plaque brachytherapy.

Of the five baseline factors, darovasertib can favorably improve all four modifiable factors by causing tumor shrinkage.

Now I'll hand it over to Darrin, who will discuss the additional results from OptimUM-09 study and how they link to endpoints of the registration trial that is being initiated. Darrin?

Thank you very much, Dr. Singh. It was terrific. So based on the safety and efficacy data gathered from the OptimUM-09 study, a registration trial testing darovasertib in the neoadjuvant setting has been initiated.

What I will do here on this slide is describe to you the overall design of the registration trial. And in subsequent slides, I will provide you data from the OptimUM-09 study that supports each of the primary and secondary endpoints chosen for the analysis.

OptimUM-10 is a 2-cohort study enrolling subjects with small to midsized tumors requiring plaque brachytherapy and also patients with large tumors requiring enucleation. Eligible subjects will be those with a high risk of metastases and also moderate to high risk of vision impairment. Subjects will be randomized in a 2:1 ratio to either immediate primary local therapy or neoadjuvant therapy with darovasertib, 300 milligrams twice a day for up to 6 months.

Patients will be subsequently followed for the endpoints listed on the right of this slide. The primary endpoints include vision preservation measured by the reduction in the proportion of subjects with best corrected visual acuity greater than or equal to 15 letters lost in the plaque brachytherapy cohort and eye preservation rate in the enucleation cohort.

The secondary endpoints include the proportion of subjects with clinically significant macular edema, visual acuity of 20/200 or worse and radiation reduction in the plaque brachytherapy group and overall response rate and event-free survival will be evaluated in both cohorts.

On this slide, we will address the first key primary endpoint in the registration trial associated with vision preservation, which is supported by data from the ongoing OptimUM-09 Phase II trial. Data from this study shown in the left portion of the figure reveals that after darovasertib neoadjuvant therapy, there is significant tumor reduction measured by both product diameters and apical height. And in addition, this correlates with radiation reduction in the majority of patients.

This is further associated with a greater than 20% reduction in radiation dose to at least one key visual structure seen in nearly half of the patients treated. This is significant since a 20% reduction in radiation dose is known to correlate with improved visual outcomes.

In addition, looking at the individual vision-associated eye structures on the right, in this patient population, a significant reduction in dose to the fovea, optic disc, and lens was observed.

The goal of the registration trial is to reduce the loss of three lines of vision, that is 15 letters in the treatment arm versus the control arm in 20% or more of subjects. With this level of radiation reduction, it seems likely that darovasertib provided in the neoadjuvant setting will have a relevant impact on visual outcomes, and I will show you more evidence to support this in the next few slides.

Focusing for a moment on the enucleation cohort, where eye preservation is the primary endpoint. Data from two trials, both the OptimUM-09 study and the NADOM study that tested darovasertib in the neoadjuvant setting show that most subjects, both enucleation and plaque brachytherapy subjects experienced tumor shrinkage with 61% of subjects scheduled for enucleation able to undergo eye-preserving therapy instead.

Based on this data, darovasertib received breakthrough therapy designation from the FDA for patients with primary uveal melanoma for whom enucleation has been recommended.

In the registration trial, a lower confidence interval bound of only 10% needs to be exceeded in order for the study to have a positive outcome, which appears readily achievable.

In this slide, we move on to data that supports the secondary endpoints for the OptimUM-10 registration trial. I've already shown you data regarding the ability of darovasertib to reduce radiation dose. This reduction is likely to be associated with a lower level of macular edema, which is relevant since radiation-induced macular edema is the leading cause of post- plaque brachytherapy visual impairment.

Using the vision prognostication tool described by Dr. Singh, data from the OptimUM-09 trial shown here reveals that neoadjuvant darovasertib can impact four of the five predictive factors that affect visual outcomes. In this data set, 2/3 of the patients had reduction in the risk of 20/200 vision or worse at 3 years and nearly 40% had a 20% or greater reduction in this risk.

In addition to longer-term visual outcomes predicted to improve, data gathered from the OptimUM-09 trial revealed that darovasertib in the neoadjuvant setting could also improve vision while subjects were receiving treatment.

In this trial, 65% of subjects had any improvement in visual acuity score. The median number of letters gained was 5. And 8 out of 20 subjects had a greater than or equal to 5 letters gained on two consecutive visits.

Other examples of benefit during the neoadjuvant period included a reduction in subfoveal fluid and improvement in retinal detachment.

And finally, addressing the endpoint of overall response from the registration trial. The response rate is predicted to be high based on the waterfall plots you have seen thus far. And with respect to event-free survival, the objective of this study is to show that delaying primary local therapy by using neoadjuvant treatment results in no detriment with respect to local or distant relapse. This would seem likely since protein kinase C is the key driver of this disease and darovasertib is an effective protein kinase C inhibitor.

Also, thus far, the relapse rate from the OptimUM-09 neoadjuvant trial remains low. And even in those few subjects that progress on neoadjuvant darovasertib therapy, patients are taken directly to primary local therapy as soon as they show evidence of tumor growth.

Therefore, the design of the OptimUM-010 study, registration trial and current supportive data suggest that a neoadjuvant approach should be safe and effective without causing detriment in EFS.

And in closing, I would like to first take a moment to thank the many investigators that helped us design and execute our clinical studies in uveal melanoma. Some of them are listed here. This specific group worked with us to design and execute our trials in the primary uveal melanoma setting, where a neoadjuvant therapy that can save eyes and preserve vision does not currently exist.

We've had extensive discussions with this group regarding the implications of our study results and the probability of success in the OptimUM-10 study. Unanimously, these investigators have high enthusiasm for darovasertib in this setting. And they believe our trial, as designed, has not only a high likelihood of providing benefit to uveal melanoma subjects, but also has a high likelihood of meeting the primary endpoint.

Therefore, in conclusion, for this update, darovasertib represents a novel therapy for primary uveal melanoma. And importantly, for patients, it has received FDA breakthrough therapy designation in the neoadjuvant setting for patients who require enucleation as well as Fast Track and orphan designation.

Data from OptimUM-09 has revealed that, 3/4 of plaque brachytherapy subjects treated with darovasertib experienced greater than 20% ocular tumor shrinkage by product of diameters. Half of the patients achieved greater than 20% decrease in simulated radiation doses to at least one key visual structure. 65% had any degree of visual improvement during neoadjuvant therapy and 40% achieved greater than or equal to 5 letters gained at three consecutive visits.

Results from a vision prognostication tool revealed that 2/3 of subjects received at least some reduction in the risk of 20/200 vision or worse at 3 years and nearly 40% obtained a greater than or equal to 20% risk reduction.

A clinical data update in greater than 90 enucleation or plaque brachytherapy subjects who received darovasertib in the neoadjuvant setting will be presented at ESMO next month as an oral presentation. And the Phase III randomized neoadjuvant uveal melanoma trial, OptimUM-10 has been initiated.

So now what I would like to do is turn it over to Dr. Singh to provide some of his thoughts regarding the evolving data from the OptimUM-09 trial and the implications for the uveal melanoma landscape.

Dr. Singh?

So just as I -- just to summarize, everything in uveal melanoma is size dependent. We classify tumors to small, medium and large and things we offer to the patient, the treatment choices and the outcomes are all size dependent. For large tumors, we offer enucleation, they lose their eye. For medium-sized tumors, we offer radiation therapy and they lose their vision. And all of these tumors, small, medium and large, are causing metastasis and the risk of survival or metastasis is also size dependent.

And darovasertib is reversing this tumor growth. It is converting large tumor to medium-sized tumors and some medium-sized tumors will also transform or reduce to the classification of small-sized tumors.

So one can, therefore, derive that the rate of enucleations or globe preservation will go up. Radiation toxicity, which is size dependent, will also reduce. So they'll have vision preservation and all of it will also impact the risk of metastasis. This is a major change in how we think about uveal melanoma and what we may be able to offer in the near future and hasn't happened since 1915. That's when the radiation therapy was started for uveal melanoma.

So I'm excited and everybody else in our business are excited. Thank you so much.

Now we're going to transition over to a program that probably everybody has been thinking about in the last 24 hours. So it's the IDE849 program for subjects with small cell lung cancer and other neuroendocrine tumors.

What I'll be presenting in the next 15 or 20 minutes is data from the first-in-human trial of IDE849 that was recently presented at the World Conference on Lung Cancer in Barcelona, Spain, sponsored by our colleagues at Hengrui Pharmaceuticals.

Let me begin with some background information. Small cell lung cancer is a highly aggressive neuroendocrine carcinoma with a poor prognosis and limited treatment options. Importantly, in small cell lung cancer, DLL3 is a surface protein expressed in a large proportion of these tumors, allowing targeting with an antibody drug conjugate.

IDE849 is an antibody drug conjugate compromised of a humanized IgG1 monoclonal antibody linked to a Topoisomerase 1 inhibitor payload via a cleavable linker. In preclinical studies in tumors that expressed various levels of DLL3, IDE849 inhibited growth and demonstrated a bystander killing effect in small cell lung cancer cell lines and was also effective in small cell lung cancer xenograft models. This set the stage for the clinical testing of IDE849 in a first-in-human trial.

So this slide provides the study design for the first-in-human study, IDE849. It was a multicenter trial that enrolled subjects with small cell lung cancer and other neuroendocrine tumors that expressed DLL3. Patients were required to have progressed or recurrent disease after standard therapy and have a performance status of 0 or 1.

Patients with brain metastases were eligible, and the total number of patients for this analysis was 100 with a data cutoff of June 20, 2025. A standard dose escalation design was performed beginning at a starting dose of 0.8 milligrams per kilogram every 3 weeks with a top dose that was tested of 4.2 milligrams per kilogram.

During the conduct of the trial -- of this trial, an additional cohort of 3 milligrams per kilogram was included. The primary endpoints included safety in defining a recommended Phase II dose with secondary endpoints, including efficacy, pharmacokinetics and immunogenicity. Dose escalation proceeded up to 4.2 milligrams per kilogram. And at that dose, a grade 4 decrease in platelets was observed. Therefore, this dose level was discontinued. Due to the fact that the majority of antitumor activity occurred between 2.5 and 3.5 milligrams per kilogram, these two cohorts, along with the 3 milligram per kilogram cohort were expanded.

This slide presents the demographics of the patients enrolled in the study. There were 70% male, 30% female. Median age was 60. Most subjects had a performance status of 1, and most patients had a diagnosis of small cell lung cancer with advanced disease. Patients with brain metastases constituted approximately 1/4 of the population. About half of the patients had at least two prior lines of therapy and immunotherapy had been used in the majority of subjects.

Here, we provide the pharmacokinetic profile of IDE849. Following a single dose systemic exposure of IDE849 total antibody and payload increased proportionally with doses ranging from 2.4 to 4.2 milligrams per kilogram. Across the 2.4 to 4.2 milligram per kilogram doses, the mean half-life ranged from about 10 to 11 days.

A tumor stasis concentration of 3 micrograms per ml derived from preclinical tumor growth inhibition modeling justified the clinically effective dose range of 2.4 to 4.2 milligrams per kilogram. Exposure of free plasma payload was low across these dose levels with the mean half-life ranging from 4 to 5 days.

The following slide displays the safety profile observed in the early phase of this trial. The most common treatment-related adverse events were myelosuppression. In the entire patient population, 69% of patients experienced neutropenia, 33% were high grade. Febrile neutropenia was uncommon. This was followed by anemia and thrombocytopenia. Here, the Grade 3 or greater adverse event rate was only 6% to 7%.

The GI organ class was the next most commonly affected, but the overwhelming majority of these events were low grade. Treatment-related adverse events leading to dose reduction or discontinuation occurred in 15% and 2% of subjects, respectively. Serious adverse events were reported in 16% of patients. More importantly, at the 2.4 milligram per kilogram dose, the Grade 3 treatment-related adverse events rate or greater was below 20%. A 7% rate of interstitial lung disease was reported across the patients in the study, of which 1% were Grade 3. There were no Grade 4 or Grade 5 cases reported.

Tumor response is represented in this waterfall plot and accompanying table of subjects treated with doses ranging from 0.8 to 4.2 milligrams per kilogram. The vast majority of the subjects experienced tumor shrinkage with over 70% having a best response of PR. A significant proportion of these were confirmed.

In fact, at the 2.4 milligram per kilogram dose, a dose with a highly favorable benefit risk profile, the confirmed response rate in second line was 70%. Antitumor activity was seen in subjects with varying degrees of DLL3 expression and even in subjects where DLL3 levels were below detectable limits. The disease control rate was over 90%.

The efficacy data is expanded in this slide as we look at the response over time. In these figures, you can see that the majority of patients respond within the first several months. And in several subjects, this durability goes beyond the 6-month time period. Keep in mind, the data is still immature. At this time, the median follow-up of the patient population is only 3.5 months.

Looking at subjects specifically who had brain metastases upon entering the study, all subjects showed evidence of tumor shrinkage and a confirmed overall response rate of 67% with a disease control rate of 100% was observed across all dose levels tested. A confirmed response rate of 83% and a disease control rate of 100% was observed specifically in those subjects who received 2.4 milligrams per kilogram dose.

As mentioned, although the data remains immature, this progression-free survival curve looking at subjects who were treated at doses of 2.4 milligrams per kilogram or greater, showed a median progression-free survival of 6.7 months in subjects who received second-line therapy or beyond. And the median progression-free survival was not reached in subjects who were treated in the second line only. This is meaningful since with standard of care therapy, even in first line, the progression-free survival is typically less than 6 months.

In conclusion, IDE849 demonstrated a tolerable and manageable safety profile in patients with relapsed small cell lung cancer. The most common high-grade adverse events were associated with hematologic toxicity, and the treatment had a low rate of dose reductions and discontinuations due to adverse events. There were no treatment-related deaths thus far observed on the study.

IDE849 demonstrated promising antitumor activity with the best response of PR in nearly 3/4 of patients, including patients with brain metastases with early evidence of durability and follow-up is underway to evaluate longer-term outcomes.

A study of IDE849 has been initiated in the United States, which will include global sites outside of China, and we'll be dosing its first patient very, very soon.

And with that, I'll hand it over to Dr. Michael White, our Chief Scientific Officer, who will talk to you about some of our combinations that we'll be testing in the clinic very soon or are currently underway. Mike?

Thank you, Darrin. Thanks for saving us some time. I'm not going to have to run through this at 3x ordinary speaking speed. I think as we are all aware, the clinical experiences like the one that Darrin just described here means that oncology is enjoying a real renaissance in ADC therapies. And that's driven primarily because of advances in linker payload strategies that are focused on Topoisomerase 1 inhibitors.

The next challenge is going to be optimizing strategies for sufficient payload delivery to drive robust responses in tumors with otherwise suboptimal antigen density. And it's in the context of this challenge, that a unique synergy between IDE161 and Topoisomerase inhibitors offers a potentially spectacular combination opportunity to be able to enhance both efficacy and duration of Topoisomerase-based ADCs.

So those of you not familiar with the program, IDE161 is a potential first-in-class small molecule inhibitor of PARG, a Poly ADP-robose glycohydrolase that takes PAR chains off of PARylated proteins in order to resolve DNA repair events that are initiated by PARP. This is particularly important to maintain replication for stability in cancers with replication stress.

And if you inhibit PARG, you get the accumulation of these complexes as chromatin roadblocks on the chromatin and these cause DNA replication catastrophe and cancer cell death. Now that mechanism of action is what is offering a potentially stunning opportunity to amplify the potency of TOP1, Topoisomerase 1 inhibitors in cells. And that was first reported by investigators at the National Cancer Institute and summarized in the schematic right here.

As many of you are likely aware, Topoisomerase inhibitor works by stabilizing a covalent linkage between Topoisomerase 1 and the DNA nick. That means to get out of the way before replication 4 comes through or you're going to have replication catastrophe and potentially kill the cell. This lesion is recognized by PARP and it is PARylated by PARP in order to recruit DNA repair proteins that will chew off Topoisomerase 1. This is via the proteasome to expose that nick to allow it to be repaired.

However, before that happens, this complex needs to be dePARylated to expose Topoisomerase to the proteasome. There's only one enzyme that does that, and that is PARG. So if you inhibit PARG, you wind up with the sugarcoated boulder on the chromatin that accumulates and causes cell death through mitotic catastrophe. So it's that mechanism that can enhance the cytotoxicity of an otherwise subtherapeutic dose of a Topoisomerase inhibitor.

And consistent with that, we see very, very nice combination benefit of IDE161 plus a Topoisomerase inhibitor across over 400 cell lines here with responses that are 10 to 100-fold more potent than what you would get with either single agent. We see this across multiple lineages, as shown in this panel. And some of these lineages, the vast majority of the cells are responding much better to this combination than either single agent.

As you would expect, when you put this combination in cells, you see a big up-regulation of PAR chains because of the cycles of futile DNA repair events, and that comes along with an accumulation of these topoisomerase cleavage complexes. These are those covalent links that I was just telling you about that accumulate because they cannot be dePARylated and degraded by the proteasome.

Importantly, these mechanisms translate very nicely with respect to efficacy. So here is a small cell lung cancer model. It is very poorly controlled by IDE161 or a maximally efficacious dose of topotecan, a topoisomerase inhibitor. But you can see the combination, we get complete regressions.

Here's a high-grade serous ovarian cancer. It is somewhat controlled by topotecan. It does have a response to IDE161, but that relapses over time. The combination, however, gives you complete regressions and those are maintained off treatment. So as you might imagine, this offers a really exciting opportunity to enhance the activity of ADCs that have topoisomerase payloads. And we evaluated that here using one of everybody's favorite ADCs in HER2. So here are three different models, non-small cell lung cancer, colorectal cancer that's HER2 low, small cell lung cancer that's HER2 low. Each one of these models is poorly or completely not affected by IDE161 alone. They have responses to a HER2 ADC, but they can be limited to varying degrees in various models. But in every case, when we put that combination together, we see deep regressions that can be durable, that are very, very tolerable.

So we view this as important mechanistic substantiation preclinically of the opportunity that this is going to afford in the clinic to make ADCs work more broadly across all tumor indications.

Two shots on goal that I'm very excited about that we have in our own portfolio, the DLL3 asset that Darrin just described. As you heard, this is doing very well by itself in small cell lung cancer. We also reported this morning at the World Lung Conference that we see nice combination benefit with IDE892 together with IDE161 in tumors that have low antigen density. Here, you can see this. Look at this fantastic combination opportunity or combo activity here. This bodes well for delivering a durable response in tumors with low antigen density, it's actually probably particularly important as we expand beyond small cell lung cancer into other important neuroendocrine tumor types that are DLL positive.

Second opportunity we have is our IDE034, the B7H3/PTK7 bispecific antibody. We view bispecific antibodies as a particularly important opportunity to combine with IDE161. That's because if they are avidity tuned to only bind double positive cells, they can have very specific tumor binding versus normal tissue, but that can also come with an efficacy penalty. You could get suboptimal payload delivery because of heterogeneity of the exposure of each of those antigens on the tumor.

This is a very, very nice ADC bispecific. You can see here, we get good double positive binding. We also see double positive internalization with the bispecific versus either single-agent antibody. And as we showed you guys last year, we get good durable tumor control in double-positive tumors. But if you have tumors with a low expression of one antigen or the other, you have suboptimal control. Here, we see multiple dosing with IDE034 and the generation of resistance. IDE161, which doesn't do anything by itself, turns that response into a regression that is durable.

So nice opportunity here for us to maximize benefit across solid tumors with topoisomerase-based ADCs.

Okay. So now I am going to keep you on tenterhooks a little bit before Jasgit's presentation of our next clinical data disclosure, give you the science behind our exciting collaboration with Gilead looking at IDE397 together with Trodelvy.

So MTAP deletion. Yujiro introduced that. This is lost because you lose CDKN2A, 15% of solid tumors, very important therapeutic opportunity because homozygous loss of MTAP installs two distinct vulnerabilities that can be targeted with a MAT2A inhibitor.

First, you have accumulation of MTAP substrate, MTA. MTA is a SAM competitive inhibitor of PRMT5. So you partially reduce the ability of tumor cells to maintain high fidelity alternative splicing that's required for them to grow and divide.

Second opportunity, when you lose MTAP, you lose its products and its products contribute to nucleotide synthesis. So you have reduced refilling of the nucleotide pools that are required for the high demands of DNA replication and repair in tumors. This generates a very strong dependency on MAT2A to produce sufficient SAM to be able to overcome MTA inhibition of PRMT5 and to be able to refill the folate cycle to make up for de novo purine systhesis and pyrimidine synthesis, so that you can keep your nucleotide pools intact to be able to repair your DNA.

As you can see here, IDE397 can give you two hits in the MTAP null setting, inhibition of PRMT5 together with loss of MTAP causes increased DNA damage. I'll tell you why in a second, at the same time as it reduces DNA repair capacity.

You can see all of that in action here. From global untargeted metabolic profiling, we see strong suppression of nucleotide pool in the MTAP null setting as compared to the MTAP wild type. You can see that in the cytoscape plot focused on nucleotide subcluster. These are all nucleotides, nucleosides, the building blocks required for nucleotide biosynthesis that are lost selectively in this setting.

Why does that happen? Well, exactly as you might expect, if we look at targeted metabolomics, we see that in the presence of MTAP-deletion, IDE397 causes the loss of homocysteine, because of insufficient SAM to maintain that SAM conversion to homocysteine. And this results in a block of the ability of 5-methyltetrahydrofolate to cycle back into tetrahydrofolate to now fuel the cell cycle and produce nucleotides. And you can see that here.

So loss of homocysteine breaks the connection between the methionine cycle and the folate cycle. The accumulation of this metabolite can also back inhibit the enzymes in this pathway to further reduce folate cycle production of nucleotides and inhibit DNA repair capacity. Those mechanisms underpin what we see as a very high association of cell lines that are sensitive to IDE397 as being the same cell lines that are also sensitive to topoisomerase inhibitors or DNA synthesis inhibitors or pyrimidine synthesis inhibitors that we saw across 700 cell lines using the DepMap informer data set.

And the presence of topoisomerase at the top of this list really underpins this mechanism here that's related to perturbation of RNA splicing. So if you have paturb splicing, the RNA polymerase senses this and stalls as part of a checkpoint repair mechanism. That stalling creates the formation of these R loops, which are RNA, DNA hybrids that can be detected, as you see here, induced by IDE397, specifically in MTAP null cells.

These R loops need to be resolved before a replication for comes through. Otherwise, you're going to have replication for collapse, DNA damage, the activation of a DNA damage response. That's exactly what we see with IDE397 in tumors here read out by phosphorylation of CAP1 and ATM substrate. The way that these get repaired is through topoisomerase, which releases RNA polymerase in order to allow replication through that region that was a former R loop. So you can imagine the consequence of putting a topoisomerase inhibitor together with IDE397.

These relationships were substantiated in kind of a spectacular fashion in my opinion, through multiple genome-wide genetic enhancer screens using CRISPR technology. As you can see here, the top biological pathways, the top gene enrichment that was observed to be synthetic lethal with IDE397 across multiple MTAP cancer models were components of the DNA repair machinery, components that are involved in the activation of a DNA damage response and components that connect the methionine cycle to the folate cycle. You can see the GSEA plots down here.

And then if we map each of the individual top enhancers to biological pathways, here's where we line up. We see knockouts that enhance MTA production through activation of polyamine synthesis. We see knockouts that block the connection between the methionine cycle and the folate cycle by blocking the synthesis of homocysteine or blocking the activity of methionine synthase. We see knockouts that directly interfere with the import of the building blocks that are required for nucleotide synthesis, and we see knockouts that take away the ability of cells to repair their DNA or to resolve RNA-mediated replication stress through resolution of our loops.

All of this translates preclinically as shown here. So this is an aggressive MTAP-null bladder cancer model. It is poorly controlled by IDE397. It is somewhat controlled by irinotecan, a topoisomerase inhibitor, which loses control over time. But the combination produces deep regressions, which are quite durable. This is all the way out until day 75 before [ Claire ] stopped the experiment, and they're very well tolerated.

So to sum up here, we see a very strong preclinical mechanistic opportunity to be able to combine IDE397 together with Trodelvy in the context of MTAP-deletion, because this combination here does two things. It reduces repair capacity together with triggering genomic instability. These are synthetic lethal with topoisomerase inhibitors, put the topoisomerase inhibitor on an ADC to maximize the benefit and you have something that might be very effective for patients with MTAP tumors who often have shorter PFS and OS with standard of care agents like EV and CPI.

And so with that, I will turn the floor over to Jasgit, minutes and 35 seconds under the time that I was allotted to tell you the important part of this story.

Thank you, Mike. Hi, everyone. I'm pleased to share with you today the preliminary safety and efficacy results of the first-in-human evaluation of the combination of Trodelvy plus IDE397 in subjects with MTAP-deleted urothelial carcinoma.

Recently, the incorporation of IO agents in the maintenance setting or as part of first-line standard of care regimens has improved the overall survival in patients with advanced or metastatic urothelial cancers. As such, enfortumab plus pembrolizumab or EV plus P has become the standard first-line regimen for these patients in the United States.

However, patients with MTAP-deleted urothelial carcinoma are less likely to benefit from these treatments given the cold tumor microenvironment associated with these tumors. Moreover, there are no targeted therapies approved for MTAP-deleted urothelial cancers.

The combination of Trodelvy, a TROP2 targeting TOP01 inhibitor payload ADC, plus the oral MAT2A inhibitor IDE397 that is currently being evaluated in the dose escalation and expansion study, IDE-397001, represents a novel targeted treatment regimen that has the potential to improve outcomes for this poor molecular subtype of urothelial carcinoma.

Monotherapy IDE397 at the recommended Phase II dose of 30 milligrams daily in MTAP-deleted non-small cell and urothelial cancers showed promising efficacy and this data has previously been presented at the ENA meeting in 2024.

Today, we will focus on the combination data for Trodelvy plus IDE397. Based on the overall safety observed during dose escalation, two expansion doses have been selected for further evaluation. As a background, it is important to note that Trodelvy as a single agent produced an objective response rate of 23% in the randomized Phase III TROPiCS-04 trial in a patient population where more than 90% of patients had no prior enfortumab exposure.

A more recent real-world data set showed an objective response rate that is about half of that at 11% with monotherapy Trodelvy in patients who had prior treatment with EV or enfortumab.

This slide describes the patient demographics for the safety population treated at the two expansion dose levels for the combination. As you can see, this is a late-line population with majority of the patients having received two or more prior lines of therapy that included standard of care treatments like platinum and IO agents. 1/3 of the patients had received prior enfortumab. This represents a higher proportion of EV treated patients compared to the TROPiCS trial population.

Presented here are the most common all grade and Grade 3 or greater treatment-related adverse events among subjects treated at dose level 1, which is 10 milligrams per kilogram of Trodelvy with 15 milligrams of IDE397. This AE profile reflects the known safety profile of both agents. However, it is noteworthy that the rate of neutrophil count decrease and neutropenia reported thus far in this trial is lower than what has previously been seen in a urothelial cancer population treated with Trodelvy.

Proactive measures to reduce infectious and other complications from neutropenia in high-risk patients are incorporated in the adverse event management guidelines in the trial. As such, there's only been one case of febrile neutropenia reported at this dose.

The rates of GI adverse events, especially high-grade events likewise, are also low, thereby making this a feasible dosing regimen from a safety standpoint. This dose level is being expanded further and continues to enroll patients.

A second dose level that combined the recommended Phase II dose of IDE397, that is 30 milligrams once a day plus 7.5 milligrams per kilogram of Trodelvy was subsequently explored. As noted, this dose level delivered an even more favorable safety and tolerability profile for the combination as evidenced by the very low rate of Grade 3 or greater treatment-related adverse events, particularly hematologic events.

No Grade 3 or greater neutropenia has been reported so far at this dose level. Additionally, no treatment-related serious adverse events were reported at this dose. This dose level has been selected as the second expansion dose for further evaluation of safety and efficacy of the combination.

We now come to the preliminary efficacy observed with the combination regimen in this heavily treated population of MTAP-deleted urothelial carcinoma patients. The best overall response for subjects who were treated at 1 of the 2 expansion doses and had at least 1 evaluable post-baseline scan available at the time of the data snapshot is shown here on the waterfall plot. There are 7 observed partial responses among 16 evaluable subjects, of which 6 are confirmed responses.

If we now look at the breakdown of these responses by dose level, we see that the objective response rate for dose level 2 is impressively higher than that for dose level 1. Four of seven or 57% of the patients at dose level 2 have had a partial response, three of which were confirmed on a subsequent scan and the fourth is pending confirmation.

This highlights the important contribution of IDE397 to this combination, whereby despite a lower starting dose for Trodelvy, the efficacy at this dose level appears to be more favorable.

In addition, as shown, the safety and tolerability of this dose promises to provide an ideal risk-benefit ratio for this patient population. As noted before, the efficacy of Trodelvy in a post-EV setting as reported from the real-world data set shows an objective response rate that is in the low double digits, about 11%.

The median progression-free survival and duration of response have not yet been determined since several patients are still on treatment and follow-up is short. What we can say, as shown in the spider plot, is that the time on treatment without progression in several patients has already exceeded the historic benchmark of about 2.5 months reported in a late-line urothelial cancer population with standard of care treatments.

What's also striking is the rapid onset and depth of responses seen with the combination, which also compares favorably to that seen with monotherapy IDE397 in this trial.

I'm now going to share a couple of case studies with you from among the participants treated with a combination regimen in the IDE397001 trial. The first one shown on this slide is a 78-year-old patient with a good performance status who enrolled in the trial after having experienced progression on standard of care treatments. His prior treatments included a combination of cisplatin plus gemcitabine followed by maintenance with an approved anti-PD-L1 agent, Avelumab.

Progressive disease on Avelumab then prompted a switch to an ADC targeting Nectin-4, the same target antigen as enfortumab. This patient experienced further disease progression with a heavy burden of disease in the liver. Some representative liver lesions on his baseline scan are shown in the image on the right. This subject was enrolled in dose level 2 and by week 12, experienced a dramatic reduction in the liver metastases consistent with a partial response. This partial response was subsequently confirmed on the week 18 scan. Patient continues on treatment at this time.

Shown here is another example of a patient who derived clinical benefit from this treatment after his disease had stopped responding to the best available standard of care therapy. In this case, the first-line regimen selected for metastatic urothelial cancer was enfortumab plus pembrolizumab, followed subsequently by cisplatin plus gemcitabine.

The tumor had metastasized to both lungs by the time the patient enrolled in our trial. The baseline scan shows a lobulated lung mass in the right lower lobe. This patient was enrolled and treated at dose level 1. And as you can see in the follow-up scan, there's complete resolution of the metastatic lesion in the lung with therapy.

Tumor shrinkage was also noted in the other target lesions, resulting in a 65% reduction in the sum of target lesions corresponding to a deep partial response on the first on-treatment scan. This patient's confirmatory scan was performed after the data snapshot, and this response has now been confirmed.

In conclusion, we're very encouraged by the preliminary safety and efficacy of this first-in-class targeted combination for the treatment of MTAP-deleted urothelial cancer, which comprises about 1/4 to 1/3 of all urothelial cancers. Additionally, this regimen is also being evaluated in MTAP-deleted non-small cell lung cancer, which represents about 15% to 20% of that indication.

What you've seen today is the feasibility of 2 dose levels for this combination with the responses noted at both doses. The objective response rate with the combination is higher than that reported with single-agent Trodelvy in an EV-naive or EV pretreated population as well as that reported with IDE monotherapy in this trial.

In particular, dose level 2, which combines the optimal dose of IDE397 at 30 milligrams daily with an efficacious dose of Trodelvy is trending towards being the optimal dose for the combination. Further evaluation of both doses is underway with an aim to define the recommended Phase II dose for this combination by year-end which will be determined by the long-term safety and tolerability as well as ongoing demonstration of favorable efficacy with a target objective response rate of 40% or greater and durability that exceeds 6 months.

And with that, I'm going to have Dr. Mike White come and talk to us about IDE892, our best-in-class PRMT5 inhibitor.

Okay. So that's all the clinical data. You can all relax. We'll talk about what's coming next.

IDE892, potential best-in-class PRMT5 inhibitor. As Yujiro noted, a key priority for our MTAP enterprise is to bring IDE397 together with a PRMT5 inhibitor that is MTA cooperative. And that's because preclinically, this combination routinely over and over again delivers complete durable responses at a fraction of the dose required for maximum monotherapy activity with either a PRMT5 inhibitor or IDE397. And that monotherapy activity is often inferior than what you can see with that combination.

There's really two aspects that are driving this combination benefit that I'm going to take you through that have really led us towards what our target profile is for an IDEAYA PRMT5 inhibitor that's MTA cooperative. So the first is obviously maximal PRMT5 pathway suppression to deliver deep regressions.

And the second is reciprocal inhibition of bypass mechanisms that occur on monotherapy to be able to deliver this durable response. So with respect to the first, as you all know, MTA is a SAM competitive PRMT5 inhibitor. So the ability of an MTA cooperative PRMT5 inhibitor to block this enzyme is completely dependent on the MTA SAM ratio. And this can be very variable across tumors depending upon the extent of MTA synthesis and the extent of MTA export. But as we showed earlier this year and then also last year at the two different AACR meetings, this ratio can be optimized by inhibition of SAM production by an allosteric inhibitor of MAT2A, IDE397 to really drive things towards locking PRMT5 in the inactive confirmation.

And you can see this directly here with an assay that is a NanoBRET assay that we developed in collaboration with Promega that can show a direct target occupancy in cells. The yellow is 100% occupancy of PRMT5. And in these dose matrices, we only get that in the combination setting, and we don't see that in the wild-type setting. So very important to optimize the MTA SAM ratio in order to be able to get maximum PRMT5 pathway inhibition. But that is not enough.

What about these durable responses that we are seeing? So to uncover the biology behind this, we simply molecularly profiled the tumors that were resistant or becoming resistant to monotherapy doses that are maximally effective. This is using the BMS Mirati PRMT5 inhibitor or IDE397, maximum effective doses established resistance, maximum effective dose established resistance, combination at 1/10 of these doses, we get durable responses.

When we profile these, the first thing that we found was that these tumors that relapse on the BMS compound do not lose control of inhibition of splicing. So that BMS compound maintains pathway inhibition, even after relapse, you can see that here with SDMA IHC from the end-of-study tumors. And you can see that here, these tumors are thriving despite the fact that the pathway is inhibited at day 35, just as much as it's inhibited at day 7. They just don't care anymore.

If we look at the whole genome transcript profile from these end-of-study samples and compare them to each other and to day 7, we find that IDE397 has the ability to maintain control of epigenetic alterations of chromatin that can establish resistance and to inhibit MYC pathway activity, which you do not see with the PRMT5 inhibitor.

In contrast, the PRMT5 inhibitor seems to have the better capacity for persistent inhibition of mRNA splicing fidelity, as you can see here, which is consistent with this alternative splicing analysis that we see over here on the left.

So in aggregate, we see a situation that in combination, we are able to interfere with reciprocal bypass mechanisms that would overcome either a PRMT5 inhibitor or a MAT2A inhibitor to deliver a durable response. So observations like those guided our plans for an MTA cooperative PRMT5 inhibitor that is designed really exclusively for combination benefit with IDE397.

And our MedChem's strategy to be able to deliver this was heavily influenced by a series of mechanistic studies together with our lead discovery team that I'm going to summarize here.

So first, our lead discovery team identified a previously unreported mechanism by which SAM, SAH and MTA metabolites can exchange in the PRMT5 active site even when it's blocked by an MTA-cooperative PRMT5 inhibitor. And that is because at the back of this pocket, there is a dynamic interface that can create a channel to the cytosol, to the solvent exposed milieu, such that SAM and MTA can dynamically exchange with each other in that pocket.

This is important because that means that the extent to which an MTA cooperative inhibitor can block that enzyme, its residency time depends upon how antagonistic it is with respect to SAM when to keep that out of the pocket versus cooperative with MTA to pull that into the pocket. So we really want to solve for that and make sure that we evaluate MTA-cooperativity and SAM antagonism at the same time when we build our IDEAYA molecule.

Now second, the group designed a very nice novel surface plasma resistance protocol that allows us to directly quantify target occupancy of PRMT5 in a purified system and how inhibitors can bind that in the presence or absence of distinct metabolites.

So here's an example here, we start out by flowing DMS control or the metabolites or a metabolite mix over a chip that has a mobilized PRMT5, then we add an inhibitor for a certain duration and measure its occupancy on the protein through the release of the plasmas that are associated with that differential size.

As one example here, this is an MTA cooperative PRMT5 inhibitor profile in the presence of DMSO. So we add the inhibitor, we get a little bit of binding, but not a lot. So this is kind of still in the, what shall we say, baseline range of the molecule being able to bind the APO form. And in contrast, here is a 1:1 ratio of SAM, MTA metabolites added ahead of the inhibitor, and we can enhance the binding.

Over here on the right, you're seeing the aggregate PRMT5 occupancy data, IDE892, our clinical development candidate. Here, you are seeing how it binds with pure SAM versus a SAM, MTA ratio that is equivalent to the average MTAP wild-type cell versus pure MTA or a SAM MTA ratio that is equivalent to your average MTAP-deleted cells.

And as you note, there is a very, very evident SAM antagonism here. We have less binding of our inhibitor to the protein in the presence of SAM than we would see with no metabolite at all. In contrast, we see very, very nice MTA cooperativity.

Over here with this Epizyme compound, as you would expect from a SAM competitive inhibitor, we see very high binding in the presence of SAM, no binding at all in the presence of MTA. This molecule is kind of in between the two. It has strong cooperativity with MTA and is also SAM cooperative, which is something that we're trying to avoid with our molecule. And the BMS compound, Mirati compound has a profile that's very, very similar to IDE892.

As you would expect from a biochemical profile like this one, IDE892 has absolutely no activity in HCT wild-type xenograft models. This is HCT MTAP wild-type xenograft model that's dosed with IDE892 at a maximally effective dose as compared to what you would see in the MTAP-null setting. And we see very, very strong single agent and combination activity in multiple CDX and PDX models, including in the setting of relapse. So the IND is filed, and we're excited to bring that combination to patients very, very soon.

Okay. So AI/ML drug discovery. What are we doing as a company in this space? We often get asked by some of you, in fact, how it is that we maintain a level of productivity that is perhaps somewhat more than you might expect from a company of our size. And I would just like to point out that from a discovery perspective, a major strength of IDEAYA is structure-based drug design together with the physics, the structural biology, the MedChem expertise that is required to apply structure-based drug design to novel targets.

So for us, AI and ML, that big explosion of capabilities in that space is best deployed by integrating that with our in-house capabilities in computational physics, our battle-tested in-house capabilities in computational physics and biophysics and then to use that integration as a force multiplier in order to accelerate sustainable delivery of new first-in-class opportunities as well as pursue exceptionally challenging activity profiles.

And I'll walk you through some cases here, some use cases that really point out why it is that we have prioritized investing in building these capabilities in-house.

So I'm going to start by calling out the most daunting challenge that our industry faces with respect to delivering durable therapy to cancer patients. And that is massive mechanistic heterogeneity and adaptive cellular phenotypic plasticity. Those things limit the number of patients that will respond to a given therapy and limit the amount of time a patient will respond to therapy if they're lucky enough to be an initial responder.

Some strategies to deal with heterogeneity include attacking truncal vulnerabilities, things that occur during tumor initiation and therefore, are more likely to be carried forward during tumor evolution or disrupting epigenetic modulators that allow for that phenotypic diversification in the first place that can cause resistance. And then also eliminating these tumor-persister cells and pluripotent progenitor cells that serve as incubators for acquired resistance over time.

So how do you do that? We're kind of excited about the fact that lysine acetyltransferases are gaining recognition as important players within these biological systems and therefore, may offer themselves as targets to be able to intercept these things and deliver a durable therapeutic response.

The lysine acetyltransferases are enzymes that function by acetylating the tails of histones at specific locations in the chromatin in order to be able to relax it enough for transcription factors to bind and induce expression of the adjacent gene. Where that happens is specified by these multi-protein complexes that bring the enzymes to the appropriate locations in order to be able to serve specific in enhancer and promoter regions.

The key piece I want to kind of remind you guys here is as we showed at the AACR earlier this year, KAT6 and KAT7 are key epigenetic modulators of cell identity and lineage specification that get corrupted during oncogenic transformation to support transcription factors that act as lineage survival oncogene network activators, so a truncal vulnerability. They act to maintain tumor-initiating cell identity and they act to maintain or allow for a switch of cells into this drug tolerant or persister cell state.

So these associations offer an important therapeutic opportunity if you can deliver a KAT6/7 dual inhibitor, but that comes with a very, very substantial discovery challenge, both because of the difference of the size and sequence in the pockets of KAT7 and KAT6 and then also the need to be able to avoid the close-in lysine acetyltransferases family members, KAT5 and KAT8 that perform essential functions in wild-type cells.

So how did we get around this? So one of the important pieces of IDEAYA's Enterprise in the context of going after new targets are physics-based tools like free energy perturbation that together with machine learning-based training for parameter optimization can allow you to predict the affinity of a molecule that has never been synthesized before to a specific domain in a protein that has never been drugged before.

We applied this for late lead optimization in the KAT6/7 program because our lead series had an issue with exposure based on its polarity properties. And in order to get around this, the MedChem team panned over 500 innovative design ideas in a way to try to get around this issue. And in order to sort through those, free energy perturbation calculations were used to assign predictive binding affinities in a distributed manner across these molecules and landed the team in a particular space such that out of those 500, a very small number were synthesized, which eventually led to our clinical development candidate, IDE574.

So the fact that we were able to prioritize 20% of these design ideas to have success meant that we shaved at least a year off of this program as compared to what we otherwise would have done if we didn't have these predictive tools to be able to sort things based on their predicted affinity.

So why should you care? Well, that delivered what we believe to be the world's first KAT6/7 selective inhibitor, you can see that it binds KAT6 and KAT7 very nicely, avoiding KAT5 and KAT8, both in vitro and in cells. This modulates the pathway appropriately. We see nice inhibition of lysine 23 acetylation and lysine 14 acetylation, the substrates for KAT6 and KAT7. And this profile was able to substantiate a number of the mechanistic hypotheses that we had on the table, including the fact that KAT6 and KAT7 are stronger modulators of chromatin architecture than KAT6 inhibition alone.

So here, you're seeing a comparison of our dual inhibitor versus a KAT6 selective inhibitor for chromatin modulation. And this is the clinical compound from Pfizer that is seeing some success in metastatic breast cancer in combination. with estrogen receptor inhibitors.

And what you see in the red box here are individual genomic loci that are much more strongly suppressed by the combination of the dual inhibitor versus KAT6 inhibition alone, both K23 and K14. And down here, you can see at the resolution of transcription factor start sites, superior modulation of H3K9 by dual inhibition of KAT6 and 7 versus KAT6 inhibition alone.

And this translates to very, very strong sulfate modulation by the dual inhibitor versus a KAT6 specific inhibitor. So here, we use gene expression analysis that was summarized and integrated using open AI large language models where the output was tuned by a custom retrieval augmented generation to be able to deliver a line of sight in an unbiased way on the modulation of lineage specification and epigenetic regulators that is superior by dual inhibition versus single inhibition and then validated by ATAC-seq-mediated enumeration of transcription factor motifs.

And so here, we're seeing in breast cancer cells, GATA3 is very strongly suppressed. This is a linear specification gene. In lung cancers, FOXA1 is strongly suppressed. This is a pioneering transcription factor. And these are some highlights from breast cancer and lung cancer models that are going to be described in detail at an international cancer conference coming up in about a month.

So the other thing that you might remember about KAT6/7 is we showed at the AACR earlier this year that metastatic breast cancers treated with KAT6 are associated with both intrinsic and acquired resistance which can be bypassed by dual inhibition of KAT6 together with KAT7. So here, you're seeing an RNA-seq experiment where we are evaluating the individual contributions of these inhibitors to cells, looking at the individual gene expression programs and seeing how they relate to each other.

And you can see emergence of a specific clone in the KAT6 inhibitor treated cells with a distinct phenotype that happens in that arm and not the others. That clone, the gene expression programs that are associated with that include endocrine therapy resistance and components that are associated with drug-tolerant persister cells. This is a drug-tolerant persister cell population that emerges upon KAT6 inhibitor treatment, but does not emerge in the context of KAT7 inhibition together with KAT6 inhibition, because a dual inhibitor kills these drug-tolerant persister cells and also blocks the maintenance of the pluripotent tumor-initiating cell population.

Remember, these are the cell types from which resistant populations are derived for acquired resistance. So those phenotypes come together to deliver very, very strong control of preclinical models. This is a PDX model, luminal breast cancer model that has an estrogen receptor mutation, makes it resistant to fulvestrant. This model cannot be controlled by monotherapy KAT6 inhibitor at any dose.

What you're seeing right here is the clinically relevant dose. But at a fraction of the clinically relevant dose of a KAT6 inhibitor, this dual inhibitor IDE574, gives you complete regressions, which are durable off treatment. We also see activity beyond breast cancer as we had hoped in a biomarker-specific fashion. And if you profile hundreds of cell lines with IDE574, you can see that we have potentially broad opportunities for monotherapy activity across meaningful patient populations, including breast, lung, ovarian and esophageal gastric cancers.

Okay. So in order to be able to apply this kind of delivery of first-in-class molecules, we are marrying AI and physics-based capabilities across our pipeline from Hit ID through to Hit to lead and then lead optimization.

I'll give you 3 examples of those. So MTAP program 3, this is a program that was really enhanced by an in-house built property prediction tool called HARMONY. This is a property prediction tool that is dynamically trained on measured data to be able to predict solubility, permeability or stability phenotypes of molecules.

And as you can see here for this program, it did a very nice job of predicting designs with respect to those that would be soluble versus not, those that would be permeable versus not or those that would be stable versus not. Again, we can go very, very quickly and avoid designs that would be ineffective because they lack these drug-like properties.

From Early Program 1, this is a program that saw a big step change in potency through AI-mediated generative design. And this is one that I'm very excited about because this kind of approach is usually limited by the need to read through an incredible amount of noise, which is indicated by all these gray dots.

The way the team solves for this problem is through a distributed ranking across chemical spaces is a 2-dimensional projection of a 200-dimensional Euclidean space to evaluate the predictive binding in these different areas using free energy perturbation. And that allowed the team to go in a single hop from their early lead into a compound that has very potent activity as well as nice drug-like properties and is exceptionally different from the Early Hit. So very nice advancement in this space and something that we're looking forward to applying to many more programs.

Early Program 3 -- sorry, Early Program 2. This is a program where the initial feedback from the MedChem team and the lead discovery team when we were going to launch this program was that it's probably impossible, but exciting enough to try. And this is a situation where image enhancement, machine learning-based image enhancement of very, very large crystallography fragment screens allowed us to find a toehold that would have otherwise been invisible. And then putting that together with ligand-induced protein dynamics helped us land on a molecule that has both a go-forward potency as well as a spectacular selectivity between our target, Target 1 is a therapeutic target and our anti-target. Target 2 is the anti- target. So moving forward now in a very solid position to be able to do hit to lead finding for Early Program 2.

And I'm going to stop with this slide, virtual high-throughput screening. This is something that everybody wants to work. This is one of the most frustrating aspects of small molecule discovery, and that is finding some starting matter against targets that have never been drugged before.

Current technologies seem to be performing adequately for previously drugged targets or for some target classes that are very, very well understood, but they are not performing for targets that have never been drugged for first-in-class targets. And we're excited to try to help overcome this limitation by bringing the accuracy of absolute binding free energy to the picture such that we can, at scale, make the calculations that are required to be able to decode intermolecular interactions inside reasonably sized domains of targets that have never been drugged before.

We have generated a collaboration in order to build the computational infrastructure required to do this at scale as well as introduce the machine learning cycles in order to decode these interaction networks. It's picking up steam. We're getting some key deliverables in place, and we hope to tell you more about that soon.

And with that, Yujiro, I'll turn it over to you for closing remarks.

Well, great. Thank you, everybody. We're going to move here into the analyst Q&A portion here in a moment. But really thank you to Michael, Darrin and Jasgit, really just terrific presentations, and it's been really just great going through all of this new clinical data and various updates that we're working on across the portfolio.

So in the last 10 years, as you've just seen, we believe we've built one of the broadest and deepest pipelines in precision medicine oncology today. As you heard earlier in the presentation, darovasertib is now launched into multiple registrational trials across the uveal melanoma patient journey, including in the metastatic and neoadjuvant setting, and we're targeting to start a registrational study with our partner, Servier, next year in the adjuvant setting.

Next, as you heard today, several key clinical data updates, including first-in-human data across our IDE849/DLL3 program that was presented yesterday in Barcelona and also the first-in-human data on the IDE397 Trodelvy combination and MTAP urothelial cancer.

As you heard from Mike just earlier, we're continuing to make significant investments in the area of AI-enabled drug discovery that we believe will continue to fuel our future pipeline.

Lastly, we're not done for the year. We've got a lot of catalysts that we're focused on and that we're very excited to be able to present here in the next few months. The next step is at ESMO. As noted earlier, we have over 90 patients in neoadjuvant uveal melanoma data that's been accepted as a proper paper oral presentation. In addition, fairly recently, we also noted we have an oral presentation accepted at SMR that will also get presented in October. And this will be our first reported survival data in the frontline metastatic uveal melanoma setting.

And then lastly, our PFS results to hopefully enable our first Accelerated Approval filing.

So with that, that's the end of our prepared remarks. So we'll now move to the analyst Q&A portion. I'm going to ask several members, Daniel, Stu, Mike, Josh, Darrin and Jasgit to please come up. I will work with the left side team here to hopefully facilitate the analyst Q&A portion.

So we'll just ask folks to raise their hand, ideally try to keep it to one question per analyst. Please just say your name, who you're with. And we'll try to do this within 30 minutes, and I know everybody has a busy morning schedule.

We'll try and do it as orderly as possible. I will call the name of each analyst. And again, if you could just raise your hand so we can easily find you with the mic, that would be helpful. We'll begin with Anupam Rama from JPMorgan.

This is Priyanka here for Anupam at JPMorgan. For the IDE849 update, can you help us understand what you are seeing from the safety perspective by doses that are 2.4 mg per kg or higher? And how does that play into your dose selection?

Darrin, do you want to take that?

Yes. As shown, we've tested a number of doses with IDE849. And again, this is a Chinese patient population, right? We're getting ready to enroll our first patient in the U.S. patient population. And ultimately, the 2.4 milligrams per kilogram dose looks like an attractive dose in terms of benefit risk. Whether that will be true in the U.S. patient population, we're going to know soon, but seemingly, that's a really great guidepost.

Long and short of it is, I think if you look at our data and you compare it with anything out there with respect to ADCs in this space, I won't mention any names, but suffice it to say, at that dose level, we compare very favorably. And based on the efficacy data there, as I mentioned, we're looking at a drug that has the kind of activity that some in this space would call maybe the most active agent in small cell lung cancer.

Remember, in that group, patients get combined chemotherapy, they get a checkpoint inhibitor upfront, and they have a median progression-free survival less than 6 months in first line. We're talking about relapsed patients. We're talking about a very high response rate. We -- it looks seemingly durable. We have a dose that seems extremely tolerable at this point. And so we're very, very excited to move the program forward in the U.S. And the data is still evolving. It's early days, but we're obviously highly excited. especially for patients with small cell lung cancer, a really bad disease.

Great. Next question from Maury Raycroft, Jefferies.

Congrats on all the progress over the years. I'll also ask -- this is Maury from Jefferies. I'll also ask one on DLL3. The reported 6.7 months PFS in the second-line plus population looks good. What's your early perspective on how PFS might evolve specifically in second-line patients, acknowledging current follow-up is limited at this time?

Well, like I said, we're hoping we're going to stay well north of 6 months and only time will tell. Like I said, even if we were to stay where we're at now, again, we look like maybe the most active agent in this space. And so, we want to play a role in small cell lung cancer as early as possible. And also, we're thinking about other neuroendocrine tumors.

There are a number of other high-grade neuroendocrine tumors that could benefit from this kind of therapy. As not only a monotherapy, but as Mike pointed out, with IDE161, there's a tremendous opportunity to make tumors that perhaps have lower levels of DLL3 expression also be sensitive. So it could actually expand the number of tumors for which this may be relevant.

And maybe just a follow-up to the prior question, too, related to dosing. For the combination with PARG, you've got monotherapy data with PARG already. Maybe talk about how doses could work for both of those drugs together and just thoughts on potential overlapping toxicities as well.

Yes. I would say that the good news is with 161, we've really come up with, we think, a treatment schedule that's highly favorable in terms of a safety profile. That being the case, it makes us much less concerned about overlapping toxicity, quite frankly. I think the way we're delivering 161 is good for patients. It's allowing us to maintain dose intensity. And I think we'll still have to do a standard dose escalation sort of design in order to put the two drugs together. But I think we're very, very bullish that we're going to be able to deliver the appropriate dose of our DLL3 ADC along with 161 based on what we've seen recently.

Yigal Nochomovitz with Citi.

Could you just explain in a little more detail how you adjudicate the events in terms of AEs between 397 and Trodelvy given you showed the table. Can you just clarify how you parse those out, please?

Sure. Jasgit, do you want to take that?

Yes. So these are investigator adjudicated, as you know, for most trials, this is an investigator determination. In a combination regimen, sometimes it's hard to tease out one agent versus other. But we know that there are some specific toxicities that may be linked more likely to be from Trodelvy versus 397. So that's what the adjudication represented if there was a toxicity more likely to be related to one agent versus another. That's how it was attributed.

Yes. And maybe just on that point, in many cases, I would suspect the adjudication was to both molecules. So I don't think you would just add the two numbers together.

Okay. And I was curious on the -- I don't know if the expert on the ocular is here, but regarding the prediction tool, is that more of a static tool that's kind of forward-looking? Or is there any like iterative component, AI-driven aspect to how that's done? Obviously, as you collect more data, you could potentially refine the algorithm and have to do a better prediction job. Just I was curious about that.

Dr. Singh?

So this tool was developed 10 years ago, and there wasn't much of AI then. And nowadays, we are actually treating patients with radiation retinopathy. So we do not have data on untreated cases. So it's very difficult to develop this model. But we are -- there's a current trial going on, DRCR trial, protocol AL that has untreated component in it that gives us data on untreated patients. So that will be used to refine this predictive tool. It will happen, but it will be another maybe 2 or 3 years from now.

Tyler Van Buren, Cowen.

Great. Thank you very much for the very interesting presentations. Related to the neoadjuvant vision data, can you tell us what proportion of patients had a greater than or equal to 15 letter loss in the Phase II and what you would expect in the control arm in Phase III? And maybe just a follow-up for Dr. Singh. What is your confidence in the Phase III being successful in this endpoint given the tumor reductions and reduction in radiation observed?

Dr. Singh, do you want to go first?

It's hard to be highly predictive, but we know, like I emphasized before, there are five things that drive vision after brachytherapy and four can be modified and that are being modified with this drug. We do, therefore, feel that it will help not all patients, but vast majority of them because some vision loss is due to tumor location itself.

For example, if melanoma is in the macula where the vision is, you can reduce it to anything, but patients will never get any better vision. So there'll be some percentage of patients where this will not work. But in the rest of it, 80%, 90% of it, there will be an impact on vision.

Then with respect to your question about 15 layer loss, there's a couple of issues here. One is the follow-up is relatively short. And also, as you know, for 009, it's a proof-of-concept study, so there's no control arm. So even if we had that data, it would be hard to sort of make a whole lot of sense out of it, but that's where the registration trial comes in. It's a well-constructed, very, very well-designed study to have a control arm, a treatment arm.

And we know pretty well based on what's been published what our expectations are. What do we know? We know that in that patient population, they'll be coming in -- there'll be patients with moderate to high risk of visual impairment, which means based on published data at about 3 years, nearly half of them will have 20/200 vision or worse. That's like 35 letters lost in the ETDRS chart.

Now we're only looking for 15 letter loss. So that's less vision loss, and there'll be a control arm. And in the treatment group, there'll be -- we predict based on the data that you saw today, significant tumor shrinkage, radiation reduction. So that degree of letter loss, 15 letters, we think, based on the data we presented to you today seems to be quite honest, in my mind, maybe I'm biased, but readily achievable based on what we've seen. And again, that list of investigators that I mentioned, they're very bullish about the study and the outcomes based on the data that we've shown so far.

I don't know, Dr. Singh, if you wanted to add anything to that.