Verastem, Inc. Aktie

Good morning, everyone. For those that don't know me, I'm Julissa Viana, the Senior Vice President of Corporate Communications, Investor Relations and Patient Advocacy. We're really excited to have you here today, and thank you for those that are listening via the live stream. Please note that this event is being recorded and will be available on our website afterwards.

This morning, we are very excited to discuss VS-7375, our best-in-class, highly selective oral KRAS G12D ON/OFF inhibitor, which is being evaluated in multiple clinical trials. Today, we'll share new clinical data from our TARGET-D 101 trial, including for the first time, U.S. efficacy data and updated safety and tolerability results in KRAS G12D mutated pancreatic, colorectal and lung cancers.

This morning, we issued a very long press release detailing these results, along with a slide presentation that we'll reference today. Both are available on our website.

The next slide. Let's see... all right. I won't be reading the slide, but I do need to point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially.

We encourage you to consult the risk factors discussed in our SEC filings for additional details. Joining me today to present the data are Dan Paterson, President and CEO; Dr. Michael G. Kauffman, President of Development; Dr. Ting Wu, Vice President of Clinical Development; and Dr. Manuel Hidalgo, who's the Director of Gastrointestinal Cancer at NYU Langone Health and Professor of Medicine at NYU Grossman School of Medicine.

And as many of you know, he's a leading medical oncologist and he's currently also an investigator in ongoing trials. Along with our presenters, Dr. Jonathan Pachter, our CSO, will also join us for Q&A. And I will now turn the presentation over to Dan.

Well, good morning, and welcome. We're very excited. This is kind of, in many ways, the beginning of really a new journey for us now as we accelerate the development here and really the end of what's been a 4-year journey where we set out and made a conscious decision working with GenFleet to have a G12D selective agent. Everyone's been talking about pan-RASi versus G12D. And I think within the last month or so, I think folks have come to realize RevMed did an amazing thing as a drug that's a leap forward for patients.

But when you look at things like quality of life and tolerability, having a selective molecule matters. And in order to have a selective molecule, there were a couple of key things that we really needed. We wanted it to be potent, very selective, ON/OFF inhibition.

And one of the more important things, and if we go back a year or so ago and you looked at as this area was evolving, I'd say Mirati/BMS is probably a good example where these molecules didn't have good oral bioavailability. And that's really the starting point. And so we've got a molecule here that we can give orally, we get dose proportional exposure. And one of the things that's amazing, and hopefully, you'll take this away from looking at the data is the consistency around what we saw in vivo, what they reported out of China and now what we're seeing in the U.S. And I think what differentiates this molecule from a lot of others in the space is you give more drug, you get higher blood levels and you get better efficacy.

And we'll walk through that. And I'd say PDAC is probably our best example of that so far today where you can clearly see that, and we expect the same thing with lung. We will be showing data on PDAC, CRC and non-small cell lung cancer. I think we've set a new benchmark in PDAC, efficacious and safe, and we'll go through that. CRC is a little earlier, but we've shown we can combine with EGFR inhibitors and are seeing early antitumor activity.

And the data set that you'll see today in lung is at the 600-milligram dose, our go-forward dose is 900 milligram, and we expect to see the same dose response as that data comes out. And then I think lastly, the favorable safety profile. What you're seeing now, it's largely grade 1 and 2 gastric AEs and it's effectively -- it's the pill in the gut. There's no systemic cause here. And down the road, we'll do things like different formulations and stuff to even make that better. But even where we are today, we're able to deliver 97% dose intensity at the 900-milligram level, and it's very combinable with the standard of care agents that will be critical to combine within frontline. And so with that, I'll turn it over to Michael to take us through the clinical data. But again, the picture that's emerging is what we had dreamed of 4 years ago. So Michael?

Thanks, Dan. As some of you know, I was sitting on the sidelines on the board for over a decade with this company, watching it go through various excellent lives. And back in December, as the data started to emerge with this molecule, I just kept running on to the field and getting penalties. So finally, I just said I'd better join the team, and Dan let me.

And it's been an absolute pleasure working with him. We're going to continue to work together, and I'm looking forward to working with Michael Bailey going forward. But let's switch gears now to talk about this. I have to say in a career that I left practicing medicine in 1995, and I have never been involved in a program that could squash solid tumors this way with the kinds of side effects that we're seeing. And keeping in mind, this is a once-a-day oral pill. We dreamed of this. If you had told me when I graduated med school or left my residency that we would ever be able to treat pancreatic cancer with a single agent. I would have laughed at you, and so would every one of my colleagues.

So it is absolutely thrilling, honestly, to be up here and present these data. We all know that the current therapies are very limited. Chemotherapy, I mean, we say FOLFIRINOX, it is brutal. It is like being run over by a truck. We -- even Gem/NabP, which is chemo-light, isn't pleasant at all and everybody gets neuropathy within months. We'll talk about that towards the end that chemotherapy is okay at the beginning. It's very unpleasant to put it nicely.

But nobody stays on the therapy because they're really toxic. And that means that nobody's tumor remains under good disease control. We have a different molecule here that so far can be given indefinitely. And we don't think that these -- so the durability of our molecule is what is emerging, and we'll be able to update you in the future.

The other issue, as we talked about, is the toxicity burdens of all of these therapies are very high. and very difficult. And even a pan-RAS inhibitor, which is a breakthrough for sure and wonderful doubling lifespan in second-line disease, even that is difficult. People have rashes. These are very tough to treat rashes. People do get rashes from other drugs in oncology and other diseases, but the cetuximab, panitumumab rashes are generally much easier to treat and take care of than some of the pan-RAS rashes.

And mucositis and stomatitis are big deals with chemotherapy or a pan-RAS inhibitor because you want people to be able to eat, especially with pancreatic and colorectal cancers. And the other G12D inhibitors, as Dan alluded to, just have limited absorption, and they have limited ability to get into the tumor at levels that kill the tumor.

The first thing you learn in cancer 101 drug development is you've got to achieve a dose that hits the cancer cell, not the bloodstream, the cancer cell. And you'll see evidence today that we are the best-in-class in that area. Okay. The goal in the program, the sort of holy grail here is, of course, to cure the disease and the best chance for at least prolonged disease control with a good life for patients is to get into the frontline setting as quickly as possible. And I'm happy to let you know and you've seen from the press release that we have been -- our FDA has approved our Phase 3 trial design for frontline pancreatic cancer. The beautiful design has some new elements in it that I think FDA has recognized the unique qualities of this drug, and we'll talk about that. That trial should open by the end of the year. While we have that frontline potential, I just want to focus everybody now where we are. Today, we're talking to you about single agent and combination potential across 3 of the worst G12D tumors we have. Remember that G12D is a bad prognostic factor for all of these. So we're treating the worst of the worst.

We already have 3 potential accelerated approval trials ongoing in each of these diseases that are accruing today. We expect accrual for pancreatic and colorectal to finish by year-end and lung cancer in the first half of next year. So our intention is to establish a beachhead in the second line. But as we say, frontline is where we all want to get to because that will address the most patients at the time when their disease is most susceptible to impact.

The pancreas study, as you heard, will start by the end of this year, and we expect the lung and the colorectal Phase 3, pardon me, frontline studies to start in the first half of next year. Okay. So let me -- let's move now quickly to the data that we've all been waiting for. This -- I can tell you that seeing CAT scans come in every week and presenting them to our team and looking at these tumors that have been really difficult to treat. Remember, 30%, 40% frontline response rates with horrible cocktails of cytotoxic agents was where the best we had.

And now we're looking at things that look almost like antibiotic responses. We're not quite there yet, but we do see remarkable responses in people. A couple of ground rules. We present data to you the way we present them to the FDA. There's no baloney here. There's -- this is mITT. It's every patient we've treated. This is the cohort of 900-milligram pancreatic treated patients in our Phase 1. This is it. This is everybody.

There are 20 patients here. There are 2 patients who didn't make it to their first scan. So we don't have any waterfall data for them, but they're on the swimmer plot you'll see on the next slide. mITT, everybody. The second thing is that these are all confirmed responses. Remind everybody that the RECIST rules in single-arm trials do not recognize a single response. They don't exist. An unconfirmed response is not as far as FDA is concerned or EMA is not a response.

These are all confirmed responses. 4 out of the 8 patients who had second-line pancreatic cancer had confirmed responses. 5 out of the 14 patients who had third and fourth-line disease had confirmed response, including a confirmed complete response and a patient who had a confirmed partial response who has their first reading of a CR, and we have every reason to believe based on tumor markers and how the patient is doing that, that CR will go on to confirm.

As far as we are aware, there have never been a report of a G12D pancreatic cancer complete remission. Part of the reason we think the FDA granted us some of the design elements in our Phase 3 trial was a recognition that this is a very, very different drug. CRs in any solid tumor, as you know, is remarkable. 2 CRs out of 22 in patients with heavily pretreated pancreatic cancer is unprecedented. This is a change in medicine, and we hope to see this change it for all of humanity.

We believe it will. The patients have the standard background, median of 2 priors, et cetera, et cetera. The swimmer plot. We also try to give you guys all the data. There's no covering up anything here. We try to -- this is a combination of a swimmer and a kind of spider. So the size of the circles for each patient represents the antitumor activity of the drug. The bigger the circle, the more the antitumor activity. You can see, for example, here, we have the CR here, again, the confirmed CR. You can see that most of the patients who have a response, it takes 2 scans to get to the response. That means it takes 12 weeks. Nobody is surprised about that. Pancreatic cancer is a highly fibrotic, difficult-to-treat tumor. Not only do you have to kill it, but you have to get the macrophages and everybody else in there to clear the debris.

This is a war zone. It's the patient with their armed with our drug fighting these tumors. And you can see that most of them are ongoing. 16 out of 22 patients are ongoing, 15 of them without progression. What does that mean? What that means is we had one patient whose tumor grew 22-ish percent above their smallest tumor size. One of the unfortunate problems with RECIST is that you are blamed for having a great response.

So if your tumor grow really shrinks and then it grows a little bit, you can have a progression event. That patient feels better than he ever has. His tumor is smaller than it ever was and he asked to stay on the therapy and he is approaching a lifespan, which is literally 4x what we would have expected for a third line, fourth-line pancreatic cancer patient. He feels great. Interestingly, this tumor, by the way, hasn't grown during this time since the progression. So it grew enough to be progression, but then it stopped growing. And he continues on therapy. Really exciting for these folks.

The PFS -- remember that the best data we have on progression-free survival in third and fourth-line pancreatic cancer is from daraxonrasib's Phase 1 study in New England Journal, that's 4.3 months. We have crossed that. We are at 6.5 months now and increasing. We are at least 2 months longer than the best data in third and fourth line, at least 2 months better.

And these are probably going to keep going at least for a bit. The second thing to point out is that the best data we have in second-line pancreatic cancer for PFS is 7.5 months, and we are about to cross that 7.5-month threshold in the next month or so.

So everything seems to be going along that we'll be able to deliver a better disease control as well as a response rate in pancreatic cancer that has been previously treated. Running through some of the data, and of course, this is cross-trial comparison. We have to disclaim any ability to do that. I remind folks all the doctors, Manny and everybody else, we all do that every day. That's how we make clinical decisions. We do cross-trial comparisons. We have very little head-to-head data in oncology and other diseases. So with those caveats in mind, just to remember, but in second-line disease, the best response rate in G12D so far in 2L pure second-line disease is 24% with daraxonrasib, just came out in the FDA documents last week.

We're 50%. In third line plus, the best response rate, daraxonrasib is 21% in the G12X population and highly likely to be lower than that because we know that G12D did much worse on daraxonrasib than G12D and some of the others. We're at 36%, and it's solid. Part of the reason we have such good responses in these heavily pretreated patients is because we're a very well-tolerated drug relative to the others.

And when you're tolerated well, even in a frail patient, you can continue therapy. This is a constant battle for the patients. You've got to deliver the drug consistently. Ting will show you some data on that. We are thrilled with the consistent use of this agent to beat up this cancer. And then in the second-line plus setting, where the most data are available with some of the G12Ds, the main competitors, if you will, are zoldonrasib and Incyte's compound. These are unconfirmed ORRs. You all -- many of you have already dug into these data and looked. You know that the Incyte confirmed ORR rate is 29%, not 37%. -- the confirmed rate is 29% -- and you know that the zoldonrasib is less than 30%, and we don't know what it is and the data haven't been updated. Also, the durability of these agents is not known. Setidegrasib, we have real data, but it's not really very competitive compared to the oral agents.

So we believe that this has best-in-class potential, as we've said. Why is that? Well, as Dr. Pachter likes to say all the time, it's all about getting the drug into the body and delivering it. Most of the other drugs seem to sit in the middle lane here if you look at therapeutic windows. That is to say that you max out for most of the other competitors, best we can estimate is that they sit in the green box, but our drug has linear PK.

So 900 delivers more drug than 600, delivers better area under the curve here. exposure. And this was actually the goal. It's the first time in my life, honestly, that I've seen animals actually predict mice predict what humans should do. And we wanted to be above this magical 2,000 AUC, and we've done it for 80-plus percent of the patients. And we're not bad on the other 3 here. So terrific PK. That has translated into molecular responses. If you look across the board, and of course, these are different assays, slightly different times, but basically, it's all the same data. There's not any real subtleties here. For VS-7375, 12 out of 12 patients had at least a 50% reduction in their tumors. And not every tumor sheds, which is why we don't have 23 patients there.

12 of the tumors shed enough to pick up ctDNA, so we can use that. But all 12 had at least a 50% reduction. Oncologists will tell you, 50% is nice, but we really want at least a log reduction. 11 out of 12 patients delivered a log reduction. The 12th patient was at 80%, but that patient was very nice. He went and got a partial response, confirmed partial response.

So even an 80% reduction here confirmed -- led to a confirmed PR. We annihilated the variant allele frequency in almost 60% of the patients gone. That means we penetrated the tumor sufficiently that there's no more tumor cells releasing DNA. And by the way, the CA19-9 data track very nicely. The tumor marker data track very nicely. One of the things that we all know CAT scans do in pancreatic, they don't tell you functional. You can have a dead pancreas tumor with a lot of stroma left over and a lot of inflammation, and you won't pick it up on a CAT scan very well. And so it still counts as a mass. We know from the molecular data that we are better than any of the other competitor drugs just looking across with all the differences that you're all aware of. The other drugs just can't do it.

daraxonrasib is the strongest overall, but it's limited by its tolerability. zoldonrasib has most of the patients that are above the 50%, still not bad, but problem. And then Incyte's drug has many patients whose the VAF grew who got higher. So strong on the molecular side. All of these data are consistent with a very potent molecule. And of course, people ask us, where are you with Project Optimus?

What do you know? Well, we have a dose response, just like the pharmacokinetics showed you up here that 600 doesn't do it. It leaves half the patients below that goal line. 600 milligrams is an active dose for sure of our drug in American patients.

But if you take this curve and shift it to the right and then make deeper responses, you get 900, which is exactly what it should do. We can do this because the side effect profile of 600 and 900 are virtually indistinguishable, so much so that we didn't put the 600-milligram data in the deck. You don't need to see it. It's basically the same. There is -- and it's mainly due to irritation of the GI tract, which Ting will show. So this is critically important.

Dose really matters, and you can see we get these extremely deep responses. The last point I'll make, and I didn't make it before, is not a single patient who had a follow-up CAT scan had a tumor that grew. That is a remarkable, remarkable story. You're going to see that in CRC, and you're almost going to see it at the low dose in lung.

Can you imagine having a patient come in with third-line pancreatic cancer and tell them that they have a 90-plus percent chance that this tumor is going to shrink on a single oral therapy after what they've been through. They're going to ask you why the heck you didn't give this drug before. Terrific, terrific, terrific for patients, and we're all thrilled to move this program as expeditiously as possible. We'll get into that at the end. Okay. Let's switch gears for a minute to colorectal. Early data yet. We had to clear 600 milligrams plus, we'll show you the dose response in a minute, and we're up at 900. This cohort has only 10 patients. You will see the 10 patients in December. The other 4 patients are too early. You have 5 patients on the graph. One is missing. Why is that? He jumped off the study before getting the first scan quick due to some logistical issues getting to the site and supposedly some nausea.

So 5 out of 6, but the denominator is 6 mITT. Median follow-up is already better than any of the therapies that are approved in third-line colorectal cancer, where the high bar here is LONSURF plus Avastin with a 5.6-month PFS. We're already beyond that. We obviously want to see a response rate north of 30%. We are in that range right now early on. One of these is unconfirmed. The other is confirmed. We have this patient whose CAT scan is still waiting for the report, unfortunately.

But you can see everybody's tumor shrunk again. That's never been seen before in heavily pretreated colorectal cancer ever. Small numbers, but if you believe the pancreatic data, you'll believe this. Now we see the same thing on dose response. This drug is extremely predictable. You go from 600 where you see decent antitumor activity, certainly more competitive than what's currently available, but not the thresholds we want for accelerated approval and to get this drug to patients fast. 600, we have responses. We have ongoing patients. I think I heard about another one that converted yesterday to a response, but not good enough. 70%, 80% of the patients had a shrinking tumor, but we had these patients on the left who did not. We want pure waterfalls. We got pure waterfall again here. We had it in pink. We got it here. Everybody's water fell, okay? That's what we want to see in this disease, get on the drug and it works. Okay?

So that's where I have. We'll have more updated data in a couple of months in colorectal. We're super excited about this. And the trial -- the Phase 2 trial is enrolling beautifully. And now let's switch to 600-milligram lung. I want to keep saying that 600 milligram. These data are terrific. We believe they are acceptable for accelerated approval. We believe you need about a 30% ORR with good durability and a decent side effect profile to get accelerated approval.

There is nothing for G12D available right now for lung. And this is a bad actor, and we'll get to that in a minute when we talk about the frontline early data. So at 600 milligrams, our waterfall is almost pure. We have one patient who's continuing on the left slightly growing tumor. We don't really know why. Patient is symptomatically much improved. We see that a lot, by the way. We see pain, shortness of breath, bloating, appetite, really remarkable on this drug getting better. In the deck that's on the web, you'll see some PET scans that help you explain why this drug works almost immediately. But back here to lung, you see we have at 43% confirmed overall response rate. We have a patient who's cooking to a complete response here, but we're not quite there yet because they have a couple of target lesions, but all the nontarget lesions.

All the target lesions are gone. The other thing you'll notice here is we don't play games. This is the mITT cohort. This is everybody who got the drug with lung at 600. We did not exclude 1/3 of the patients who got prior taxanes. There's no reason a priori that we can think of why it should matter whether you got prior taxanes or not.

The taxane previously treated patients are in the gold bars. Great responses there, no problem treating those patients. So when we compare to other drugs, it is critically important to remember that we didn't leave anybody out. FDA has looked at this data set. The 900-milligram lung data are in an accelerated approval Phase 2 study. This is because it's in a different division of FDA. We won't have 900 lung data to share with you. But you can do the extrapolations of what happened in pancreatic and GI. You'll also note that the 600 lung data are terrific. These responses tend to occur very quickly. All of the PRs that happen happened in the first scan. That's different than a GI tumor. So we're penetrating the lung very well. This is pretty well known. Lung cancer generally is more susceptible to these therapies. And every one of the PRs here are continuing, all right? -- every single one.

So these are durable partial responses. One of them looks like it might convert to a CR, we shall see, but we want to see great data here in this difficult-to-treat subset of non-small cell. Now just quickly, we'll review the bit of VAF data that we have, variant allele frequency data here for lung at the 600. Here again, we annihilated the VAF. I mean every single patient has undetectable. It's only 5. That's what we picked up.

The other patients did not have levels of VAF that were above the detection limit. But every single one of these has undetectable variant allele frequency. And that's consistent with our penetration into the lung and the activity. Zoldonrasib in contrast, about 1/4 of the patients don't make it. They just can't get there. They just can't get there. Moving to frontline. The lung group has been interesting, the docs. We had kind of a mediocre initial reception and then it picked up. And then suddenly, they said, well, we just want to move this to frontline. We're convinced. And really, that's what's happened. These are the first 8 patients. Again, mITT, One patient came off due to a very frustrating KEYTRUDA reaction and decided to leave against medical advice and just quit the trial frontline. So I don't know what happened to them, but on the denominator because they did get a single dose of our drug.

This is again, 600 milligrams, 75% overall response rate to date, some of these confirmed, some of these unconfirmed. And some of these responses are just with KEYTRUDA because the patients had high TPS levels. So that, as you know, KEYTRUDA is indicated if your PD-L1 levels above 50%, KEYTRUDA single agent. It doesn't matter. These are fast responses. I would argue that these responses occurred primarily due to 7375 because KEYTRUDA takes a while to get to a PR. And these are pretty deep PRs already.

We're -- and more importantly, the lung key opinion leaders are thrilled about this data. The expected ORR in G12D lung cancer is on the order of 35% to 40%. It is worse than the overall adenocarcinoma population with triplet chemoimmunotherapy. And that's because G12D is a bad actor. So again, very early data, but very exciting and a consistent water-only fell profile. Okay. So let us turn it over to Dr. Hidalgo Medi?

Good morning, everyone, and thank you for inviting me to this meeting for the opportunity to share with you our experience with this drug with RAS inhibitors in -- mainly in pancreatic cancer, which is what I do. I'm a physician scientist. I work actually down the street at NYU. And I have been involved in the development of this agent, both in the Phase 1 and the Phase 2 colorectal pancreatic.

I'll be talking mainly about pancreatic cancer today. And we will be involved as well in the Phase 3 as soon as that is activated. This drug and the RAS inhibitors in general are changing the landscape of the way we're managing and treating this disease. I think most of the relevant points were already addressed by Michael earlier in his presentation.

So what I would do is I'm going to show you one case, one of the patients that I have the privilege to care for and who has been involved in the study and enrolling the study, a patient actually who came from Europe to be enrolled in the trial. And that I think it's a good example on how this medication as a single agent is changing the outcome of patients, very simple, the outcome of patients, the quality of life their pain, everything.

And then I will touch on a few points that I think are very relevant for what we have now and for what we -- I think we will be looking at in the future. So let's get to the case. Here, you have a very, very classic and unfortunate situation, young male, 55 years old. We're seeing more and more younger patients with cancer, by the way, not only colorectal, everything is coming younger.

Presented with -- was diagnosed with an adenocarcinoma of the pancreas with a KRAS G12D mutation. -- started on multi-agent systemic chemotherapy, which is the standard of care, and you have the scans of the baselines with this when he started on the trial, but prior treatment was chemotherapy, modified FOLFIRINOX, very intense, very toxic, not very effective. Gemcitabine/nab-paclitaxel in some patients, a little bit lighter, but not so much, also very intense and with significant toxicity. And these patients unfortunately progress very, very rapidly to these 2 prior lines of treatment. So for these patients, when he presented in the clinic, there is no standard of care, as you know. And there is very little investigational agents that we know were effective before these drugs came sort of age. Patient came to the clinic and he was a young gentleman, still with a good performance status, but with very classic and severe pancreatic cancer-related pain. That pain is horrible. It's the worst pain that you can have.

It's a pain in the abdomen. It goes to your back. You need to be sitting like this. You can't eat, you can't sleep because the pain is more intense at night. And the patient was, of course, taking morphine, narcotics, high dose. And the way these narcotics work is that they work for a little bit. But then when they went off, the pain is back. So he started on the medication and went through all the process. and call me 3, 4 days later saying, "Hey, doctor, pain is gone.

I'm off morphine, completely off morphine. I'm taking an Advil here and there, but my pain is completely gone. The medication causes a little bit of nausea in learning how to use it, and that's an important topic. The side effects are minimal and can be managed by the patients because they learn when to take the pills, what to take the pills with at night, in the morning, midday. So a little bit of nause, but it's fine. And this is doing -- it was a terrific and very impressive clinical improvement. which responses, as mentioned before, can come late, and we see that. They continue, but symptoms improvement occurs very rapidly, which there has to be something that the drug is doing to decompressing the tumor to affecting the tumor infiltration in the nerves.

There has to be something that I think we will study at some point. And this patient continues to be on study and has a very nice partial response confirmed 3 scans. Now it's more than 50%. And you can see the scans at week 12 compared to baseline and it's particularly noticeable, the liver lesion, which is basically gone. The liver lesions are basically gone.

And he still has some peritoneal disease. And of course, as mentioned before, the RAS allele that was present is gone. It's not there. And that's also a very important factor that we're learning with these medications, which is we have the ability because we know what the target to really measure the molecular response. And we think that, that will correlate not only with PRs, but will correlate with future outcomes, progression-free survival and survival. So very, very, very good partial response. What I think is important, as mentioned before, is the clinical improvement, the good tolerability. And the tolerability allows a few things. One, of course, is great for the patients because they don't have the side effect of chemotherapy or the side effects of other medications, but allows you to do combinations. You saw the combination with cetuximab, very interesting.

You have heard that there are many ongoing combinations with very high response rate, not only combinations with chemo, but we are more interested in combination with other targeted agents in patients who have co mutations and alterations in other relevant genes. So it allows you combinations.

And then the patient takes the pill every day, and this is very important because we're learning that the moment you stop, this is like the break and the accelerator. The moment you stop, the cancer flares back. And now we have experience with patients who have very good CA19-9 secretors where you can really monitor when you stop the drugs because of toxicity, a week later, tumor marker going up you start, it goes down.

But at some point, we think those on and off may actually favor resistance. So the ability to take the drug every day because of tolerability is very important. And the last point that I want to mention is that I think wasn't mentioned before. Of course, the PKs are super interesting. I think drugs work well when they have clean and predictable PKs that when you know what you're giving, what is getting in plasma, what is getting to the tumor, what is hitting the target. It's all linear and logical.

And that's very -- it's easy to develop drugs that way when they have these properties. But one final point I want to make is that we are learning that these patients are progressing in a different manner. With chemotherapy, when patients progress, everything is just going up. Everything is growing. and there are multiple lesions, new lesions.

Here, what we're seeing is that -- and of course, this is early data, that the patient, everything is under control and then one lesion starts growing, which probably means that there are clones that are developing resistant mutation. We don't know what they are yet. We're investigating those. But -- so that has an important clinical implication because then you can treat those patients locoregionally and not take them off the drug. So I envision that these medications eventually will be taken past progression and that by providing us the ability to then manage the disease in a more oligometastatic fashion, we have probably a much more impact on overall survival than what we think by just looking at the studies that we have.

So these are, I think, the major points I wanted to mention. And then, of course, I'll be happy to take questions now or later whenever it's appropriate. Thank you very much, and I'm going to pass the podium to Dr. Wu, who will continue the discussions. Thank you.

Thank you, Dr. Hidalgo, for sharing this remarkable case and also the insights for using RAS inhibitors. For people who don't know me, my name is Ting Wu. I'm Vice President of Clinical Development at Verastem. I'm a medical oncologist by training and have the privilege to lead the development of VS-7375 on the clinical side and also having the privilege to share tolerability data of VS-7375. I want to start with the consistency of patients able to stay on the 900-milligram go-forward dose. And I think this is best highlighted through the dose modification statistics. If you look at the numbers of discontinuation, it's only 2%, either due to TA or TRAE, which is quite remarkable. If you couple with the median related dose intensity of 97%, this is, I would say, extremely favorable compared to any class of target therapy. If you look at a reduction in interruption rate, they are also low.

I want to point out that the interruption rate is slightly higher than reduction rate, and that is by design. If you are following the story of Verastem, we have a very consistent safety profile across time points. And also one thing that we noticed is that the safety profile of 600 milligram and 900 milligram are identical. Therefore, there's no point of dose reduction because this doesn't really help with managing these AEs.

Rather, a short interruption up to 3 to 4 days can mitigate these AEs and effectively match these AEs. And these short breaks are supported by the favorable half-life as well as long residence time of VS-7375. -- essentially no impact on activity of the drug. And patients can resume at the same dose, continue to benefit on the high exposure and also the better activity at 900 milligram. Another way to look at tolerability of VS-7375 is to look at the serious -- the rate of serious event as well as the high-grade events. We did not see any Grade 4 or 5 treatment-related events in the monotherapy cohort, and that's important. And only 10% of patients experienced a grade 3 treatment-related event. While the predominant AE of VS-7375 is gastrointestinal disorders, only 2% of the patients experienced a Grade 3 or 1 patient experienced a Grade 3 GI TRAE. If we drill down into the GI disorders, you can see the most frequent ones are nausea, diarrhea and vomiting.

These are predominantly Grade 1, around 10% to 15% of patients experienced a Grade 2 TRAE and only 1 patient experienced a transient grade 3 nausea. However, these safety table does not tell the full story. We need to importantly understand the dynamics of these GI AEs. We noticed that these GI AEs are not accumulated and gets better over time. Around 25% of patients started in cycle 1 without any GI AE, and this number continues to increase to 40% 6 months into the study.

Importantly, I think this gives us implication to manage these AEs upfront more proactively. We know that patients after they go on through the first 2 cycles, they tend to get better for these AEs. So that's why we introduced the antiemetic prophylaxis for the first couple of cycles. And this really increased the patient experience, able to deliver high dose intensity to these patients. And also, we have seen patients who taper off these antiemetic agents later on because of consistency of these GI AE dynamics we have seen in the clinic. It's very important to note that VS-7375 is highly selective to KRAS G12D mutation.

It doesn't affect any wild-type RAS or KRAS. And it doesn't have the liability of that of both RAS and pan-RAS inhibitors, which is outlined in this table. You can see extremely low rash rate, and this also compares favorably even compared with other allele-specific inhibitors, highlighting the high selectivity of VS-7375. And also no mucositis and stomatitis are reported in this study.

Together with the encouraging activity, coupled with this differentiated safety profile compared to existing pan-RAS inhibitors I think it strengthens the narrative that VS-7375 is emerging as the best treatment options for patients with KRAS G12D-driven cancers. Now we know that the major AE of VS-7375 is GI disorders, but other than these GI AE, the tolerability profile is very clean. And it's extremely important when it comes to combinability. We have consistently did not observe any clinical significant hematologic AEs. And that has been very consistent across data set. We have presented earlier this year, midyear and also in this data set, which means that VS-7375 is highly combinable with cytotoxic agents. Similarly, we did not observe any clinically significant AST/ALT elevation in the U.S. population or ex-China population. This opens the door for combined with immune checkpoint inhibitors, which are important backbones in first-line non-small cell lung cancer as well as selected tumor types such as first-line biliary tract cancers.

To summarize the progress we have made in these combination therapies, we believe VS-7375 is highly combinable and eventually can address a very wide population with KRAS G12 driven cancers. I want to highlight a few observations of these anti combination therapies. Starting with anti-EGFR combination. It's highly combinable with anti-EGFR agent without any overlapping toxicity.

The safety profile is essentially monotherapy plus with the addition of the cetuximab classic rash. The presentation, severity and frequency of these rash are in line with what we expect for single-agent anti-EGFR agents. In cytotoxic combination cohorts, we did not see significantly overlapping GI AE overlapping toxicities. And these AE can be easily managed with standard prophylaxis and supportive care that are associated with standard of care with cytotoxic agents. Also importantly, we did not see an uptick of liver function test elevation or other concerning irAEs that's associated with immunotherapy or other older generation of RAS inhibitors when combined with checkpoint inhibitors that we continue to explore checkpoint inhibitor combination with chemo IO combination.

On the left-hand side, you can see this summarized the progress we have made for combination. We have cleared 900 milligram with anti-EGFR agents and currently going full steam for PDAC and CRC cohort in the Phase 2 study. That's also the same for combining with Gem/nab-paclitaxel. We have cleared 900 milligram and currently actively enrolling for frontline PDAC for this combination. This data will be available Q1 next year.

Also, we have made progress in frontline non-small cell lung cancer, the excellent activity you have seen in the previous presentation. We have cleared 600 milligram with the chemo IO and moving to evaluating 900 milligram with the combination. Last but not least, we are actively enrolling for a frontline CRC combination regimen, which is an anti-EGFR plus modified FOLFOX with VS-7375. This will be the go-forward regimen in our future frontline randomized study for CRC. So together, we have demonstrated the tolerability of VS-7375 and also the excellent combinability. The next step is to continue to execute and bring VS-7375 to a broad population with KRAS mutant driven cancer. And that being said, it's important to have a well- fleshed out plan and continue to execute. Therefore, I'll hand it to Michael to talk about future development of this agent.

Thanks, Ting. It's remarkable to present that kind of a side effect profile with the drug with that efficacy profile. Let me just reiterate one thing Ting said that I think is amazing. 25% of patients on this drug don't have any GI AEs in their first cycle. They're getting antitumor efficacy with almost nothing on the side effects.

That's a miracle. By the time they're on for 6 months and the tumor shrunk and a lot of these AEs are worse because these tumors are pushing on abdominal organs or you're short of breath. 4 out of 10 patients don't have GI AEs. Again, that's unbelievable if you think about it. It's really, really, really moving thing very well. So let's talk about where we are. We've made great progress. It has been an absolute pleasure working with the FDA on this program. They've gone from skeptical as they should be when it was early to quite complimentary and helpful moving us forward very expeditiously. Let's look at this comprehensive program focused on the big 3 cancers here.

We have, as I mentioned, ongoing Phase 2 trials, the TARGET-D 200 series in pancreatic, lung and colorectal that are ongoing and enrolling patients. Again, pancreatic and colorectal are expected to finish accrual to get us to the 80-ish kinds of numbers that we think will be enough to support accelerated approval if we have the good durability, which will be available in the first half of next year.

Lung cancer is taking a bit more -- a bit longer because it's only 5% of lung cancer that have G12D, but we expect that accrual to finish by middle of next year, and we'll be able to move from there. The Phase 2 programs are all designed for potential regulatory approvals, as I mentioned, with blinded independent radiological review as is expected and the duration of responses will be critical there. The goal line generally is 30% ORR confirmed, which we believe we've already hit in our cancers as well as durability north of 6 months. okay? This would be unprecedented for all 3 of these disease, particularly in the G12 allele subpopulation. We then moved to the Phase 3s, which is the ultimate goal here. We are very cognizant that we want patients to have the best chance to get their tumor under long-term disease control by moving to frontline. You all know this is a standard practice in oncology. If drugs work in refractory disease, let's get them up in front line, let's beat these tumors down and let's help the patients have the weapons that they can continue to take the drugs.

And as Dr. Hidalgo mentioned, this drug seems to have no limitations on durability in terms of side effects. So no clinically significant cumulative side effects could allow for extremely long-term tail therapy, if you will, once the chemo is gone, once even the antibodies are gone and once the KEYTRUDA is gone. This is a potentially game-changing for tumors that have heretofore been essentially death sentences.

And you should all -- we should all remember that. The 301 study is geared to start up by the end of the year to open. I'll go through the design there. We have some very important design elements that the FDA has agreed to. We think based on the logic that we've discussed with them. The 302 study, we'll be discussing in lung with them in the coming months as we will with the 303 colorectal, and we expect those 2 Phase 3s to start in the first half of next year. I think there are 2 major changes here that I think are unique to our program and FDA has agreed to. But let me start with why. Well, let's start with the design first, perhaps.

So these are patients with frontline disease. We allow people to get 1 cycle of chemotherapy or whatever therapy they're going to get in order to have their G12D typed and confirmed. It's a 3-arm trial, 1:1:1. So 2/3 of the patients will be getting the cool new small molecule, 1/3 will be getting standard chemotherapy.

We went to the FDA with the argument that it was essentially medically suboptimal for anybody in this day and age not to have at least a chance to get a RAS inhibitor if you have pancreatic cancer.

And it would be inappropriate given our emerging data, and this is data that we discussed with them several months ago, the data today are even better, that it would be inappropriate for them to be forced to go and get a drug either on the market or another experimental RAS inhibitor rather than our own RAS inhibitor. It's a long-winded way of saying we allow crossover. This is well published and is well known to drive compliance, especially on the control arm because patients coming into these studies put their lives literally on the line, and they should all have the chance to get 7375. 2/3 chance to get it to begin with is good. But if you want to get your trial done, you've got to get patients to complete that third chemotherapy arm. and get to a progression event, unfortunately.

That's how it works. We all know that. But then they get to cross over. Given that they all get to cross over, it becomes a study essentially of 7375 frontline versus second line. That makes overall survival as an endpoint very difficult to interpret. It confuses the endpoint. And they agreed with this logic. So as far as we are aware, for the first time ever, the FDA has allowed a Phase 3 randomized controlled trial for approval in frontline pancreatic cancer to move overall survival to a second endpoint, secondary endpoint.

They also, for the first time, as far as we're aware, have allowed us to include overall response rate as a co-primary endpoint. Some of you are aware of the program FDA has the FrontRunner program where you're allowed to potentially go to -- we're allowed to go to them. They didn't agree to accept it, but we go to them. We have the potential now to use program FrontRunner to use accelerated approval in frontline disease based on overall response rate of us versus chemo control and potentially win early in the trial before all of the progression events are hit. In fact, the statistical design allows for us to go to FDA after only 2/3 of the patients have been enrolled into the trial.

So after instead of 360 patients being enrolled, we can go after 240, and we have a sufficient follow-up to get the response rates and talk to them about a FrontRunner accelerated approval. Again, they haven't agreed that they would give us the approval, but they have agreed to the statistics surrounding the ORR and importantly, that the ORR is a co-primary endpoint. The majority of the alpha here, the power in the study is being spent, of course, on PFS because that's the key here.

So these 2 new design elements have allowed us to have a Phase 3 trial in pancreatic cancer, which is smaller than others, gives patients 2/3 chance to get VS-7375 from the get-go and allows patients to cross over immediately to VS-7375 upon independent radiological progression, independently confirmed radiological progression. These elements, we think, are really good for patients and recognize the flexibility of the FDA and a recognition on the part of regulators that this landscape is changing.

We are thrilled with this, and we are actively contracting this trial across multiple sites in the world, and we expect to open it by the end of the year, as I mentioned. I want to make another comment because I think there's a little bit of misnomer or thinking that's a little bit off on the role of chemotherapy and other intensive therapies in any of the tumors that we treat. And you'll pardon me, it's a little bit of an academic discussion, but I just want to remind everybody, we start people off on very difficult levels, as Manny mentioned, very high levels of intensive chemotherapy that are extremely poorly tolerated.

And we give them all the supportive care we need. But if you've met anybody who've been on these kinds of combination therapies, it's very difficult for them. Often, you don't see them for a week after their infusions. People cannot tolerate chemotherapy very long. On average, approximately based on what we've been able to glean about -- it's about 2 to 3 months where patients can stay on the goal chemotherapy doses. And then you have to modify the doses and reduce them. And by 6 months, many patients are on essentially, I would -- I don't mean to be dismissive, but almost homeopathic levels of chemotherapy because there's no good data that say these reduced levels actually have antitumor activity, especially for a disease that's seen the same chemotherapy now for 6 months and is probably becoming resistant to it.

After all, the PFS expected is around 6 months in the control arm here. So you basically under -- you can't help it. It's the best we have, but you're undertreating patients with chemo. We have a huge advantage with these targeted therapies now. We can continue indefinitely. We have no evidence that we have to reduce doses or stop the drug. It's beautiful that we will have to get these patients off chemo, and they'll be very happy to be off the chemo, but we continue with 7375, which has excellent single-agent activity or -- and/or in the combination with the -- or I should say, with or without the combination with an anti-EGFR. So it's very important that we're all going to talk about amazing response rates, but the responses have to be durable to win.

The patients need that. And we are not going to get durability out of chemotherapy because you simply cannot do it. One last point. Even in the lung cancer, remember that carboplatin is only given for 3 months. It's 4 cycles of carboplatin and stop. Carboplatin is by far the most active drug in lung cancer. You cannot continue it more than 3 months. If you want to extend the current PFSs beyond 8 months or 9 or 10 months with G12D lung cancer, you better have a drug that continues well beyond 8 or 9 or 10 months and [ it is not ] chemo.

So we're all going to get excited about the combination ORRs, but what we need is durability, and we need well-tolerated drugs that can be given indefinitely. We want to see patients out to 2 and 3 years for the first time ever in the history of medicine. So on my last slide, just to sum up where we are here. I -- It's just been a remarkable almost year now since I was able to jump into this, work with people like Ting and the rest of the team, Nate, our Head of Business, Jon Pachter; and Dan Paterson, of course, Julissa and the whole team at Verastem.

We took a drug that was just starting, and we understood that 600 wasn't enough. We kicked it up to 900. We saw that the side effects were the same. We even have a bunch of dogs now that have a new formulation and the dogs went from the old formulation where all the dogs throw up to all the dogs now with the new formulation absorb the drug with the same levels of the old formulation, but don't throw up at all, 0, 0% vomiting. We'll see. We got to get into the species that matters and it only has 2 legs. But we may be able to even make this a better drug. But this is almost miraculous, I dare say it, drug to now talk about treating pancreatic, lung and colorectal cancer with a single oral agent.

It is stupendous. We've shown you today the first multitumor clinical update, very strong data. FDA has accepted these data. We've had the most rigorous reviews of these data possible. We presented you the most transparent data set, I think, that we can see, and we're happy to take questions. We're actively enrolling our Phase II trials, and they're going very well. There are some cohorts that are full, and we're even getting some nasty letters from people saying you've got to open them up again. And then the frontline potential. We are establishing the safety of these combinations, and we are eager to get these frontline Phase III studies going. And we want to start to see patients that are talking about survival well beyond a year now for pancreatic and colorectal and lung cancer.

Thank you all very much, and I'll turn it back over to Julissa.

[Operator Instructions] We have over here, Michael.

It's Michael Schmidt with Guggenheim. Impressive data. Thanks for the presentation. I had a question on the 301 study, the frontline PDAC study. The cetuximab or the EGFR antibody combination is obviously a very unique aspect of the study that others are not doing. Just talk a bit more about how much data you have with EGFR antibodies and PDACs, just curious? Or how much more you may need to generate before starting the Phase III? And then I have a follow-up.

Yes. Let me take the second part of that question first. We've generated sufficient data that the FDA is convinced that, that's a reasonable path forward. In frontline pancreatic, it's quiet -- we have a quiet cohort, I would call it, within our Phase II accelerated approval study, which is focused, of course, on second-line disease. But there is a cohort in that Phase II study that actually enrolls patients in frontline with frontline pancreatic in combination with an EGFR antibody. And that trial -- that cohort has filled up already with 25 patients.

We're strongly considering based on some pretty aggressive pushing that we need to open that up a bit more. So we'll have a lot more data, but the early indications are that this is a very well-tolerated regimen. That all said, we've investigated this combination earlier. I don't know that we've put it out publicly, but I don't mind saying we've had 5 patients at 400 milligrams of our drug, which is not an active drug dose in pancreatic cancer. This is heavily pretreated, 5 patients. When you add cetuximab, we had 5 -- 2 out of the 5 that converted that were that are PRs very quickly and very active. And if you take 600 and add cetuximab, you boost the response rates there.

I won't get into more detail, but there's adequate activity. Last point, Dr. Pachter and others have generated really good data that preclinically that this is a common pathway that pancreatic cells like to use to try to get around it, to get around RAS blockade and the preclinical data strongly support this.

Okay. Very interesting. And then you did not include FOLFIRINOX combination as an option in the 301 treatment arm. Just talk about that decision.

Yes. I have a somewhat cynical, and I don't mean to be pejorative or irinotecan has helped many people live longer. And I certainly watched its development when I was an internist. It's a very, very difficult drug. And the -- even grade 2 diarrhea should not be discounted, but the grade 3 diarrhea can be life-threatening. It's very tough. We do not want to combine our very nice drug with an excellent safety profile, tolerability profile with some of the most brutal chemotherapy around. We think we can achieve as good data or better, frankly, much better than any FOLFIRINOX combination, much better tolerability, either with GemNabP or we hope with just the non-chemotherapy backbone.

Okay. And then just on a tolerability profile, just remind us what the prophylaxis regimen looks right now in the clinic?

Certainly. So we asked the patients to be on a 5-HT3 antagonist throughout 2 cycles, which is 2 months. We do see a large proportion of patients able to taper off [ antiemetic ] agents. But this really helps the dose intensity and helping these patients to keep on treatment. That has helped like tremendously on our safety profile. If you look at the difference between the U.S. and all the Chinese data, I think that's one of the distinguished factors that result into that differences.

And Michael, keep me honest here, but that one patient that had Grade 3 nausea, they forgot to take the Zofran dose. And came in the hospital, got it and was the [ transient ]

.

So why don't we do, Graig here? And then we'll go to the other side.

It's Graig Suvannavejh from Mizuho. Just a couple of questions. One, just you seem to have a really great drug here. There's a lot that you can do. I know you announced a financing this morning as well. But as you should think about the overall program and where you want to take it, can you just maybe walk us through like what your current financing provides for, what you can do with that? And kind of as you think about what's next, like how do you think about financing those ambitions and considerations of partnerships or not?

No, great question. The raise we did today takes us well into '28 and gets us past the readout of the Phase IIs, which is really important, and I think will be a real value-creating event. This is one of these opportunities where I think we have a true blockbuster where I've spent almost all my career in smaller companies. We can be nimble, we can be fast. We can't do things big companies can do. And so this is one where I truly believe partnering it makes the pie bigger, and you're not just bringing in financial resources, but expertise and scale.

And so we are likely to do some kind of partnering in an ideal deal, we keep upside, and we're working alongside our partner, and we recognize how challenging it can be to be in a partnership. And one of the things that I thought was quite attractive in Michael Bailey's background is he's lived these after the deal. And that's all in many times as important as the deal itself. And so it is likely we'll do some kind of partnering to really accelerate this. But we felt it was the right thing for the company and for patients to push forward with all 3 of these indications as quickly and aggressively as possible.

Great. And then maybe a question for Dr. Hidalgo. Really incredible time we have in pediatric -- I mean, pancreatic cancer with all these experimental agents. This profile looks remarkable. I'd just love to get your perspective of where we are in clinical trials. You've got all these agents. How are you directing patients to one trial versus another when there just seems to be so much activity?

Yes. So that's a great question. I agree there -- I mean there are so many agents out there now in development, which is a terrific opportunity for patients. It's also a much better situation for physicians because we cannot prescribe or administer medications that are better tolerated and more effective, but there is a competitive or broad landscape of how you direct patients. Daraxonrasib is approved with a broad indication and it's being used, I think, across multiple scenarios based on the FDA approval.

I still think or we think that for patients that you know the mutation, the allele, allele specific agents tend to be better tolerated and maybe in some alleles in the noncomparative data more effective. So for us, the preferred is still a clinical trial if we can. But -- there are -- so that's 1 point. Second point, and we're very interested in non-chemo combos. And in dual targeting, PRMT5 combinations that you have heard, are very, very interesting. I like the EGFR combo.

I think that we tend to think that, that's only applies to colon, but the reality is that pancreas is also dependent on that. Tarceva is approved. We sometimes forget that. But marginal, very small activity, but there is some EGFR dependence on these tumors that hopefully we'll see that data. And many, many other non-chemo combinations that are very, very exciting. For that, you need an agent that is -- can be well -- is well tolerated, of course.

And then final point is that -- and I think we didn't mention that, of course, because we're now in sort of in the Phase III's approval. It's moving these to earlier stages. That's the real front runner. And here, you have a drug that we envision could be easily study in the adjuvant setting, colon, pancreas, lung, of course. And in maintenance in patients with early disease move to preoperative. It is very important to see these responses can take more patients to surgery.

That's another very important area of research and 2 more points, very briefly, the molecular markers, now designing studies and using drugs on a molecular based test, not just waiting for CT scans or CA19-9, really looking at what matters and being able to pivot from 1 to the other depending on that. And eventually, I think cancer interception and even earlier, we're doing studies with IPMN intrapancreatic mucinous neoplasia, which is about 20%, 30% of patients with pancreas cancer come from the cystic dilatations in the pancreatic and we're -- we have now the tools to.

So it's a complex but fascinating landscape and I think the next few years are going to be quite remarkable.

Yes, I'll add a point to that. Last week, I gave a talk of the RAS initiative at NCI and Frank McCormick kind of is the father of the field. He's believed in all these years. He gave the closing comments in the meeting. And what he said is he can picture in the future that we have a G12D selective that's just amazingly safe and a G12V selective that's amazingly safe and maybe a G12C and everybody takes them and you prevent cancer.

And that's his dream. And I think Michael talked briefly about the alternative formulation that we're proving in the lab that looks great in dogs that get rid of the GI tolerability. I think our drug could be one of the most important elements of that kind of combination that everybody could take because if it's really well tolerated and RAS is such a bad actor, why not just head it off.

It's not a dream to think that some time from now, there will be a good enough cell-free DNA test, quantitative test that will be monitoring like your A1c hemoglobin in diabetes. When you go up, you know something is wrong and then you don't need to wait for. I mean it's dreaming, but I think it's -- we're getting there.

We're going to turn to Eric?

Eric Schmidt at Cantor. Congrats on some great data. I'm intrigued by the commentary around treating post progression. So can you talk about whether that will be allowed in the Phase III? If not, how you might follow up that finding?

Yes. Our intention and FDA, of course, had to approve that. I mean we sent it in, they blessed it. The physicians want it, the patients want it. The progression is, of course, radiographic. It's not necessarily symptomatic. And I think doctors and patients generally that they wanted -- they worry about symptoms primarily. I mean they're upset that the tumor [indiscernible]. So this patient was treated I think he kept on 900 for a while, and he even kicked up to 1,200 eventually.

So we see if we could get it to come down again. One of the little talked about reasons for progression because it's not very exciting is simply drug dose. -- that is drug delivery to the tumor. And at least some tumors, you don't get to publish papers on it, but at least some tumors are progressing because they're just not exposed to enough anticancer therapy because they found a way to be avascular enough that they can live and grow. And then oftentimes, and we've seen other cases there where 600 mg patients are given 900, and that tumor that started to grow just crashes.

And localized radiotherapy will be...

Yes, you can do. I mean we do what we always -- we really have made a culture at Verastem of doing -- and I'd just say this. There's always -- the regulators are always open if the physicians request it and the company is supported.

If I may, I hope that as studies are designed based on our PFS, hopefully, molecular responses, and that is going to be the determinant for approval. Then the progression -- the treatment on progression, which may impact OS, I think in my opinion, should be allowed. Patients are progressing in a different manner. And not everyone is a candidate for post-progression treatment. If there are 20 lesions growing up, you need to switch the systemic treatment, but we're seeing patients with just 1 lesion, 2 lesions popping up, likely reflecting there is a clone that now acquire another alteration and that is bypassing.

So our protocol is to biopsy those, to learn, but also to do local regional radiation, radiofrequency ablation, resections. So I think that should be allowed in protocols because it's for the benefit of the patients. And then you already have your PFS, your primary endpoint readout. So you're not messing with that.

And when you think about where the frontline pancreatic cancer market is evolving to and your future combination with an EGFR therapy, what do you think is the likely comparator? What do you think that you need to beat in the future frontline setting for G12D therapies? What's your confidence you're going to get there?

I think we've designed it the way it needs to be right now. I think once we get the approval, medicine will help people like Manny will lead the revolution to use the drug properly in the combinations they want. I can imagine if we get combination approval, which we fully expect to win. Many patients will start on the combo and then decide I don't want to get the IV anymore. And I'll just keep an eye on this tumor and monitor molecularly and monitor CA12-5. And if I need to go back on an IV every couple of weeks, I will.

But I think the future is that. And then, of course, we have all these other new targeted therapies like PRMT5 inhibitors and so on. We're doing defactinib. We're super excited about that. It has really good preclinical support I think once we get it on the market, there may be some post-marketing studies in the future. But once we establish it as a beachhead, this will become a foundational medicine for other combos.

Last question, breakthrough designation -- where are we?

So our intention is to let the data become -- evolve a bit more. We made some provocative statements about where we think the PFS is heading. Overall survival is excellent. With this, we want to evolve it a little bit more and then go to the agency and all the caveats across trial and blah, blah, blah and say, we think this is highly differentiated, both on efficacy and on tolerability. And we think this deserves that and we'll see if they agree with us.

Yes. I mean, typically, you need at least 20 patients with 6 months follow-up, and we want patients from the U.S. for that.

Jeet [indiscernible]

Great. Jeet Mukherjee, U.S. Bank BTIG. Congrats on the wonderful data and looking forward to the ASCO plenary soon enough. Two questions from me. Just as a reminder, for the front line, PDAC Phase III, what are your expectations for ORR, PFS and OS for the control arm? And do you anticipate patients to receive more GnP or the modified FOLFIRINOX?

So I think the important point is that PFS, FDA has commented this in several indications and several incidents that your PFS delta needs to be clinically meaningful, which means that probably 1.5 months kind of increment is not sufficient. So we want to have like sufficient delta, which means probably clinical meaningful, at least like 3 to 4, 5 months around that range. And of course, in a control arm we want to be realistic, right? What is the -- because we're allowing either GnP or FOLFIRINOX, what is the kind of the PFS for those pivotal studies in the past will use similar to what you expect for the control arm.

Okay. Got it. And second question was granted this will be data-driven, but you've talked about exploring combos with EGFR, pan-RAS and hinted at perhaps a PRMT5 combination soon enough. Which of these combination agents do you see as most promising across the tumor types you're evaluating?

Yes. I think there'll be specific situations. If you have pancreatic cancer and you're lucky enough to have MTAP deletion in addition to your G12D, it could be amazing in the front line to be able to take a doublet of 2 targeted agents, PRMT5 inhibitor and our G12D and that should really have astounding control of the disease.

The preclinical models, it just never grows when you treat with the combination and really impressive data from the Tango combination with the [indiscernible], but we think we can make that better still. So I think that's really exciting for that subset of patients. I think a lot of these are exploratory. I mean we're looking at with a RAS dose pan-RAS. We'll see if it's better.

I think there might be situations where it's better and other situations where you'd rather go with our single agent or something else. But I think the more we explore these things, and I agree with Manny, I mean, there are lots of other combinations we're excited about that are with targeted agents that should be well tolerated, but we'll find a place.

Yes, agree I think PRMT5 and EGFR are probably the 2 that we have more clinical data and then they're very exciting period, but you need to have the dual target. I don't know. There are not a 10, 15 like -- this is like pembrolizumab days, like now everything that you combine with a RAS inhibitor is effective, right? So they're -- if you look at the preclinical papers, there are multiple new targets claiming synergistic efficacy. I think it will be important to rapidly test those in clinical trials to make sure which ones are really promising versus other.

The fact I think another 1 that there's strong preclinical data, but a strong clinical data in -- with 12C in lung cancer and in colon, not in pancreas yet. So multiple possibilities, we need to do rapid molecularly driven clinical trials, exploratory trials to pick the ones that should go to more advanced development.

And I think it's also important to think on combinations that you're going to use upfront versus combinations that may be effective at the time of resistance and progression -- this may be the same may be different than maybe patients are very sensitive to begin with, and they progress because of a specific alteration that you can target. So that's going to be a fascinating drug development scenario in the next few years.

And Jeet, the other part of the answer, we have a very active investigator-sponsored trial program. So what we're talking about are things that have risen to the level of the company-sponsored trial, but we're getting a lot of proposals of novel combinations actually from Manny as well. And we're really trying to drive some -- that's a very cost-effective way to see is our G12D plus this agent or that really an amazing combination. And then we can promote that if it's a really exciting signal, but those are ongoing.

Yuan Zhi from B. Riley. Has a great data today and great to see almost everybody can get tumor shrinkage. Maybe a couple of follow-ups. I don't mean to push the limit here, but when can we expect the next data update? And what will be included there? That's the first one.

No, Yes, sure. Easy one. Probably by the end of the year, we'll have some -- as Michael mentioned, we'll have a little bit of updated data from the cohort of the colorectal that you saw and a little bit of the [ Panc600 ] combo data in GnP -- and then we're pursuing some medical meetings. I know folks have been anxious about that instead of showing the data in that form. So hopefully, those will come through. And then I think expect next year to be a very data catalyst-rich year at medical meetings and multiple updates from the Phase II in the first half and the latter half as well and lots of progress on our enrollment and so forth. So it will be a busy 8 -- 6 to 12 months.

Got it. Got it. And my second question is related to the combination of 900-milligrams 7375 and EGFR. I know you have some data adverse event data in the back of the slides. So what are the highlights you want to share there? Do you see anything concerning about the Rash? Or it's just as you expected with the monotherapy EGFR inhibitor?

The Rash, what we also asked the investigator to better like characterize the Rash, we have got like really good feedback as the Rash is identical to what do we expect for single-agent anti-EGFR agent. In terms of this presentation acneiform predominant and also in terms of frequency, severity, you can see in the table that's in line with what we've reported for the single agent. So no concern of overlapping toxicity.

Well, just give it to Josh, and then we'll come back over to this side.

Josh Brew with RBC Capital Markets. Really great data today. Congrats. Yes. So I guess 1 thing that I was interested in was how you guys had disclosed alignment with the FDA, but only for the -- in the PDAC indication, -- and I was wondering whether you can give a little more color there for the other indications? And are you looking at this dual ORR PFS approach there as well? And then second question, Were there any interesting kind of patient baseline characteristics that you found correlated with deeper responses across all the indications?

Yes. So we're intending that the trial on the Phase III be global. We've had the discussion with FDA got and sign off on the -- ironically, we had our end of Phase II meeting to agree on Phase III while we were doing our Phase IIs, which is always fun. For the pancreatic, the lung and the colon meetings are scheduled. So those will be coming up. We have sent our protocols into the Europeans. The lung protocol Phase II is being done is including European sites.

The others Phase IIs, I don't think they're going to make much ex U.S., I mean, a little bit of Australia, but they're recruiting too fast to get Europe up and running. And our expectation is Europe will hopefully, and I think you implied maybe they're not as comfortable probably with this without OS, but we'll have the OS data, and I think our compelling argument will go. We expect it to get through. We intend those to be in international Phase IIIs.

[indiscernible] from Jefferies. 2 for me, 1 for the company, 1 for Dr. Hidalgo Medina. First for the company, just if I can ask for a little bit more specificity because it matters so much for the Phase III. On the PDAC early-stage combo data sets, can I just get a little more granularity on what combos you expect to share and what time frame and how many patients investors should expect?

Sure. Yes. Sure. We went -- as we told you in June when we weren't ready to show you these data and we ask you to wait, and I think we're all pretty happy that we waited. These responses don't happen quickly. they shrink quickly, but they don't hit the magical 30% quickly. So we want all to get there, and we're going to get some durability because I think everyone agrees these RAS inhibitors are active, so you need to see duration. We will -- I think the first half of next year is probably the right time. We'll be able to give you maybe a little bit by the end of the year.

But I think mostly for PDAC in the combos, it's going to be the first half of next year. That said, and I think that will include the first-line data set as well, possibly.

Got it. And that's both chemo combo and the EGFR.

Yes. With GnP, right. I mean, we -- right now, we have GnP Safety is cleared in second-line treatment. So a lot of the patients already got GnP and now they're actually enrolling people who already got GnP to GnP plus us, which tells you what investigators think of the ability of our drug as you would never put somebody on GnP and then GnP again, they progress. and people on FOLFIRINOX who blew through it and then get GnP plus us.

So that will be as well. We're not doing FOLFIRINOX, as I mentioned. We're not doing it in colorectal or we're not doing NALIRIFOX. We're just not going to deal with a Grade 3 diarrhea, irinotecan compound that makes people wretched.

Got it. Okay. Makes sense. And then for Dr. Hidalgo Medina, can I ask you for first-line pancreatic cancer, can I ask you to rank how promising you see each of these 4 approaches, chemo and RAS combinations, G12D with multi-RAS, G12D with PRMT5 and G12D with EGFR?

So we need to wait for the trials. I think all of them make sense. I presume you are asking what is my expected outcomes for those.

I mean just based on like kind of your expertise in the field, the biological hypothesis, the early data we've seen so far?

So for the MTAP RAS mutant I think we're seeing probably the best activity we have ever seen. And so which means when you have the 2 targets that are relevant and you target both of them, you get the best. The others, I don't have data to compare. We will see at ESMO very prominent chemo combo data with [ 12D's ] inhibitors. The panRAS, they are less -- they can be combined with chemo as easy. So I think the responses are a little bit lower.

The -- but likely each 1 of those is killing different cell populations. So I think it would be at the end of the day, interesting to see how not all at once because that won't be tolerable. But sequentially, we may, I think, think on ways to combine more -- 1 or more of these strategies. But the chemo versus the EGFR, I think that will need to be -- we'll see.

Kalpit Patel from Wolfe Research. I wanted to push on the choice of the first-line chemo combo strategy here. I guess we know that daraxon or a panRAS inhibitor does better than chemo. So why not entertain a panRAS combo with your G12D right from the beginning? And then second question, any color on how long a first-line study would take now that it sounds like you could potentially use ORR as an accelerated approval endpoint?

Yes. I'm not going to -- I don't know how long it will take. We'll update you guys next year once we open it up, and we'll see. We expect I can say that accrual to our second-line pancreatic study has not taken any hit that we can discern since daraxon was approved. People are coming in, and I expect they will continue to flood in and that will hit by the end of the year.

As far as why not combined with the panRAS, frankly, to be blunt, we think our EGFR combo will do at least as well, if not better, will be better tolerated. The Rash from cetuximab and panitumumab is easier to treat. People know how to treat it. It responds better to the doxycycline, minocycline and steroids. And it doesn't carry much mucositis or stomatitis, which are a big deal. And lastly, I'd just remind you, I mean, again, cross data comparisons, the combo data from darax plus zoldon are very exciting. But frankly, I think they had a couple of CRs. We have a couple CRs, they had good response rates.

We have good response rates. And it's not clear to me that you need both drugs and it seems overlapping to me to do that. Our drug penetrates the tumors. It kills -- you saw what it does to the G12D alleles. We need -- we want a different mechanism. We think that will give the best chance for not only great responses, but most importantly, durable disease suppression.

A lot of these combinations might be -- might kind of speak to weaknesses of the individual drugs. I mean if you -- if your G12D selective can't get good enough exposure to maximally hit the target, you might need something else. It's a similar drug. If your -- panRAS isn't tolerated enough to maximally hit the target you need to combine. So I think that we're interested in the panRas combination because those drugs are more different. But I think -- those can often be just kind of showing the weaknesses of the individual drugs that need to put 2 very similar drugs together.

A last question for Matt, and we'll wrap it up.

Matt Venezia here from Alliance Global Partners. Congrats on the impressive data this morning. So first, I wanted to ask the panRAS inhibitors, the AEs build over time. I know you guys are saying or showing that yours are not building over time. In your last data update, you showed that the AEs actually diminished after 1 cycle. Did you see this trend continue after 2, 3, 4 cycles? And can you take us through a little bit of the AEs over time?

Yes. I mean the trend is very consistent with what we announced last time. I think like looking at these different kind of metrics like at this time, we look at like patients without GI AE, I think that tells the same story that these AEs tends to [ changing ] over time. And that's also very, very consistent what we have heard from our investigators that the first 2 cycles is where you need to more proactively manage, whereas after that it's like smooth sailing after 2 cycles. And that's how we define the timing. We use the antiemetic prophylaxis or associated with those practices.

Great. And then just lastly, I wanted to ask about the CA19-9 trend over time as compared to your last data update in June.

Yes. We didn't -- we chose not to present it today just because of the abundant -- it looks like last time only longer. In fact, even the patient who had radiographic progression didn't have a bump to CA19-9 which is just consistent with the lack of symptomatic progression. But it's very stable. It's -- there are a few signs at this point that these diseases are starting to progress across most patients, we'll have to see. I mean, evolution drives natural selection to get these tumors that figured out a bypass pathway or hide out in the body in an anatomically inaccessible site. But so far, it's been very nice.

Thank you. Well, that concludes our event and our live stream. So thank you. We can -- we'll still be here for further questions.

Good afternoon and welcome to Verastem Oncology's second quarter 2026 earnings conference call. My name is Livia and I'll be your call operator today. Please note this event is being recorded. [Operator Instructions] I will now turn the call over to Julissa Viana, Vice President, Corporate Communications, Investor Relations and Patient Advocacy at Verastem Oncology. Please go ahead.

Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss Verastem's second quarter 2026 financial results and recent business updates. This afternoon we issued a press release detailing these results along with a slide presentation that we will reference during our call today. Both are available on the investor relations section of our website.

Before we begin, let me point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional detail. Additionally, today we'll be discussing certain non-GAAP financial measures. Reconciliations to the most directly comparable GAAP measures are provided in the press release we issued today.

Joining me on today's call to deliver prepared remarks and take your questions are Dan Paterson, President and Chief Executive Officer, Dan Lyons, Chief Commercial Officer, and Dan Calkins, Chief Financial Officer. Dr. Michael Kauffman will be joining us for the Q&A portion of the call. I will now turn the call over to Dan.

Thank you, Julissa. Good afternoon and thank you for joining our call today. We delivered a strong second quarter with meaningful progress across both our commercial business and pipeline. For the quarter, we generated net product revenues of $25.1 million, reflecting continued execution of our commercial strategy, putting us back on track and reinforcing the long-term opportunity for the avutometinib and defactinib combination. We also strengthened the balance sheet with a non-dilutive royalty financing agreement with Oberland Capital to secure up to $75 million in funding, of which we expect to draw $50 million at closing.

Combined with a $15 million milestone payment from Secura Bio for a Copiktra sales milestone, the incremental $90 million in non-dilutive funding strengthens our balance sheet and allows us to get beyond key data readouts, advance partnership discussions, and preserves strategic flexibility as we evaluate future financing opportunities. Also, as we shared previously, we continue to expect the LGSOC business will become self-sustaining by the end of 2026, meaning that commercial revenue will support both the ongoing commercial organization and the existing avutometinib and defactinib development franchise. As Dan Lyons will discuss, the commercialization of the combination is progressing well, and we're encouraged that the changes we made are having an impact.

Since the first quarter, we've seen a meaningful rebound with significant quarter-over-quarter growth driven by growing physician confidence and initiating treatment for new patients, prescribing to more patients in earlier lines, and increasing patient refills. In addition, our field teams are continuing to support prescribers in helping patients stay on therapy to realize the full benefit of the treatment. These trends reinforce our belief that adoption will continue to grow as physicians become increasingly comfortable using the combination at a patient's first or next recurrence.

In June, we reported a positive update on the RAMP 205 pancreatic cancer data. Looking ahead, we believe the regimen of avutometinib plus defactinib in combination with chemotherapy can play an important role in the second-line treatment of PDAC following either a pan-RAS or KRAS G12D inhibitor to help address resistance mechanisms that are expected to emerge. Turning to VS-7375, we have an opportunity to meaningfully advance treatment for patients with KRAS G12D-driven cancers. Our goal isn't simply to extend patients' lives, but to do so with a treatment designed to specifically target the biology of these cancers without unnecessary on-target toxicities.

Ultimately, we want patients to spend more time living their lives, not managing nasty side effects from their treatment. The progress we've seen across the RAS field is validation of the possibilities. At the same time, it has also made clear that there remains significant opportunity to improve both outcomes and the overall treatment experience for the approximately 60,000 patients diagnosed each year in the U.S. alone with a KRAS G12D-driven cancer. Recently, I heard about a young woman in her 30s who was participating in our trial, and her story and experience in the trial reminded me why this work matters. She was diagnosed with a KRAS G12D-mutated advanced non-small cell lung cancer. She'd never smoked and did not respond to current standard of care chemo plus immunotherapy. She was not only living with cancer, but experiencing constant symptoms of the disease that disrupted her quality of life.

When she entered our study and began treatment with VS-7375 at 600 milligrams, her primary tumor shrank by more than 65% within six weeks, and her symptoms also started to improve. She remains on treatment today and continues to do well. While this is one patient's experience, it serves as a powerful reminder about what is at stake and that behind every data point is a person and family member hoping for not just more time, but more quality time. In June, we shared preliminary clinical data from the Phase 1/2 TARGET-D101 study, which further strengthened our conviction that VS-7375 has the potential to not only become the best-in-class oral KRAS G12D inhibitor, but a treatment that patients can truly tolerate. We continue to be encouraged by the emerging antitumor activity across multiple tumor types and the favorable tolerability profile we've seen so far.

Together, these data support the advancement of our three ongoing Phase 2 registration-directed studies in pancreatic, colorectal, and non-small cell lung cancers. Operationally, we've continued to execute the VS-7375 development program at an impressive pace. We completed target enrollment in the pancreatic, colorectal, and non-small cell lung cancer dose expansion cohorts of the TARGET-D101 study, received FDA fast-track designation for non-small cell lung cancer, and initiated all three of our Phase 2 registration-directed studies with the first patients now dosed in each trial. These studies represent an important step toward generating additional data to support the potential for the accelerated approval pathway and set the stage for our upcoming frontline Phase 3 studies. We look forward to sharing a meaningful data update on VS-7375, including response rates across our three lead tumor types in October.

With that, I'll turn the call over to Dan Lyons for our commercial update. Dan?

Thanks, Dan. We continue to make meaningful progress in the second quarter as the launch matures. We are pleased with the quarterly sales of the avutometinib and defactinib combination of $25.1 million. Our commercialization of the combination remains focused on three priorities. Driving consistent new patient demand, expanding use earlier in the treatment journey, and helping patients to stay on therapy to realize the full benefit of treatment. Across each of these areas, we are seeing encouraging signs that the changes being made are having an impact and physician experience continues to deepen.

Our first commercial priority is to continue to grow new patient starts. We continue to see healthy and consistent levels of new patient starts and refills throughout the second quarter. As the new patient demand continues to build, we expect this to convert to future refills. We're seeing increasing evidence of repeat prescribing that is trending higher among existing writers and greater depth of prescribing among our existing accounts, giving us confidence that adoption continues to broaden. While our distribution model doesn't provide complete visibility into every prescription, we are pleased with the numbers of new accounts that adopted the combination in the second quarter across academic and community targets.

Through the end of the second quarter, adoption continues to expand as experience with the avutometinib and defactinib combination deepens with a meaningful addition of first-time prescribers and new accounts. Gynecologic oncologists are the primary prescribers, reflecting their central role in managing patients with LGSOC from diagnosis through the clinical course of their disease. Adoption continues to expand across both academic and community practices. In the community setting, our site-specific alerts help identify patients, and we are already seeing early returns from that effort. We are expanding this work to more practices in the third quarter.

Our second commercial priority has been to drive use in the right patients at the first or next recurrence. As we've discussed previously, the earlier months of the launch were characterized by a higher proportion of heavily pretreated and later line patients. During the second quarter, we saw multiple indicators that physicians are initiating treatment earlier. These observations are based on several inputs, including our internal prescribing data, field insights, physician discussions, and market research. As we move up in earlier lines of therapy, the patients and outcomes are beginning to change, similar to what we saw in our RAMP 201 trial.

With this shift, we will continue to work with prescribers to help these patients stay on therapy longer. Other efforts like our reimagined recurrent LGSOC direct-to-physician and patient campaign are focused squarely on the shift of identifying the right patient. We can attribute our success in Q2 to that message resonating with prescribers. Our peer-to-peer programming are also creating opportunities for doctors to understand where the combination fits in the treatment paradigm from the respected leaders in the field.

Our third commercial priority is ensuring patients remain on the combination to get the greatest benefit. As the active patient pool has grown, we saw refill consistency in Q2 that suggests patients are remaining on therapy longer. Physician feedback on the combination has been positive, with tolerability consistent with their expectations. As with any new therapy, there is a learning curve as physicians and their staff become familiar with managing patients and setting expectations around treatment. Our operational execution is strengthened with the changes that we made last quarter across all our field teams.

We are working to ensure prescribers are setting appropriate expectations for patients and managing adverse events so patients can have the best outcomes while taking the avutometinib and defactinib combination. Our reimbursement continues to not be a challenge, and patients are getting their medicines quickly. Taken together in Q2, the combination of new patient starts, increased refills, expanding physician adoption, and the appropriate patients being identified, we drove meaningful growth in the adoption of the combination, and we are seeing that momentum continue in Q3. I'll now turn the call over to Dan Calkins.

Thank you, Dan. Our full financial results are included in our press release, so I'll focus on the highlights here. For the second quarter of 2026, we recorded $25.1 million in net product revenue and $3.8 million in product cost of sales. Cost of sales increased in the quarter in line with the percent increase in net product revenue. We also recorded $15 million in license revenue from the sales-based milestone payment under the terms of our agreement with Secura Bio, which was triggered by cumulative worldwide net sales of Copiktra surpassing $200 million during the second quarter of 2026.

Research and development expenses were $41.3 million for the second quarter, incrementally increasing as expected from the first quarter of 2026. These expenses continue to be driven by the ongoing TARGET-D101 clinical trial in the U.S., the initiation of the three Phase 2 TARGET-D clinical trials, associated with clinical supply and drug production activities related to our expanded VS-7375. SG&A expenses were $27.4 million for the second quarter of 2026, and roughly in line with the first quarter. These expenses continue to be driven by commercial activities and operations, including personnel-related costs to support the ongoing combination launch.

Let me reiterate that we expect SG&A expenses to remain roughly the same on a quarterly basis throughout 2026 as we remain disciplined in our expense management, making the right investments at the right time to support the ongoing commercial launch efforts. For the second quarter of 2026, non-GAAP adjusted net loss was $30.6 million, or $0.31 per share diluted, compared to non-GAAP adjusted net loss of $41.3 million, or $0.62 per share diluted, for the second quarter of 2025. Please see our press release for reconciliation of GAAP to non-GAAP measures.

Moving to the balance sheet, we ended the second quarter of 2026 with cash equivalents and investments of $136.4 million. When you include the $50 million received at closing from the non-dilutive royalty financing with Oberland and the $15 million Copiktra milestone payment, our pro forma cash balance at the end of the second quarter of 2026 was $201.4 million. Based on our current cash position, expected revenues from the combination sales, and access to the future tranche from our Oberland facility, we believe we have sufficient capital to fund operations into the second half of 2027 and reach meaningful value-creating inflection points before needing to access additional capital.

As Dan mentioned earlier, we look forward to building on the combination's growth into 2026, and given our current trajectory, we believe the LGSOC franchise will be self-sustaining by the end of the year, with combination revenues funding both the commercial operations and our avutometinib plus defactinib clinical trials. With that, let me turn the call back over to Dan Paterson.

Thanks, Dan. Before we open the call to Q&A, I'd like to reiterate that our focus for the second half of 2026 is very clear. Drive strong execution of our commercial strategy to expand adoption of the avutometinib and defactinib combination, complete enrollment in our three Phase 2 registration-directed VS-7375 trials, and prepare to initiate our three Phase 3 trials for VS-7375. In October, we expect to provide a more comprehensive data set for VS-7375, including response rates across our three lead tumor types, pancreatic, lung, and colorectal cancers, with approximately 20 patients in each, as well as an early look at durability.

The progress we've made this quarter reflects disciplined execution across the organization. We've continued to optimize our commercial business and advance our clinical programs, and this positions us well for a productive second half of the year. With that, we'll open the call for questions. Operator?

[Operator Instructions] And we have a question from Cantor. Caller, please go ahead and introduce yourself and ask your question.

Maybe just on 7375, can you talk perhaps in broad strokes about partnership activity in the G12D space and any updates you could provide? I know last time we spoke you had alluded to a potential collaboration with Erasca, but any other comments you want to provide on what it might take for you to form some sort of a collaboration. Thank you.

Yes, Eric, thanks for the question. We continue to work on the Erasca partnership, and we'll have more details as time goes by. We're working through details on what a first study would look like, what our respective roles would be, and really, you know, kind of when we'll be able to start the study. We still remain interested in PRMT5 and are looking at a number of different options there. And then we have had considerable inbound interest from Strategics.

And you know, I think in an interesting way, you know, RevMed putting out their G12D data earlier, as well as we'll have our data coming out in October, I think will really spur additional interest. And as is always the case in these discussions, it's really a judgment call on how early or late you do a partnership. The value goes up over time, but the potential acceleration of a program that a partner can bring has a bigger impact the earlier it is. So we continue on all those fronts and, you know, the funding that we announced today I think gives us a lot more strategic flexibility to not have to rush into something nor rush into an equity financing at, you know, the current stock price.

Thank you, Dan. That's very helpful. And maybe just a quick follow-on for the other Dan. Gross margins to be running in the last couple quarters look better than at least I've been modeling. Is this a reasonable run rate going forward?

Dan C., you want to take that?

Yes, sure. Thanks, Eric. Yes, I think that that is a reasonable run. I think as you look at cost of sales, the majority of that really is still continues to be royalty-based. You know, the margins on the product are relatively high. So but going forward from a modeling perspective, I think what you're seeing this quarter, which we've seen historically, should be indicative of what we should expect going forward.

Thank you. Next in queue, we have a question from Guggenheim. Caller, please go ahead and introduce yourself and ask your question.

I just wanted to ask on 7375 regarding the October update. So you cited, I think a general 30% overall response rate and six months durability as an FDA accelerated approval bar. So just heading into October, I want to know, is that still the right framing across the three of these indications? Or does, you know, the competitive landscape in PDAC, for example, shift how you might think about what's needed to establish best in class? Thanks so much.

Michael, you want to take that one?

Sure. We think that's generally a very good guidepost. You probably saw the very recent approval of [ 2-DRCF ] in melanoma with a 24% response rate, which got accelerated approval. Granted, we never want to go through what they went through. But 30% is a great metric in this disease. Six months is also terrific. And I would remind you, we all know that 35% is the second line response rate that we're all looking for, but 30% is very good. Let's not forget, there are drugs that are very easy to take and there are drugs that are very difficult.

Having a rash that is as extensive as we've seen with some of the pan-RAS inhibitors is real difficult, nevermind the mucositis or stomatitis. So remember that accelerated approval looks at both activity as well as the safety and tolerability profile drug.

Thanks, Michael.

Next in the queue we have a question from RBC Capital Markets. Caller, please go ahead and introduce yourself and ask your question.

I was wondering whether or not like how you were feeling about the translatability of the ORR data that you've been seeing in the GenFleet China study, and whether or not that will be recapitulated in the U.S. population given the known differences in PK behavior or disease management. Thanks.

Thanks for the question. We do get compared to the GenFleet China data all the time. I would remind everybody that the most important benchmarks are going to be the U.S. data from other products and, as Michael said, really hitting a bar that we need for the U.S. accelerated approval. We are seeing quite different toxicity profile. We are showing peak that goes up as the dose goes up, and we believe, especially with an isoform-specific molecule, hitting the target really hard will translate into both depth of response and durability. I don't know, Michael, if you want to give any more color there.

I think you can definitely say from the China data the drug is active. We know that. In our hands, you've seen the CA 19-9 data is very active. Direct translation, probably not direct, but within the ballpark, and we're really looking forward to the October update across all three tumor types.

Thank you. Next in the queue we have a question from Jefferies. Please go ahead and introduce yourself and ask your question.

Just wanted to ask on the combination performance, really nice to see the uptake in revenues this quarter. Can you help us understand a little bit some of the metrics around what you're seeing on like new starts and duration of therapy? Because I know in the past you had mentioned that short duration was impacting the growth. So just trying to understand the extent to which this great quarter was driven by new starts or driven by improving duration or a bit of both. Thank you.

Thanks for the question. I would say a bit of both, but maybe Dan, if you want to give... Dan Lyons, if you want to give a little more color.

Yes, thanks for the question. It's a bit of both. And so what we saw, as you know, Faisal, our three priorities are to grow new patient starts, to move up in line of therapy, and to keep patients on so they can have the best outcome with the avutometinib and defactinib combination. What we saw in Q2 was a bit of both. We saw a meaningful increase in new prescribers and new accounts. And so that has us very encouraged what we're seeing from a new patient start perspective. We're seeing consistent new patient starts, which is what we want to see in this disease. And then from a refill perspective, we're encouraged that all the execution and focus that we had is leading to the outcomes we're looking for overall.

Thank you. Next in queue, we have a question from the Mizuho group. Caller, please go ahead and introduce yourself and ask your question.

Two questions if I could, just maybe on the combination, maybe piggybacking on the last question. As we think about the dynamic between new patient starts and refills and newer prescribers, is there a way to think about, is there any one particular segment that early in this launch process is going to be a bigger contributor to driving sales or is it just a combination of all three relatively equally? And then second, if I could ask a question on 7375, appreciate the color on what you're looking for in the upcoming October data. But just maybe generally speaking and in light of the comments you made about RevMed disclosing some data on their G12D, as you look at the landscape, and certainly there's a lot of excitement around the G12D inhibitor space, how do you hope to best differentiate your compound versus others that either are already out there or could be coming? Thanks.

Thanks, Graig, for the question. I'll take the second one first, and then I'll let Dan Lyons address the first one. I would say, you know, against pan-RAS inhibitors, we intend to show better efficacy and significantly better tolerability. With the G12D inhibitors, I think what we've said all along is, and if you look at, you know, as we've been able to escalate the dose with very little change in toxicity to hit the target hard, we believe we're going to be able to hit the target harder to have deeper response and hopefully better durability tolerability.

But against the pan-RAS, I think the big difference is going to be tolerability. And against other G12D inhibitors, we've said we thought we have the best in class based on preclinical data. I would say where we're starting to see that in the data that we're getting clinically and, you know, hopefully we can show that in October. Dan Lyons, you want to take the second question, and if Michael wants to add any more color, you can feel free.

Sure. I'll go first, then Michael if you want to add anything. So as you look at the question around the segments, right, whether it's new patient starts first, refills first, moving up the line of therapy, all three of those are critically important. Those new patients start to turn into refills very quickly. And as we look at the ability to keep patients on, that's where our team has been focused this last quarter, and that's where we're seeing that come through. So I think you need all three to answer your question. Now, when you look at the segmentation, I think it's important to point out that we're seeing new patient starts not just in the academics, but also in the community, right? And so we need to win in both places. And so overall, I think it's a bit of all three, but we are focused on those new patient starts as well as keeping patients on. Michael?

Yes, just one last, just to add on to what Dan said. I think unlike most of the G12D inhibitors, and in fact some of the pan-RAS, our PK continues to climb as we go up from 400 to 600 to 900, and you guys have seen the data, we've made it public. That has not generally been seen with the other drugs. Generally they tend to threshold out and more drug doesn't deliver higher exposures. And we believe and we will assert that we're seeing that. We can get more consistent responses, deeper responses, and we believe eventually more prolonged responses because of that at very tolerable doses.

I'll just add also that our main side effects which are nausea, vomiting, and diarrhea, really not much else, that are at levels that are actually below most of the pan-RAS inhibitors. We have no rash and no mucositis. When we go up on the dose, we don't see any increase, and this is likely due to an irritant effect of the drug rather than a particular effect of the drug when it circulates. So it irritates the stomach and causes some GI distress, but going up on the dose doesn't matter. I think we'll see all that manifest in the clinical data we'll have in October.

Thank you. Next, we have a question from H.C. Wainwright. Caller, please go ahead and introduce yourself and ask your question.

Just a quick one on the commercial frontier. I think you guys touched upon it, but I would appreciate a little bit more color. On the, you know, how much of the prescribing is moving into first and next recurrence? And if that's happening, can you talk about if that's happening beyond the major academic centers? And then on the flip side, you know, how are the potential for dose interruptions or reductions if needed, and if they're helping patients maybe stay on treatment longer? And then a quick one from the TARGET-D developmental strategy. So particularly for CRC, I guess, you know, we just saw data recently from the KRYSTAL-10 study, obviously different inhibitor, different subset. What would justify continuing 7375 monotherapy without an EGFR inhibitor? Thank you very much.

So, just real quickly on the CRC, you know, we don't intend to develop it as a single agent. It's going to be with an EGFR inhibitor. That's really what's needed in CRC. Dan Lyons, you want to really give a little more color on the commercial question?

Thanks, [ Andre Salvinato ]. So, I think there was two questions in there, line of therapy and then dose interruptions. So let me try to tackle both. We're very encouraged by what we're seeing. I mean, we do not have full visibility into our data, but what we are seeing, we're very encouraged that we are moving up in line of therapy. This is not only in the academic, but also in the community. And it goes back to our messaging around being the treatment for the first or next recurrence. And so the data we're seeing is encouraging there and we're going to continue to focus on that.

In terms of dose interruptions, dose interruptions were part of our clinical trial. We expect some dose interruptions with this treatment. I think the important part is limiting that time by providing that support for practices so they understand how to manage dose interruptions and when appropriate, having patients restart at the starting dose of the avutometinib and defactinib combination. And so that's how we're seeing things. And I think the overall focus and collaboration we've seen across the teams on line of therapy, on managing AEs, managing dose interruptions, has been something that throughout Q2 continue to build.

Thank you. [Operator Instructions] Next in the queue, we have a question from BTIG. Caller, please go ahead and introduce yourself and ask your question.

So two questions from me. When it comes to 7375 and thinking about other partner agents, PRMT5, for example, are you inclined to look to strike another partnership similar to the one that you did with Erasca or is in-licensing your own PRMT5 inhibitor something that's available as well. And then as a second question, just could you remind us what you have aligned with the FDA on in terms of the bar for approval across your various TARGET-D trials?

Yes, I will just say on the PRMT5, we're exploring all options. There are a number available for either, you know, kind of partnerships around a clinical trial, and there are some agents that are available, and we haven't ruled anything out. Michael, you want to comment more on the accelerated approval?

Yes, the FDA, and I've been through three, actually five accelerated approvals. The FDA has never told us what they need, but we can all look back at the numbers. I mean, they're always north of 20%. Typically these days they'd like to see 30, but I just mentioned on the phone call a recent approval today, I think, or yesterday in melanoma, which was 24%. I think durability really matters. But generally, I think the 30% ORR with at least six months durability is a great rule of thumb. We also know in colorectal that it's combo therapy.

We know from the accelerated approval there with the combination what we need, similar numbers. And although it's not yet been done in pancreatic, certainly in lung, we've seen accelerated approvals with these kinds of numbers and even higher. And then we feel like we're in very good shape to achieve those.

And I might add, based on the accelerated approval we went through with our current product, you know, yes, response rate and durability are critically important, but it was the totality of the data, and they absolutely look at tolerability.

Thank you. And our final question from Alliance Global Partners. Caller, please go ahead and introduce yourself and ask your question.

I had one on doctors with patients who have KRAS G12D-mutant patients. So these patients in the coming months, there's going to be a decision process for these doctors to either put them on an approved RAS inhibitor, pan-RAS, or to put them on a trial like yours. What does that decision process look like for each doctor, and how do you plan to differentiate your clinical trials from an approved RAS inhibitor product? Thanks.

Matthew, thanks for the question. Michael, I know that's come up specifically at the ad boards we've been having with our investigators. Maybe if you want to comment on that.

Sure. The discussion is fairly straightforward with patients. Anytime you have a discussion of a new drug, particularly oncology, it's an efficacy and a tolerability discussion. So that's the discussion they'll be having. To a tee, I mean, I think amongst, I would say, around 30 different key opinion leaders participating in three different ad boards, colorectal, pancreatic, and lung, everyone agreed that given our tolerability profile and the data that they were privy to, they would recommend for a G12D patient that they go on to a G12D specific drug. They particularly liked ours because of what they saw. Of course, they were at our ad boards. And then they would come out with a pan-RAS inhibitor later, given the very significant reaction stomatitis, but also, frankly, the higher levels of even nausea, vomiting, and diarrhea, as well as other side effects.

So targeted therapy for patients with a tumor that has a targeted oncogene, that's not a new concept at all. That is targeted molecular oncology, and that's what we like to do.

Got it. Great. Thanks, guys. Thanks for taking my questions.

At this time, we have no further questions in the Q&A queue. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, and welcome to Verastem Oncology's VS-7375 R&D Update Conference Call. My name is Towanda, and I will be your call operator today. Please note, this event is being recorded. [Operator Instructions] I will now turn the call over to Julissa Viana, Senior Vice President of Corporate Communications, Investor Relations and Patient Efficacy at Verastem Oncology. Ma'am, you may begin.

Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss our potential best-in-class, highly selective oral KRAS G12D on/off inhibitor, VS-7375. We will share progress from our Target-D clinical development program, including preliminary data from the Target-D 101 dose escalation and dose expansion trial. This afternoon, we issued a press release detailing these results, along with a slide presentation that we will reference during our call today. Both are available on the Investor Relations section of our website.

Before we begin, let me point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional details. Joining me in today's call to deliver prepared remarks and take your questions are Dan Paterson, President and Chief Executive Officer; Dr. Michael Kauffman, President of Development; and Dr. Jonathan Pachter, Chief Scientific Officer. I will now turn the call over to Dan.

Thank you, Julissa. Good afternoon, and thank you for joining us today. We're excited to share the progress we've made across the VS-7375 development program and to discuss why we believe 7375 is a potential best-in-class, highly selective oral KRAS G12D on/off inhibitor that could become the preferred treatment option for patients with KRAS G12D mutated cancers.

Today, more than 60,000 patients are diagnosed each year in the U.S. alone with a cancer harboring a KRAS G12D mutation. Which has the worst prognosis of the RAS mutations and yet there's no approved treatment specifically targeting this mutation. Our conviction in VS-7375 is grounded in the design of the molecule, its differentiated preclinical profile and the emerging clinical profile generated to date. While broader RAS inhibition strategies have helped to demonstrate that RAS remains one of the most important targets in cancer, greater selectivity may ultimately prove advantageous.s

By specifically targeting KRAS G12D, we avoid unnecessary toxicities that are on target for a pan-RAS inhibitor, but not with a selective KRAS G12D inhibitor. Precision targeting has transformed cancer treatment across multiple tumor types, and we believe that in 2026, we must apply these same principles to KRAS G12D mutated cancers. Selectively and potently inhibiting the cancer driving mutation in both the on and the off states could provide meaningful advantages over approaches that target the on-only or off-only KRAS protein or broader RAS inhibition strategies.

As you'll see from the data we present today, we believe many patients with KRAS G12D mutated cancers will require deep and durable pathway suppression to achieve meaningful improvements in outcomes. That belief has guided the design of VS-7375 from the very beginning and continues to inform our development strategy. Our goal was straightforward, develop a highly selective and orally bioavailable KRAS G12D inhibitor capable of delivering meaningful efficacy with favorable tolerability that would be expected by targeting a specific oncogenic driver mutation.

To achieve that, we focused on selectively targeting the KRAS G12D variant to enable deeper and more potent sustained inhibition of the intended target without affecting normal RAS-mediated pathways. And we selected a candidate molecule that could hit the target hard and could support broad combination strategies that are often preferred in order to maximize patient outcomes. These principles continue to guide the program today.

As we advance the development of VS-7375, we've seen evidence that it's delivering on the attributes we set out to achieve. 7375 has demonstrated deep target inhibition, prolonged target engagement and a differentiated on-off inhibition profile designed to drive deeper pathway suppression. Importantly, VS-7375 has shown good oral bioavailability and sustained exposure that increases as the dose is raised. Along these lines, we are particularly pleased with the PK and the associated preliminary antitumor activity and tolerability results we've seen with the 900-milligram once-daily oral dose.

We've also been encouraged by the antitumor activity seen at the 600-milligram dose. However, the exposure at 900-milligram delivers the target coverage based on preclinical models without a trade-off and increased adverse events. Collectively, these characteristics support the potential for a best-in-class efficacy with a differentiated side effect profile while also enabling combination development strategies and opportunities to address areas of high unmet need, including in the frontline treatment settings.

Overall, these attributes have given us increasing confidence in the potential of VS-7375 as a preferred oral KRAS G12D inhibitor. Today, we believe that VS-7375 is positioned competitively to treat the major KRAS G12D mutated cancers. First, we have a differentiated profile versus other RAS inhibitors. We believe our truly dual on-off inhibition and long target residence time are exactly the mechanisms you need to drive deep and durable responses.

As Michael will share shortly, the emerging antitumor activity we are seeing in our Target-D 101 Phase I/II trial has the potential for VS-7375 to be the best-in-class KRAS G12D inhibitor. Let me be clear, we see efficacy at the 600-milligram dose that we're excited about, but we're also seeing a dose response at 900 milligram, which reinforces our decision to bring this dose forward into our Phase II trials.

We've also demonstrated that our safety and tolerability profile is consistent with the selective nature of targeting KRAS G12D, distinguishing it further from pan-RAS approaches that have major toxicities. This emerging tolerability profile allows us to go higher in dose, but also makes it possible for us to combine with multiple standard of care agents.

Furthermore, our emerging safety profile shows little to no rash in mucositis, which are quite prevalent with pan-RAS inhibitors. Further on our combination strategy, the preclinical data that John will share will help you understand some of the paths we're pursuing. And as announced today, we intend to enter into an agreement to evaluate VS-7375 in combination with ERAS-0015, Erasca's investigational and potential best-in-class oral pan-RAS molecular glue in advanced KRAS G12D mutant solid tumors.

In addition, we plan to evaluate VS-7375 in combination with a PRMT5 inhibitor as soon as possible. Lastly, we have multiple paths to registration. We're working quickly to enroll patients into our Phase II Target-D trials, ultimately to deliver a compelling data package to the agency for potential accelerated approval. To summarize, the data generated to date reinforce our belief that VS-7375 has the potential to become the best-in-class KRAS G12D inhibitor.

As we look next at the market opportunity, there's clearly a need for new treatment options because of the sizable patient population that remains underserved today. Approximately 40% of pancreatic cancers, 15% of colorectal cancers and about 5% of lung cancers harbor a KRAS G12D mutation with a total addressable market in the U.S. alone in excess of $2.5 billion.

In each of these cancers, the KRAS G12D mutation is associated with a particularly poor prognosis. Therefore, beyond the numbers of patients that could potentially benefit, we have an opportunity to fundamentally alter the prognosis for patients whose tumors harbor this bad-acting oncogene. In addition to our initial Phase II programs focusing on previously treated pancreatic, colorectal and non-small cell lung cancers, we see VS-7375 moving rapidly into the frontline setting, typically as part of combination regimens to optimize outcomes at this critical treatment stage.

As you'll hear today, our goal is to expeditiously generate data that will address the majority of the unmet need and maximize patient benefits across major KRAS G12D tumor types. I'd now like to turn it over to Michael to give an update on our clinical development of VS-7375. Michael?

Thanks, Dan. As Dan outlined, VS-7375 is being developed with a clear objective to maximize the opportunity to deliver meaningful outcomes for patients living with each of the major KRAS G12D mutated cancers. We have strongly executed against this vision. In the first half of 2026, we rapidly advanced a broad clinical development program for VS-7375 by enrolling more than 150 patients in our Target-D 101 Phase I/II dose escalation and dose expansion trial, initiated 3 registration-directed Phase II trials in pancreatic, colorectal and non-small cell lung cancers, and we're on track to initiate 3 pivotal Phase III trials in these indications by the first half of 2027.

That is an ambitious development strategy. As I have said time and again, this is why I decided to step inside the company in December of last year. Programs are not advanced at this pace without firm conviction and laser-focused delivery each and every day. We will now share some of the clinical data across the tumor types that are driving our development strategy and why we've chosen to continue to prioritize all 3 indications as we work to bring VS-7375 to patients as quickly as possible.

Before diving into the data by tumor type, let me highlight 4 key takeaways from the clinical experience to date. First, we are observing encouraging antitumor activity across pancreatic, colorectal and non-small cell lung cancers as well as in other KRAS G12D mutated cancers like biliary tract cancer. Second, the safety and tolerability profile is very different from the experience our partner in China has shared.

Most importantly, we have observed primarily low-grade nausea, vomiting and diarrhea and the majority of these adverse events attenuate after the first cycle of dosing. Third, the emerging profile of VS-7375 supports combination strategies with full dose standard of care therapies that we believe can further enhance patient outcomes. And finally, we have dosed the first patient in our registration-directed Target-D 201 Phase II PDAC trial last week and anticipate dosing the first patients in our other registration-directed Phase II trials very soon.

All of these trials will support discussions with the agency around an accelerated approval pathway. With these takeaways in mind, let's get into more detail about the Target-D 101 Phase I/II trial and the progress we have made. As a reminder, here is our Phase I Target-D 101 trial design. Overall, we are making a lot of progress across our program. We have enrolled more than 150 patients across the dose escalation and dose expansion cohorts seen on the slide. We are exploring a 1,200-milligram once-daily dose as dose-limiting toxicity has not occurred in the 900-milligram cohort.

While I won't touch on it further today, let me say that we are continuing to enroll patients in our tumor-agnostic cohort, and we're excited to see antitumor activity in cancers like biliary tract cancers. We will share more on this cohort in the future. Now let me discuss our updated PK findings. As described previously, based on achieving at least 30% reductions in animal tumors in our 4 key preclinical models, similar to the threshold required by RECIST solid tumor response criteria in humans, we were aiming for human exposures of at least 2,000 nanogram hours per ml.

These levels are highly correlated with the most optimal outcomes in mice and occurred at well-tolerated doses there. We are extremely pleased to confirm that the majority of patients treated at 900 milligrams who have had PK testing have shown steady-state exposures at or above this important level. We believe that VS-7375 is among the only RAS-targeting agents to demonstrate dose-dependent exposures, thus enabling optimal human PK that is associated with well-tolerated doses driven by its high oral bioavailability.

Now let me turn to our PDAC update. In our metastatic pancreatic cancer cohorts, preliminary data demonstrate dose-dependent antitumor activity across the 600-milligram and 900-milligram dose levels. In addition, the anti-EGFR combination cohort has demonstrated preliminary evidence of deeper and more rapid responses relative to monotherapy. Importantly, the vast majority of patients have not yet reached 6 months of follow-up.

As we prepare to enter the first-line metastatic pancreatic cancer setting, we are evaluating VS-7375 in combination with standard of care gemcitabine plus nab-paclitaxel, which I will refer to as Gem/Nabpp. The combination of VS-7375, 600 milligrams and full dose Gem/Nabpp has cleared dose-limiting toxicity evaluations in patients with previously treated PDAC and the enrollment of the VS-7375-900-milligram cohort plus full dose Gem/Nabpp is ongoing.

We expect to report preliminary first-line combination data in the second half of 2026. In addition to the usual CT scans, which are essential for evaluating patients with PDAC, about 85% of patients have elevated levels of the tumor marker CA19-9 in their blood. This tumor marker is often used to follow disease because it's easily obtained and generally correlates with tumor mass. While CA19-9 changes are not an accepted regulatory endpoint, reductions in CA19-9, particularly when they occur early in the disease treatment course, have been shown to correlate with improved progression-free survival, overall survival as well as overall response rate.

And despite the limited follow-up in our 900-milligram PDAC cohort, 13 of the 14 patients with elevated baseline CA19-9 levels have achieved at least a 50% reduction in their CA19-9 with several showing greater than 90% reduction. As shown in the graph, these reductions are quite rapid, typically manifesting at the first testing point at 3 weeks. These rates of over 50% reduction in CA19-9 levels are substantially higher than those reported for combination cytotoxic chemotherapy regimens, typically used in the treatment of both relapsed and even in frontline PDAC.

As the median number of prior therapeutic regimens in this 900-milligram cohort is 2, these early results give us confidence that VS-7375 can confer substantial antitumor activity even in patients with heavily pretreated chemotherapy-refractory pancreatic ductal adenocarcinoma. Now let's take a look at 2 patient case studies from our ongoing 900-milligram PDAC cohort. The first patient is a 55-year-old male diagnosed with KRAS G12D mutated metastatic pancreatic cancer who received intensive chemotherapy with FOLFIRINOX for 4 months, whereas best response was stable disease and then the tumor progressed.

He was then treated with Gem/Nabpp for only 2 months when his disease progressed. The patient then began treatment with single-agent oral VS-7375 at 900 milligrams once per day. As you can see on the baseline CAT scan, tumors were present on his liver and pancreatic surgical bed outlined in orange dot outlines. We paced the same orange dot outlines into a subsequent scan. Following 12 weeks of treatment with VS-7375, the tumor shows a confirmed partial response for RECIST with a reduction of 47% in the sum of the longest diameters or SLD of the target lesions.

The investigator also reported substantial pain resolution within 1 week of initiating treatment with marked reduction in the use of any opiate pain medications. This response is ongoing at this time, and the patient's treatment duration has already exceeded that of both frontline FOLFIRINOX and second-line Gem/Nabp. Most remarkably, this patient has experienced no treatment-related adverse events. Now turning to our second case study, which is more recent, but strengthened some of our observations above. This patient, a 79-year-old woman diagnosed with PDAC, who received frontline Gem/Nabp for 6 months and then Nanoliposomal irinotecan for 11 months and then FOLFOX for 3 months.

She entered our trial with substantial abdominal pain and dysistension caused by peritoneal carcinomatosis and [indiscernible]. In which the tumor encase the bowels and induce fluid accumulation in the peritoneum, which tends to be very uncomfortable with marked bloating, indigestion, reduced appetite and weight gain. Within 2 weeks of initiation of VS-7375 therapy, the treating physician reported that the patient's abdominal pain and distension had resolved.

In addition, this patient had an extremely elevated CA19-9 at baseline, over 17,000 units per ml, normal being less than 37 units per ml. At week 3, the CA19-9 level had already dropped more than 60%, and it fell over 97% at week 6 and more than 99% to 117 units per ml at week 9. Let's remember that declining CA19-9 following initiation of therapy is predictive of better outcomes.

Along these lines, the week 6 CT scan assessment showed complete resolution of the target lesions along with marked resolution in ascites. Of note, there were apparently nontarget lesions that could not be assessed properly due to the residual ascites and the CA19-9 tumor marker had not yet reached the normal range. And therefore, this is considered a partial but not a complete response. Her main adverse events, which have been transient were diarrhea, fatigue and anorexia. The patient is early on in her treatment course, but initial results appear to be highly promising.

Although it's likely fairly obvious, it's worth emphasizing that the side effects that these patients have experienced on VS-7375 are substantially better than those that they tolerated during multi-agent cytotoxic chemotherapy. Now let's turn our attention to a case which was inspired by our preclinical work. In this case, you will see that the compelling preclinical data describing the combination of VS-7375 with the anti-EGFR therapy, cetuximab that we've shared publicly before is beginning to manifest in patients.

Please note that anti-EGFR agents have essentially no activity themselves against KRAS-mutant PDAC as well as other KRAS-mutant cancers, including colorectal cancer. This patient is a 64-year-old man diagnosed with KRAS G12D mutated pancreatic cancer. The patient had previously received FOLFIRINOX plus radiotherapy with a partial response and then progressed and was treated for only 3 more months with FOLFIRINOX before progression occurred again. Let's recall now that the 400-milligram dose of VS-7375 alone has not shown significant activity against PDAC. He was treated with the subtherapeutic dose of VS-7375 that is 400 milligrams, but this time in combination with cetuximab.

As you can see from the baseline scan, tumors were present on his pleura and an mediastinal Lymph Node. He also had lung lesions, which were causing substantial shortness of breath. Within 1 week of initiating treatment, his shortness of breath resolved. At the week 6 CT scan, the tumor reached a PR by RECIST with a 46% reduction in the sum of the longest diameters of these lesions. At the week 12 scan, the patient's response continued with a 70% reduction in the maximum diameters of these lesions, thus confirming the partial response.

Again, as discussed previously, the patient also saw a significant drop in CA19-9 levels by week 3, starting at nearly 1,000 and dropping to less than 200 units per ml. The patient experienced several treatment-emergent adverse events that the investigator believes were not attributable to VS-7375, but instead were due to metastatic PDAC and in the case of the maculopapular rash due to cetuximab. Overall, again, as compared with typical multi-agent chemotherapy, tolerability to the combination regimen appears quite good.

Now let's turn our attention to colorectal cancer. Preliminary data demonstrate antitumor activity observed at both the 600-milligram and 900-milligram dose levels in combination with the anti-EGFR therapy in patients with heavily pretreated metastatic colorectal cancer. VS-7375 at the 900-milligram dose level in combination with cetuximab was DLT cleared last month. Consistent with observations in the emerging PDAC cohorts, no overlapping toxicity between cetuximab and 7375 has been observed to date.

Importantly, all patients receiving the 600-milligram dose in combination with cetuximab have less than 6 months of follow-up. Looking ahead, evaluation of the 900-milligram dose level in combination with cetuximab will occur in the Phase II registration-directed Target-D 203 clinical trial, which will begin enrollment shortly. As we know, more and more patients under 50 are being diagnosed with CRC, underscoring the need for effective treatment options.

As you will see in this next case, we treated such a man in his early 40s. Prior to participating in our trial, a 42-year-old man diagnosed with KRAS G12D mutated colorectal cancer had received all standard of care agents, including bevacizumab and TAS-102 Lonsurf as well as 2 investigational agents. He had massive and diffuse metastatic disease upon entry into our trial. The patient was treated with 600 milligrams once daily 7375 in combination with cetuximab.

As you can see on the baseline CT scan, massive tumors enclosed by the orange dotted areas were present in his liver on the top left and in both lungs on the bottom left scan. The darker areas in the liver and the white areas in the lung are tumor. The total sum of the longest diameters or SLD, was 370 millimeters or over 14.5 inches of tumor at baseline. We also note that liver metastases from CRC are typically refractory to chemotherapy.

At the week 6 scan, the patient achieved a reduction in the SLD of 28%, meaning that 4 inches of tumor disappeared from a CT scan. At the week 12 scan, the patient's response continued with a reduction of 29.6% from baseline, and he continues to do well. We also note that the tumor marker CEA, which is the most common marker in CRC, elevated in over 70% of patients was highly elevated at initiation of treatment at 4,000 nanograms per ml, normal being less than 3 nanograms per ml.

The patient's CEA level, the carcinogenic antigen level showed a marked and rapid drop by nearly 90% since therapy was begun, again, consistent with his radiologic findings. The investigator also reported that abdominal distension was nearly completely resolved within several weeks of initiation of therapy. The patient develops cetuximab-induced acneiform rash, which is common and occurs in over 80% of patients treated with this agent, but it is managed well and rarely results in treatment delays. No VS-7375associated events were reported.

As noted above, we will be enrolling patients at 900 milligrams of 77375 plus cetuximab in the Target-D 203 study, which should begin shortly. We expect to have more data by year's end with this regimen. Now let's talk about observations we've seen in non-small cell lung cancer. We have observed promising preliminary efficacy at the 600-milligram dose, and we believe that 900 milligrams can deliver best-in-class efficacy due to dose response observations.

As we've stated for the other cohorts, the majority of patients have had less than 6 months of follow-up. For the 900-milligram dose, we will be evaluating that dose in the Phase II Target-D 202 study, which will begin shortly. In addition, evaluation of VS-7375 in combination with carboplatin, pemetrexed, pembrolizumab is ongoing and is expected to be DLT cleared over the summer months.

Our plan is to then test this combination with 7375 in a randomized study in the first-line setting. Now let's take a look at a patient case study. This patient is a 77-year-old female diagnosed with KRAS G12D mutated advanced NSCLC. Initial treatment for this patient was standard pemetrexed carboplatinum and pembrolizumab, which has shown variable and typically lower activity against KRAS G12D mutated non-small cell lung cancer in retrospective analyses. Consistent with these observations, the patient had a best response of only stable disease on this triplet therapy and was treated for only 4 months prior to progression.

The patient was then treated with 600 milligrams of single-agent oral VS-7375. As you can see on 3 sections of the baseline scan in the left column, tumors, the white masses surrounded by orange highlights were present throughout her lungs. The patient had a partial response at 6 weeks, which is shown here, and the PR was subsequently confirmed at week 12 with a 49% reduction in SLD.

The investigator also reported that shortness of breath and tumor pain had improved within a few weeks of dosing initiation. The patient experienced treatment-related Grade 3 diarrhea, which was controlled quickly with standard agents. The dose was temporarily reduced to 400 milligrams and then reescalated to 600 milligrams after several weeks with only grade 1 residual intermittent diarrhea. Before turning to our updated safety, these cases demonstrate the potential of VS-7375 to markedly alter the course of disease in patients with heavily pretreated chemotherapy refractory tumors with adverse events that are easily managed.

In my last section, let's cover the emerging safety and tolerability profile. First, as a physician and a drug developer, I think it's very important to distinguish between safety, toxicity issues as well as tolerability issues. As we all know, current chemotherapies and some target agents can cause significant toxicities that can be cumulative and/or life-threatening. In contrast, we have been quite encouraged about the emerging profile of VS-7375, which to date is characterized primarily by tolerability issues, including low-grade nausea, low-grade vomiting and diarrhea, which attenuate after the first cycle. And these are tolerability issues that do not appear to represent major toxicities.

In fact, we've not yet identified significant major safety issues associated with VS-7375. The majority of the GI side effects are effectively managed with standard supportive care measures. All patients are advised to take VS-7375 with food, which is generally good advice anyway for patients with any cancer. Our patients receive 5-HT3 antagonist prior to initiating therapy, strongly recommended through the first 2 cycles and can receive additional medications as needed after starting treatment.

You will also see that the rates of these common GI side effects are similar at the 600 milligrams and 900 milligrams cohorts, consistent with a localized irritant effect of the drug product rather than a systemic toxicity, which would generally show a dose dependence. No unexpected adverse events were observed and rates of Grade 3 adverse events remain low. When they do occur, such as the Grade 3 diarrhea, they are transient and manageable. Importantly, no clinically meaningful cytopenias or liver function abnormalities have been reported, and we have not yet observed any clinically significant cumulative toxicities. No Grade 4 or 5 events have been reported to date.

Now let's turn to the treatment-related adverse event tables. On this slide, I will highlight a few key points. As of June 12, 2026, VS-7375 monotherapy has demonstrated a favorable safety profile with manageable AEs in the Target-D 101 Phase I/II trial, including 57 patients at 600 milligrams and 25 patients at 900 milligrams. Note that combination therapies are not included in this table and will be reported in the coming months.

As you can see from the tables, about half the patients have diarrhea and half have nausea, mostly Grade 1. Grade 3 events are uncommon, and there are no grade 4 or 5 events across all of the patients to date, including at 900 milligrams. There is another aspect of the safety data that I think is particularly noteworthy. Investigators were reporting to us that the GI complaints largely abated during the first cycle of treatment.

In order to evaluate this more quantitatively, we looked at AEs for patients continuing in cycle 2 and beyond, which is the majority of the patients. Across the 73 patients shown on the slide who continue treatment beyond cycle 1, the GI adverse events have decreased by more than 50% and the severity is primarily grade 1. There was no rash or stomatitis, no significant liver function abnormalities, minimal Grade 3 events and again, no grade 4 or 5 events. These data support the observations that patients quickly develop tolerance for the GI events, and this bodes well for very long-term dosing with VS-7375.

Now let's turn our attention to the status of the Phase II and III trials. As we close out enrollment of the Target-D 101 program this month, we're also advancing the next stage of development for VS-7375. Last week, on June 16, we announced the first patient has been dosed in the Target-D 201 Phase II registration-directed trial evaluating VS-7375 to treat patients with KRAS G12D mutated second-line PDAC.

This trial involves randomization to either 900 milligrams of 7375 alone or in combination with standard biweekly cetuximab, andatumumab can be substituted in patients with potential cetuximab allergy. We expect the first patients to be dosed in both the Target-D 203 registration-directed metastatic CRC trial and the Target-D 202 registration-directed advanced NSCLC trial by mid-2026.

We expect to enroll the last patient across all of these 3 Phase II protocols by the end of this year. We're also making progress with our trial designs for 3 frontline Phase III pivotal trials for the metastatic PDAC, metastatic colorectal and advanced metastatic non-small cell lung cancers, and we're planning to meet with the FDA before the end of this year to reach agreement on these 3 Phase III designs. We expect the first patient to be dosed in each of these trials by no later than the first half of 2027. Amazing progress in a short amount of time and much more to come. Now I'll hand it over to John to give you a sense of the future potential combinations to improve patient outcomes. John?

Thanks, Michael. VS-7375 is optimized with several properties that make it the potential best-in-class RAS inhibitor for treatment of patients with KRAS G12D mutated cancers. As Dan outlined earlier, VS-7375 is extremely potent against both the on and the off states of KRAS G12D, approximately 15 picomolar, and it has a particularly long residence time of 18 to 24 hours when it binds KRAS G12D.

It is extremely selective for KRAS G12D in contrast to pan-RAS inhibitors such as Daraxonrasib. This selectivity of VS-7375 spares T cell proliferation and avoid side effects such as rash and stomatitis. And importantly, VS-7375 shows once-daily oral dose-dependent exposure in patients. The fact that the pharmacokinetics are not saturating at higher doses enables VS-7375 to maximally inhibit its KRAS G12D target.

As we announced today, a key part of our development strategy will be with novel combinations to further extend survival for patients beyond what can be achieved with a RAS inhibitor alone. Here, we studied combinations of VS-7375 or the on-only G12D inhibitor Zoldonrasib with the pan-RAS tri-complex inhibitor daraxonrasib in a KRAS G12D pancreatic cancer model.

Although the combination of Zoldonrasib with darxunasib conferred more durable tumor growth inhibition than Zoldonrasib or darxunrasib alone, we see that single-agent VS-7375 gave more durable efficacy than the Zoldonrasib-Daraxonrasib combination. What is especially impressive is that combining our dual on/off G12D inhibitor 7375 and a pan-RAS on-on inhibitor, in this case, Daraxonrasib conferred extremely durable tumor regression.

And based on data such as these, we will be collaborating with Erasca to test the combination of VS-7375 with Erasca's potentially best-in-class pan-RAS inhibitor, ERAS-0015 in patients with KRAS G12D pancreatic cancer. In our efforts to identify and pursue the best combinations with VS-7375, we've been extremely impressed with the strong durable tumor regressions we achieve when we combine VS-7375 with a PRMT5 inhibitor across pancreatic cancer models with KRAS G12D mutation along with MTAP deletion.

KRAS G12D mutations together with MTAP deletion occurs in approximately 10% to 12% of patients with pancreatic cancer. As you can see here, combination of VS-7375 with BMS' PRMT5 inhibitor, nemetostat gives extremely durable tumor regression. In this patient-derived model, all animals achieved a durable complete response with this combination. Building on these preclinical data, Verastem is also working to enable a clinical combination with a PRMT5 inhibitor as soon as possible. With that, I will turn it back over to Dan.

Thanks, John. Before we open it up to Q&A, I want to leave you with 3 key takeaways. First, we continue to strengthen our conviction that VS-7375 has the potential to become the preferred treatment for patients with KRAS G12D mutated cancers. The field has evolved from broad chemotherapy approaches to inhibition of RAS broadly, and we believe VS-7375 represents the next step in the evolution through its selective targeting of KRAS G12D across major tumor types, including pancreatic, colorectal and lung cancers. Second, what excites us most is not any single data point, but the overall story that's emerging.

We're seeing encouraging efficacy signals across tumor types, a safety and tolerability profile that supports the potential for long-term administration and evidence that VS-7375 can be successfully combined with standard of care therapies. Taken together, these attributes position VS-7375 to deliver the efficacy needed to be practice-changing while offering a differentiated profile over other KRAS G12D or pan-RAS inhibitors. It has the potential to establish VS-7375 as a best-in-class therapy for KRAS G12D mutated cancers and the foundation of a meaningful franchise in solid tumors.

Third, while today, we focused on VS-7375, we remain equally focused on execution across our business. [indiscernible] in co-pack continues to perform well, and we're pleased that the changes we've made are having an impact. Since the first quarter, we've seen a rebound in strong physician conviction, putting us back on track with our expected growth trajectory. We look forward to providing an update in August during our second quarter earnings call. I also want to acknowledge our announcement last week regarding the results of RAMP-205.

These data show that Avutometinib plus defactinib in combination with Gem/Nabp delivered efficacy equivalent to the best results reported to date, and we believe VS-7375 has the potential to deliver the same efficacy with a more tolerable side effect profile. And as we said, we will continue to evaluate the potential role of avutometinib and defactinib in metastatic pancreatic cancer, including combinations with 7375 and potential strategic collaborations informed by the overall final survival results from the study as well as emerging data from VS-7375.

Overall, we've had a disciplined first half of the year focused on execution. We're excited by the tremendous progress we've made with VS-7375, and we look forward to providing a more mature clinical update with appropriate patient follow-up in the second half of 2026. With that, let's open the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Cantor Fitzgerald.

It's Eric Schmidt. I appreciate the very comprehensive program update, and congrats on the execution progress with 7375. Maybe just a quick question on the Erasca collaboration. Can you give us a little bit more detail on which party is going to be designing the studies? Is the primary responsibility for running the trials, either at Verastem or Erasca? -- who's going to be paying for the work as well?

Eric, thanks for the question. We actually haven't really released any details on it yet. As you can imagine, we're in the process of having discussions with others around other partnerships and don't want to impact those. As we get closer to it, we'll give a little more detail, but we're very excited to have agreed with them to do a study together.

And Dan, are we expecting that we'll get a PRMT5 announcement in the not-too-distant future, too? It sounds like you're alluding to something now.

Yes. That's probably a good bet.

Our next question comes from the line of Guggenheim Securities.

It's Michael Schmidt with Guggenheim. Congrats on the update. A couple of questions. Nice to see the progress and towards launching the registration-directed Phase II studies actually. So any updated thoughts on how you think about the approval hurdle potentially in terms of efficacy for those 3 Phase II studies in these -- across the 3 indications?

Yes. Michael, thanks for the question. Michael, why don't you take that one?

Sure. So the paths are pretty well set out in lung and colorectal cancer in lung single agent, generally activity that FDA and investigators and patients get excited about is a single-agent response rate north of 30% with a durability of 6 months or better. These are pretty good metrics. Obviously, we intend to do better than those. Colorectal cancer has also been worked out through the G12C RAS inhibitors in combination with either cetuximab or panitumumab.

Again, response rates greater than 30%. Durability 6 months or better generally gets it. So I think those areas have precedent for sure. Obviously, pancreatic cancer is undergoing the kind of renaissance we saw back with colorectal G12C cancer and to some extent, some of the targeted therapies in lung cancer now. And we're going to be working with FDA along with lots of other companies to map out a path for accelerated approval there.

We believe that a combination of both good response rates, again, north of 30% single-agent response rate with a good durability and importantly, a side effect profile that we think is second to none. So we're keeping in mind that accelerated approval can include efficacy and/or safety substantial improvement over available therapies or both, and we intend to win on both. And the last thing I'll say is that there are no agents currently in pancreatic cancer that can deliver a single-agent response rate anywhere close to 30% or 35%.

Obviously, dxasib is in the 35% range for second line. We think we can do at least that well, if not better. And we think we can deliver a side effect profile that is much, much easier to tolerate than a pan-RAS inhibitor.

Okay. And then I guess just confirming, has the FDA agreed to an accelerated approval strategy in general across these indications? Or is that still TBD? And then as you think about upcoming discussions around the planned Phase III studies, in pancreatic cancer specifically, what are possible trials that you're considering given potential changes to the landscape. You have the cetuximab combination in addition to the chemo combo. So what could a possible Phase III study look like in PDAC specifically?

Michael, do you want to take that?

Yes. So look, I've been -- as you know, we've known each other a long time. I've been through 3 success -- 4 successful accelerated approvals in my life, and there always an uphill battle no matter where they are. I think FDA is more open to them now, especially with agents that have good tolerability profiles. The FDA told us at the beginning that we had to take the Target-D 101 Phase I/II study and break it into separate disease-specific studies that is the Phase II studies, if we wanted to go for a pivotal trial in terms of accelerated approval, and that's what we did.

Obviously, they will hold us to a very high bar, which will be determined, but we are engaged with those discussions. And as you alluded to, in all 3 of the cancers. And as you alluded to, a major component of any accelerated approval is that your confirmatory typically randomized study has to be ongoing at the time of regulatory action. And we are engaging with FDA in the coming months before the end of the year, for sure, to discuss the Phase III trial designs across all 3 different tumor types.

In pancreatic cancer, as you alluded to, we have a few options. We are actively working on the dose that we're going to select for combination of 7375 plus Gem/Nabp in frontline, and we have cleared the 600-milligram cohort already, and we are investigating 900 milligrams. We've seen really good tolerability of the combination. We've had no need to reduce either drug on either side. So we will see.

The 900 should clear hopefully in the next coming months, and then we'll be able to move ahead with that as one of the components of the Phase III. The other component of the Phase III will either be most likely either be a 7375 monotherapy or if the data with cetuximab continue to look as good as we hope they will, it will be a combo with cetuximab, and that would be another experimental arm. And then, of course, this will be against dealer's choice or investigator's choice combination chemotherapy, either FOLFIRINOX or Gem/Nabpp in the control arm. So it will be most likely a 3-arm trial with 2 arms with the 7375, including a potential chemo-free arm.

Our next question comes from the line of RBC.

It's Leo from RBC. I wanted to ask on the CA19-9 biomarker. Maybe you can expand a little bit more on how reliable it is and maybe how it correlates to both response rate and then ultimately, overall survival. I mean you've mentioned sort of 50% reductions on that biomarker. I mean, how meaningful of a marker is that for driving a partial response? And I guess, ultimately, is this marker going to be more of a leading or a lagging indicator of the tumor, just noticing there's some variability in the baselines and some patients appear to have it at baseline not. So maybe if you could just expand on how valuable this marker is.

Sure. Thanks for the question. Michael, why don't you take that one?

Sure. We won't have time to go into a lot on this marker. But if you know anyone with pancreatic cancer, and I hope you don't, but unfortunately, a lot of us do, you'll know that they go month-to-month waiting for their CA19-9 results, assuming they have a CA19-9. And about 80-plus percent, 85% of the patients do have this marker and then another 10% or so will have CEA as their biomarker.

CAT scans are typically done every 6 weeks. The -- just to be very clear about this, CA19-9 is made by -- it's actually an enzyme system that's made by the tumor cells that has to do with glycosylation. -- and it changes sugar moieties and it's actually a series of proteins that are glycosylated differently and the levels are measured accurately and have been for a long time. But be clear, the tumor cells themselves make the marker. It is a leader and a predictor of how the patient's tumor mass is going.

You also know that pancreatic cancer has a lot of scar tissue. So it, in some sense, can overestimate the treatment effect in the sense that if you hold the CAT scan as the gold standard, which, of course, the FDA and investigators do, then it can look a little bit better than the CAT scan. That said, it is actually very well correlated with outcomes. And there's an extensive literature on this with multiple meta-analyses and multiple different studies that have looked at especially 50% and 80% and 20% reductions in CA19-9.

So to give you an example, one of the best and most recent studies on this was the combination of nal-IRI that is a nanoliposomal irinotecan with 5-FU leucovorin in the third line -- second, third-line setting, which is very relevant to our population. This is very intensive chemotherapy, as you know. And they had about 30% of their patients had at least a 50% reduction in CA19-9. That correlated with a 17% response rate. Now we have 3x higher the CA19-9 response rate. So we are clearly more active, I would say, and we will see when the scans are available. We're clearly more active, though on the CA19-9 than this intensive chemotherapy in the second line. That the CA19-9 changes also correlated very well statistically with both PFS and OS, so as well as ORR.

So it is very well correlated. It's also correlated in the front line. Patients with reductions, which is typically 70% to 80% of patients in frontline with FOLFIRINOX, for example, will have some reduction in their CA19-9, and that correlates with better outcomes than those patients that have no reduction or a rise in the CA19-9.

Again, it's a leading indicator. It's something that patients follow all the time. And what you might notice from the cases we put out is that the patients who had a couple of scans, if you look you'll see that as their CA19-9 preceded the scans and if the CA19-9 stayed down or went down even further, the scans tend to get better over time. It takes a lot longer to remove these pancreatic tumor beds, which consist of a lot of fibrotic tissue, so-called desmoplastic reaction than it does to kill the tumor cells themselves. So we want to give the drug a long time to clear the tumor beds, that is the body, a long time to get rid of the dead tumor tissue. And we are following, of course, CA19-9 along with the CT scans in parallel.

Our next question comes from the line of Mizuho.

This is Sam on for Greg. Maybe a little bit more color on the current strategy for the 1,200 mg, assuming it gets cleared. Any updates on what the clinical plan is for that dose?

Thanks for the question. Michael, do you want to take that one?

Yes. But I apologize, I couldn't hear very well. Both questions sort of got muddied.

It was really around the question around our plans for the 1,200 milligram.

Yes. So the 1,200 milligram really represents the maximum administrable dose, if you will. The current tablets in the formulation that we have are 100-milligram tablets. And giving people 9 tablets for 900 milligrams is doable. They don't love it, obviously, and we all taken pills before. We know that 9 is a lot. But 12 pills is really on the edge. It is a good -- it is absolutely good drug development, and it's required for any approvals to explore the maximum tolerated dose, which we have not reached or the maximum administrable dose, which is probably 1,200 with this current formulation.

So we're in the DLT period right now. I've got nothing exciting to report about how patients are doing. And if we -- hopefully, we will clear that, we will declare victory if we clear that dose, then we will stop in terms of the current formulation. We're obviously working on pills that are larger, meaning they hold more drug, and we're working on alternative formulations as well.

So we'll be able to look in the future. But the 1,200 is really to finish off the current characterization of the drug and understand what the highest administrable dose will do. We probably will, in the future, look into it a little bit more closely, assuming tolerability is similar to what we've seen so far. But right now, it's really just to close off that aspect of the drug description.

And just to remind everybody, we're seeing really good coverage at 900, which makes us really confident in that dose.

Our next question comes from the line of H.C. Wainwright.

This is Andres Malvanato from H.C. Wainwright. A couple of quick questions from us. First off, from a mechanistic perspective, can you give us a little bit more color as to why cetuximab appears to drive that deeper response we saw with the subtherapeutic dose, specifically 400 mg in PDAC?

And in that context, can you maybe provide a checklist for us on what you really need to see in that data that really supports that chemo-free PDAC path? And maybe a quick follow-up to some of the commentary on CA19-9. Obviously, the meta-analysis correlations with OS and PFS that you mentioned are intriguing.

And I want to take it a step further. Is it safe to say that, that meta-analysis also correlates to -- the CA19-9 correlate to lower levels of phospho-ERK for these patients?

Thanks for the question. John, why don't you take the first one, and you can have the second one, if you want as well.

Okay. I'll start with the first one. So there's a lot of building evidence for the importance of EGFR as a combination strategy with RAS inhibitors in pancreatic cancer. Going back to 2019, there were some nice publications by Mariano Barbacid showing that if you block RAS signaling, you really need EGFR inhibition in animal models of pancreatic cancer. There was a beautiful paper by Channing Der lab in February of this year that show -- what they did is they did CRISPR knockout of every gene in the genome together with combination with RAS inhibitors across pancreatic cell lines.

The #1 hit was if you knock out EGFR, you greatly increase the efficacy of a RAS inhibitor. And they use multiple RAS inhibitors, multiple pancreatic cell lines. They also showed that whenever they treated a cell -- a pancreatic cell line with a RAS inhibitor, they saw a great increase in phospho-EGFR, showing that it's is trying to activate EGFR to get around. So -- and then we, of course, have preclinical data we've shown before where if we combine cetuximab with 7375 in pancreatic models, as we see in colorectal models, we see very nice regression.

So that, together with our clinical observations have made us excited about this combination. Michael, do you want to take the question about what it will take for us to go forward with the cetuximab combination relative to 7375 alone?

Sure. I think it's a bunch of different things, as you might imagine. I mean the most important thing, of course, in any of these fatal cancers is efficacy. So if we can see a higher response rate with preferably better durability. And mechanistically, if you hit 2 pathways, you should see both a higher response rate and better durability. That would be the major driver.

The trade-off, obviously, is people will have to take an intravenous medication every couple of weeks. The side effects of cetuximab and panitumumab are well described. The acneiform rash is well managed and standard doxcycline or minocycline with either steroid cream or what have you is typically very effective. And you saw some of our patients really don't get much else besides the rash.

So I think it's really going to come down to efficacy. We won't have long, long-term durability, but we will certainly have the ORR and the preliminary data are very intriguing for a potentially chemo-free frontline regimen, which will be a lot easier to take than any of the current chemotherapies that are given for pancreatic cancer.

And Andres, I think you had a third question. Can you repeat what that?

Yes, there's a question on phospho-ERK and whether that relates to the CA19-9. Correct.

Yes. John, I don't know if from a scientific point of view, I'm not aware of any literature on a direct correlation between those 2. I mean CA19-9 is a direct measure of tumor cell mass, not necessarily pancreatic cancer cell size as I keep emphasizing this rather fibrotic reaction that we see a lot in pancreatic cancer. But live cells are the cells that make the enzymes that lead to CA19-9. And I don't know that, frankly, phospho-ERK levels have been studied because in the past, the only thing we've been treating pancreatic cancer with has been multi-agent chemotherapy.

I will say 2 things though. I think that given that we know that RAS is the strongest driver of pancreatic cancer now we've been seeing this really clearly. The main endpoint of that is phospho-ERK. And so I'd be shocked if we don't see the correlation of phospho-ERK with both regression by scans, but also with CA19-9.

And secondly, we are adding actually a mandatory biopsy cohort in pancreatic cancer patients to our 101 study. And we -- and one of the main things we'll measure there. We're actually -- we'll measure both phospho-EGFR and phospho-ERK in that case. So we actually will learn the answer to your question, although we don't know it today.

Our next question comes from the line of B. Riley.

This is Yuan from B. Riley. Dan, so you guys showed the encouraging plot of CA99 within the 900-milligram cohort in PDAC. What about the trend in the 600-milligram cohort?

Michael, do you want to take that? Did we look at this 19-9 in the 600-milligram cohort as well?

Take it if you like.

You alluded to it. When we say we see a dose response, we mean it both for CA19-9 and the preliminary radiographic results that we're getting. So we see that 900 delivers much more antitumor activity. 600 definitely has good activity, but 900 is 50% more drug, and you saw the PK results, and it looks very impressive on the PK side. So we're definitely getting more antitumor activity, and that does manifest in the CA19-9 as well.

Got it. Since we are short on time here. Maybe a quick question. For VS-7375, is that compound metabolized through the CYP3A4 mechanism?

John, do you want to take that?

Yes is the answer.

A quick answer. Yes, we are getting up on time here, so we should just get through the last few questions.

Our next question comes from the line of BTIG.

This is Jeet Mukherjee. Two quick ones, hopefully. One, are you seeing time to response vary in the 101 trial versus the GenFleet trial? And two, how do you see 7375's profile comparing against 1,200 Zoldonrasib as of now?

Michael, do you want to take that?

Yes. I think time to response -- first response is similar to the GenFleet trial, although I think our patients are -- seem to be more heavily pretreated, just at least in terms of the time that they were on prior therapies and perhaps some of the duration of their second-line treatments. Non-small cell, as GenFleet found, non-small cell tends to be more rapid responses than the GI cancers, which I think none of us -- certainly, none of the oncologists we speak with are surprised.

But we seem to be generally in the same ballpark. Again, I think in the GI cancers, it's we eat away at these tumors over time, and it's actually quite nice to see that people get their next scan and what's happening is that some more of the tumor is gone. So I think it might be a little bit longer for the GI tumors. Non-small cell, again, seems to be quick. And then there was a second question, I think.

I can take that second. Yes, go ahead Yes. No, I think it's quite interesting. So really, what I'm extremely excited about is we don't have an exposure ceiling. We're able to keep dosing higher to maximally inhibit the target. I think across probably all other RAS inhibitors, we see this exposure ceiling where they just get to a certain exposure, they can't get higher.

Certainly, for Zoldonrasib, if you compare 600 milligrams QD to a somewhat lower dose, you see a similar exposure. And I think that for that reason, Zoldonrasib has a 30% confirmed plus unconfirmed not extremely strong. And actually, you see a number of patients where the best response is somewhat substantial PD progression. And I think that, that's maybe a symptom of leaving some patients behind and not getting sufficient exposure as we can get.

Our next question comes from the line of Alliance Global Partners.

Matt on for Jim Molloy at AGP today. Just 2 quick ones. So should we anticipate R&D spend increasing a bit in relation to the Erasca collab and the upcoming PRMT5 collab in 2026? Or is that more of a 2027 event?

And is there any more color you can give us on the patients receiving cetuximab plus VS-7375 in Target-D 101, mainly related to safety, as I know that part of the trial is not as far along.

Yes. I would just say, in general, R&D expenses related to the G12D program should increase as the year goes by as we start both the Phase II trials and then gear up for the Phase III trials. And then the collaborations, we haven't really spoken about what they may add. And then what was the second part of your question?

Sorry, it was -- if you could just give us a little more color on the patients receiving cetuximab plus...

Cetuximab. Yes. Michael, do you want to take that?

Yes. I don't -- I mean the patients receiving cetuximab are similar to the patients that are on the monotherapy as well. Can you give me a little more specificity on what you're looking for?

Yes. Just if the patient population was similar as well as if the safety profile looks similar between the patients receiving VS alone and with cetuximab.

Sure. Great. Now I got it. Yes. So this is identical populations. And in fact, in the ongoing -- in the trial that just opened that enrolled, it's actually randomized patient population second line. But in the Target-D 101 study, the Phase I/II study, the patients were the same greater than they had to have at least one prior therapy, and then they just ended up on whatever slots were open.

And in terms of the side effect profile, what it really looks like, it looks like 7375 plus cetuximab and the main contribution of cetuximab, of course, is this nearly ubiquitous rash. I mean it's touted as 80%, but it's -- frankly, it's probably just about everybody get cetuximab.

They get a bit of an acneiform rash. They -- typically, it's grade 1 these days because they get prophylaxed -- and as you know, cetuximab has been around for a very long time. So docs know how to take care of this and minimize it. But there's no exacerbation of any of the 7375 minimal side effects. And as I mentioned on the call, the 7375 side effects are attenuated substantially after the first cycle, and patients are just frankly pretty happy on it.

Our next question comes from the line of Jefferies.

This is [Anand Chand] on for Faisal. In the treatment-emergent AE table at the end of the slides, you had 2 grade 4 events, including anemia. Could you provide more color on those and how or why those were not deemed treatment related?

Michael, do you want to take those?

Sure. The anemia was associated with the GI bleed that was absolutely due to the pancreatic cancer invading the GI tract. That's not due to our drug. That's due to the pancreatic cancer that's in the GI tract. And the hyponatremia similarly was due to -- I believe it was also a pancreatic patient, but I'm not absolutely certain, and that was again, due to somebody whose sodium just dropped precipitously when they were third spacing with as sites and so on, which is very common, and that was easily rectified with standard slow infusion hypertonic saline and then the patient was brought back.

Ladies and gentlemen, I'm showing no further questions in the queue. That concludes today's conference.

All right. Thanks, everybody.

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

Good afternoon, and welcome to Verastem Oncology's First Quarter 2026 Earnings Conference Call. My name is Daniel, and I will be your call operator today. Please note, this event is being recorded. [Operator Instructions].

I will now turn the call over to Julissa Viana, Vice President of Corporate Communications, Investor Relations and Patient Advocacy for Verastem Oncology. Please go ahead.

Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss Verastem's first quarter 2026 financial results and recent business updates. This afternoon, we issued a press release detailing these results, along with a slide presentation that will be referenced during our call today. Both are available on the Investor Relations section of our website.

Before we begin, let me point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional detail. Additionally, today, we will be discussing certain non-GAAP financial measures. Reconciliations to the most directly comparable GAAP measures are provided in the press release we issued today.

Joining me on today's call to deliver prepared remarks and take your questions are Dan Paterson, President and CEO; Dr. Michael Kauffman, President of Development; and Dan Calkins, Chief Financial Officer.

I will now turn the call over to Dan.

Thank you, Julissa. Good afternoon, and thank you for joining our call today. Tomorrow marks 1 year since the accelerated approval of AVMAPKI FAKZYNJA CO-PACK, a practice-changing medicine approved for patients with KRAS-mutated recurrent low-grade serous ovarian cancer. Since our launch in May 2025, we've seen steady growth quarter-over-quarter, achieving $18.7 million in net product revenue in Q1 with nearly $50 million in total net product revenue to date. While we're pleased with the growth we've seen, we believe there's meaningful opportunity to build on the foundation we've established. New patient starts remain consistent month-over-month. Our prescriber base continues to grow and the reimbursement environment is favorable.

As part of our ongoing commitment to optimize our launch, we conducted a focused review of our launch performance and execution and implemented targeted changes to our commercial organization and leadership. I'll walk through these details in a few minutes. I want to underscore that our confidence in the underlying demand and overall opportunity for the CO-PACK remains unchanged.

Moving to R&D. We've made significant progress with our clinical trials for VS-7375, our potential best-in-class oral and selective KRAS G12D ON/OFF inhibitor, now branded as the VS-7375 Target-D clinical trial program. The Target-D-101 Phase I/II dose escalation and expansion trial is already underway, and we continue to enroll patients and evaluate higher dose levels. In addition, we've also initiated our Phase II registration-directed clinical trials in second-line pancreatic cancer, second and third-line non-small cell lung cancer and second-line plus metastatic colorectal cancer. Michael will share more about our progress and strategies with these trials.

We continue to closely manage our expenses and remain on track for the LGSOC franchise to be self-sustaining in the second half of the year, meaning CO-PACK revenues will support both commercial operations and any ongoing clinical trials for avutometinib plus defactinib. As we look to the balance sheet, our focus remains on identifying value-creating nondilutive opportunities as we advance our pipeline and deliver for patients and shareholders.

With that, let me turn to our commercial update. With almost a year into the launch, we're continually monitoring our progress. As with any launch, there's a natural evolution as we learn more about the market dynamics. We took a comprehensive look at our commercial execution and have taken decisive actions to strengthen it and position the business for the next phase of growth.

Most notably, we've appointed a new Chief Commercial Officer, Dan Lyons, who has deep and relevant experience in oncology and rare diseases. He has a strong track record of leading global commercialization strategies across solid tumor cancers, including 2 successful rare disease and oncology launches at SpringWorks. Dan's leadership will be instrumental as we evolve our launch and bring AVMAPKI FAKZYNJA CO-PACK to all patients who could benefit from this important treatment. While Dan will not be joining us on the call today, he's already actively engaged with the team driving new and existing initiatives forward.

Turning to the first quarter results. We were impacted by the seasonal headwinds many companies experienced, namely insurance turnover and reverifications as well as more severe weather, which affected patient access. This impacted both new patient starts and refills. On closer examination, we also observed a specific dynamic where some patients prescribed the therapy by early adopters were much further along in their disease and treatment journey than we would have anticipated and therefore, discontinued the treatment earlier than expected.

This is not surprising as in many cases, these patients likely had no other alternative therapeutic options with proven clinical benefit. Since January, we've seen a rebound with a strong number of new patients through the end of the first quarter. There also continues to be strong physician conviction with the majority of physicians surveyed at our most recent ATU indicating that the CO-PACK would be their first choice at their patient's next recurrence.

Now on to the numbers. Active prescribers continue to expand and through April, there have been more than 400 unique prescribers to date. And consistent with previous quarters, we continue to see prescriptions split between GynOncs and MedOncs at a 60-40 percentage. Separately, our active patient pool has grown over recent months, indicating patients are staying on therapy longer, but it's too early to provide duration of therapy as it continues to evolve. It's also too early to give an average number of refills, but the trend we are seeing is consistent with what we would expect at this point in the launch. Approximately 65% of commercially eligible patients are using our Verastem Cares Co-Pay Program. The remaining patients did not require co-pay assistance and the average co-pay for commercially insured patients is less than $30.

Time to fill initial prescriptions continues to be in the range of 12 to 14 days due to rapid prior authorization approval and our payer mix remains consistent with previous quarters at about half commercial and half Medicare. As we look ahead and consider our recent learnings, we focused on 3 key drivers in our business to help patients realize the full benefit of the CO-PACK. The first key driver is to maintain the consistent level of demand of new patient starts. This starts with identifying the right patient for treatment. Without an ICD-10 code specific to LGSOC, we've identified other proxy measures within EHRs, including mutational status, AI or MEK use that may indicate an appropriate patient for the CO-PACK. Our team is actively working with prescribers when these proxy measures are identified in a patient file. Additionally, we've now added incremental personnel to continue to drive demand and support patient adoption.

The second key driver is to drive earlier use at first recurrence. Over the course of the launch, we've observed discontinuations that in part reflect use outside of the attended approved patient population and in LGSOC patients who are much sicker than the patient population in RAMP-201 that was the basis for FDA approval. In fact, in some cases, patients were heading into hospice. As multiple physicians have noted, disease progression and complications can make it harder for patients to tolerate and absorb oral therapies, underscoring the importance of using the CO-PACK early at first or next recurrence when patients have the best opportunity to realize its full benefits. Our recently launched Reimagine Recurrent LGSOC direct-to-physician and patient campaign is focused squarely on this shift.

The third key driver is to help patients stay on therapy. Recent long-term data from the RAMP-201 trial presented at the Society of Gynecologic Oncology showed that after 2 years of follow-up, patients on the CO-PACK achieved durable benefit with discontinuation rates consistent with the package insert, findings that physicians view as clinically meaningful. Our recent exposure response analysis also demonstrated that early side effects can be effectively managed with dose interruptions after which patients resume at the approved dose and schedule. Setting expectations with both patients and physicians around the AE profile and how to manage through it is a key initiative for the remainder of 2026.

We continue to see a substantial market opportunity for the CO-PACK with growth potential coming from multiple directions, expanding reach among prescribers who ever prescribed the CO-PACK, deepening experience among current prescribers by identifying additional patients in their practices and shifting entrenched prescriber behaviors to starting CO-PACK on their first occurrence when appropriate. LGSOC is a relatively slow growing but unrelenting cancer where patients stay on their first treatment for several years. Therefore, achieving peak share at first occurrence will take time. But we believe the earlier use of the CO-PACK drives deeper adoption, produces real-world outcomes that mirror our trial experience and establishes the CO-PACK as the new standard of care at first reoccurrence. We remain focused on our core product launch priorities and sustaining steady growth throughout the year.

I'll now turn the call over to Michael.

Thank you, Dan. We continue to make good progress across our pipeline programs, and I'll spend the next several minutes with an overview of our VS-7375 oral KRAS G12D inhibitor program. As Dan mentioned, we've named our VS-7375 trials Target-D. Target-D 101 is our ongoing Phase I/II dose escalation, dose expansion and combination evaluation trial. In the dose escalation portion, we are now evaluating the 1,200-milligram daily dose to fully characterize the dose range available.

We will complete enrollment across the various expansion cohorts shortly as well as the current cohorts evaluating combinations with chemotherapies. And importantly, we are moving to enroll patients into each of our Phase II trials, which I'll describe in more detail. As we mentioned last quarter, the FDA requested that we develop separate Phase II protocols for any trials where we are seeking marketing authorization. Thus, we have developed 3 Phase II registration-directed trials in pancreatic cancer or PDAC, non-small cell lung cancer, or NSCLC, and colorectal cancer or CRC.

I'll now provide some detail on each of these. Target-D 201 is our second-line PDAC study. This Phase II open-label study is designed to evaluate VS-7375 at the 900-milligram daily dose, both as monotherapy and in combination with cetuximab. Based on strong preclinical rationale showing EGFR pathway activation in pancreatic cancer and its role as a potential resistance mechanism to RAS inhibition, we are studying the combination of VS-7375 and anti-EGFR antibodies to potentially deepen and prolong responses.

We're also taking the opportunity to evaluate VS-7375 and anti-EGFR antibodies in first-line pancreatic cancer where we believe we can generate compelling data. It is worth noting that because VS-7375 has not been associated with skin rash to date, combination with EGFR inhibitors is expected to be clinically feasible and growing tolerability data to date support this. In addition, we are currently studying the combination of VS-7375 and gemcitabine nab-paclitaxel or GNP in patients with PDAC looking towards a frontline treatment regimen.

Target-D 202 is our advanced non-small cell lung cancer study. This Phase II open-label study is designed to evaluate VS-7375 at the 900-milligram daily dose in patients who have received 1 or 2 prior lines of therapy, including a platinum-based chemotherapy and a PD-1 or PD-L1 blocker. We are currently evaluating VS-7375 at 600 milligrams daily in non-small cell lung cancer in our 101 trial, and this will provide information at this lower dose. But as in PDAC, we anticipate that the 900-milligram daily dose will be our go-forward monotherapy dose in previously treated non-small cell lung cancer as we look towards potential marketing authorization. We are also evaluating VS-7375 monotherapy in patients with non-small cell lung cancer and asymptomatic brain metastases where there remains a significant unmet medical need and an opportunity to improve outcomes.

And as previously noted, we are evaluating the combination of VS-7375 plus pembrolizumab without or with platinum pemetrexed chemotherapy in the 101 study looking towards a frontline treatment regimen. Lastly, we have our Target-D 203 metastatic colorectal cancer study. This Phase II open-label study is designed to evaluate VS-7375 at the 900-milligram daily dose as both monotherapy and in combination with EGFR inhibitors, including cetuximab or panitumumab in patients with previously treated colorectal cancer. While we do not expect to see meaningful responses for VS-7375 as a single agent, this will be critical to showing the contribution of PARs for potential combination therapy regulatory submission.

We're also going to evaluate VS-7375 in combination with anti-EGFR antibodies and the modified FOLFOX6 regimen in the first-line setting, again, to expand the opportunity and help us improve outcomes in patients with colorectal cancer with the goal to develop a frontline combination regimen. Importantly, across all 3 Phase II trials, the primary endpoint is overall response rate by blinded independent central radiological review or BICR, with BICR determined duration of response or DOR as the key secondary endpoint, supporting potential accelerated approvals in each of these 3 indications.

The protocols have been sent to clinical trial sites, and we anticipate the first patient in each of these studies to occur mid-year, if not sooner. We continue to enroll patients and evaluate the 1,200-milligram dose, which is the highest practical dose that we can administer to define the upper end of the dosing range. We now have updated PK data that show that the 900-milligram dose delivers serum levels of VS-7375 at or above our target level and provides clear separation from the 600-milligram dose.

While we are seeing good responses at 600 milligrams, these data, along with good tolerability, support our enthusiasm for advancing the 900-milligram dose in our Phase II trials. As additional data emerge, we expect to finalize the go-forward dose across tumor types and combination settings. As we shared last quarter, our goal is to generate meaningful data sets in these tumor types, both as single agent as well as in combination with other treatments with the goal of potential accelerated approvals in previously treated cancer as well as developing combination strategies to position our regimens in the frontline setting across all 3 tumor types.

Now let me briefly set expectations for our first half update from the Target-D 101 trial. In terms of patient numbers, the safety data set will include a broad set of patients across Target-D 101. However, the number of patients evaluable for efficacy will still be relatively small. Recall that response evaluations require a minimum of 2 baseline scans, which are typically 6 to 8 weeks apart and not all responses occur at the first scan. And of course, duration of response requires follow-up for months after the initial response determination.

We note again that meaningful response duration is typically about 6 months. As we've discussed previously, we believe that administering the highest well-tolerated dose of VS-7375 will maximize the chances for each patient to have a meaningful antitumor effect. And because the 900-milligram dose has been well tolerated to date in over 20 patients in the U.S., our results of this dose will require several additional months over what was originally projected for the 600-milligram dose. At this time, we can also add that the 400 and 600-milligram doses of VS-7375 in combination with cetuximab are well tolerated and that we are currently evaluating the 900-milligram dose in this combination.

To reiterate, we will only be able to provide a preliminary view on activity overall because we've been able to utilize higher doses in our patients in the United States. That said, we see this first half update as an early checkpoint and believe the data set will be meaningful in terms of demonstrating our progress in enrollment, along with a more mature safety update and more PK data. We do plan to include some patient cases across tumor types and combinations in the update. Later this year, we expect to provide a more comprehensive data set, including tumor-specific breakdowns and more mature efficacy data as we enroll in our Phase II trials for potential marketing applications. Finally, switching gears for a minute to our avutometinib plus defactinib program. We remain on track to report an update on our RAMP-205 study in first-line PDAC before the end of the second quarter of this year.

Now I'll turn the call over to Dan Calkins.

Thank you, Michael. Our full financial results were included in our press release, so I'll focus on the highlights here. For the first quarter of 2026, we recorded $18.7 million in net product revenue and $2.8 million in product cost of sales. Cost of sales increased in the first quarter in line with the percent increase in net product revenue for the quarter. Research and development expenses were $38.2 million for the first quarter of 2026. R&D expenses continue to be driven by both the ongoing global confirmatory Phase III RAMP-301 clinical trial with the CO-PACK and the ongoing VS-7375 Target-D 101 Phase I/II clinical trial in the U.S. as well as higher costs associated with clinical supply and drug production activities related to our expanded VS-7375 program.

SG&A expenses were $22.3 million for the first quarter of 2026. The expenses were driven by commercial activities and operations, including personnel-related costs to support the ongoing CO-PACK launch. I can reiterate that we expect SG&A expenses to remain roughly the same on a quarterly basis throughout 2026 as we remain disciplined in our expense management, making the right investments at the right time to support the ongoing commercial launch efforts. For the first quarter of 2026, non-GAAP adjusted net loss was $42.7 million or $0.43 per share diluted compared to non-GAAP adjusted net loss of $42.9 million or $0.79 per share diluted for the first quarter of 2025. Please see our press release for a full reconciliation of GAAP to non-GAAP measures.

Moving to the balance sheet. We ended the first quarter with 2026 with cash, cash equivalents and investments of $181.7 million. We believe our current cash, combined with the future revenues from the AVMAPKI FAKZYNJA CO-PACK sales will provide cash runway into the first half of 2027. We remain encouraged by the initial launch and look forward to building on the CO-PACK's growth in 2026. Given our current trajectory, I'm pleased to reiterate that we believe the LGSOC franchise will be self-sustaining in the second half of the year with CO-PACK revenues funding both the commercial operations and our avutometinib plus defactinib clinical trials.

With that, let me turn the call back over to Dan.

Thanks, Dan. Before we open the call to Q&A, our focus for the remainder of 2026 is very clear, and that's to drive strong execution across our commercial launch, move our 3 Phase II trials expeditiously towards potential registrations, determine appropriate VS-7375 combinations for frontline strategies and maintain disciplined capital management while identifying nondilutive financial opportunities to deliver for patients and our shareholders. Overall, we believe we're well positioned to deliver on our key milestones this year and continue building a leading oncology franchise in RAS/MAPK-driven cancers.

With that, we'll open up the call for questions. Operator?

[Operator Instructions] Our first question comes from Eric Schmidt with Cantor.

Maybe one on each of the 2 programs. On 7375, what do you think potential partners need to see from either your Phase I or early Phase II data sets in order to be very interested in the asset? And then 2 for Dan in terms of the self-sustainability of the CO-PACK franchise. Can you be a little bit more granular in terms of the revenue that gets you to that sustainability?

Sure. Eric, thanks for the question. Just to comment on potential partners, we have had a fair amount of interest. And what typically happens in situations like this, it tends to come down to the competitiveness. I think if there's one party interested, it can go on forever. I do think the fact that we've got significant data out of China that aligns well with the preclinical profile, it's really seeing enough data from the U.S. where we show that we can give it in a tolerable way in a way that can be combined and that we start to recapitulate efficacy that puts us in the ballpark of still being potentially best-in-class. And Michael, I don't know if there's anything more you want to add there, but why don't you comment and then we can have Dan C talk about the expenses second half of the year and kind of what we're talking about being covered.

I think you covered it real well, Dan. We need U.S. data, and we need a lot of detail on the patients and their prior therapy, and we're quite optimistic that we'll be able to deliver on that.

Yes. Eric, this is Dan C. So yes, just in terms of the self-sustaining question, obviously, we haven't given guidance in terms of the revenue for the remainder of the year. But just in terms of the expenses, if you look at SG&A expenses from -- on a quarterly basis from when we were pre-commercial to where we are now, that increase has typically been around $10 million to $15 million per quarter. And then from an R&D perspective, if you look specifically at the A+ related programs, that spend has typically been about $10 million to $15 million per quarter as well. And the majority of that spend is really coming from the RAMP-301 trial, which we announced reached full accrual back in December of 2025. So that's now at full accrual. So I don't expect that, that will increase more likely be coming down. So that would give you a good sense of what it would take to be self-sustaining within that program.

Our next question comes from the line of Michael Schmidt with Guggenheim.

I had a couple on 7375. Maybe one for Michael first. You talked about the Phase I update in the first half of this year. And maybe if you could just comment a little bit more about how the patients perhaps in the U.S. study compared to the GenFleet Phase I study that we saw last year. And also, you mentioned different follow-up with -- depending on which dose was used. And so how comparable will the U.S. update be perhaps to the GenFleet data from last year?

Michael, do you want to take that?

Sure. Yes. Sure, Dan. So PDAC is generally treated the same way across the world. And frankly, these days, lung cancer, I mean, KEYTRUDA may or may not be the immunotherapy, but it's generally treated with a platinum agent, typically carbo and since these are adenocarcinomas of pemetrexed. And again, colorectal cancer, it's pretty standard, whether they're getting FOLFOX or FOLFIRI and some people are getting FOLFIRINOX, it's all pretty similar. The patients are fairly similar. I think the most important difference and the reason we want to continue to study our drug is because the tolerability in the U.S. has been substantially better than what was reported in China.

We are not seeing any significant level at all of liver dysfunction. We haven't seen any significant hematologic issues at all. And we continue to see that even with patients now who are on for many months. Some who are on for more than 6 months. We're just not seeing that. We're also not seeing cumulative toxicities, which is really great for a drug that can be given chronically. We have really not seen anything major with this drug to date, and it's -- the numbers are starting to climb. So the 600-milligram dose has been studied for a little bit of a while now, but across a whole bunch of different cancers. It was an open study.

We'll have a little bit more specifics on it. But I think the points I made in the call were that it takes a while to get responses here. I mean you can't even assess the first response until 6 to 8 weeks after initiation of dosing. And remember, when we open a trial, we don't accrue everybody at the beginning. So this is a staggered accrual, of course, with staggered dosing. We all wish this could happen immediately. But the first scan is 6 to 8 weeks and then a confirmatory scan is another 6 to 8 weeks. And then if like in PDAC when many of your responses are going to occur in the second scan after the first scan because these are tough tumors and they have a lot of scar tissue. It's going to take a while, and that's okay, and that's very good.

We absolutely have responses in the first scans after dosing starts, and we've seen responses at second, and we've seen patients who've done really well, have shrinkage of tumors and cross the important 30% threshold for a PR in scan 3 or 4. I don't want to go into any detail, but we're quite pleased with what we're seeing, and we believe that 900 milligrams will be the go-forward dose. So that won't be -- the 900-milligram details will not come until the second half of the year, as we said.

And we'll be able to give a little bit of data on the 600 milligram. But we would far prefer to give you guys substantial data sets in the 20 to 30 patient range with reasonable durability so that we can make some -- you and we can make some intelligent decisions on how this drug is stacking up against others. All of that said, we remain very, very excited about the potential for this to be a best-in-class agent. And I would lastly point out that this drug does not carry rash with it at all nor does it carry stomatitis. And these are really important considerations for patients who could spend a year or more on these drugs.

Okay. Understood. And maybe a question on your Phase II program. Specifically the 201 study on Slide 12 is schematic and just wanted to ask, so you have Part A and Part B. And I'm just curious what the decision process is for either selecting 1 of the 2 cohorts, monotherapy or combination and then whether the Part A and B patients will be pooled at the respectively selected cohort. Will this be a 100-patient type -- actually 80 patient type registration cohort? Or how should we think about the decision path as you have sort of multiple steps in these Phase II studies?

Right. Well, beautiful way to put it, and you correctly figured out what we're really doing here, which is to expect that based on what's going on right now at the 900-milligram dose currently in our Phase I, we do think 900 milligrams will be good as both a monotherapy and in combination. We think both of these cohorts are going to be important. And we do intend to pull Parts A and B. This is sort of a 2-step. It's almost sort of a baby and 2-step trial, but we're just putting it in here this way so that we can review this in case there's some unexpected findings here, which frankly, would be different from what we're finding already in the 101 study. We don't believe that's going to happen, but this was -- we discussed it with our statisticians, and we thought this was the most appropriate way to do this. It doesn't really affect our time lines at all because we think both cohorts are going to go through, and we'll have both a monotherapy and a combination.

I'll just add one more thing, and that is that these are important cohorts, assuming cetuximab can add efficacy, but it also remember, cetuximab brings about an 80% burden of it. It's a different kind of a rash than you see with some of the pan-RAS inhibitors. The cetuximab rash is so-called acneiform, and it's actually really well controlled with, frankly, standard acne medicines plus steroids. So a lot of the patients will go on prophylactic minocycline or doxycycline, and that can really mitigate these rashes. But it still comes with a rash. And there are patients even with pancreatic cancer who don't want that. So we think both of these options will be important, and we think we can deliver very significant response rates, which will be correlated with durability with this kind of a drug because it doesn't have cumulative toxicities for both of these cohorts, and we'll have 2 different options for patients.

Okay. And then cetuximab is clearly an interesting choice, I think, in PDAC, but any plans to potentially evaluate combination of 7375 with an investigational pan-RAS inhibitor?

We're absolutely considering that, and we're in discussions with folks. We have generated and continue to generate some interesting data in that regard. So we're absolutely looking into that. That said, frankly, there's a lot of different pathways that deserve study in now that we seem to have made a dent in pancreatic cancer, and we're considering multiple other options as well.

Our next question comes from Faisal Khurshid with Jefferies.

I wanted to ask about the GenFleet partnership. So when you guys did the partnership, I think you had 3 RAS programs that you were eligible to in-license. And if you look at the GenFleet pipeline, they have the G12D, the G12C and the multi-RAS. Can you confirm if you guys are able to license the multi-RAS and what the considerations around that could be?

Yes. This is Dan. So those 3 molecules were not -- well, except for the G12D, which we developed together with them and chose the lead. The other 2 programs were not officially part of the original collaboration. We continue to have discussions for us to jump into the pan-RAS space right now. We'd have to be convinced that it was a differentiated molecule and that, frankly, that combining G12D and pan-RAS is actually the preferred path we might want to go down. And we think we have so many other options. We're still considering it, but there are a lot of other options to look at for combination.

Got it. But you do have 2 more molecules that you can get from GenFleet under the current deal?

We do, and we've not disclosed those targets yet.

Our next question comes from Leonid Timashev with RBC.

I wanted to pivot maybe to the commercial side of A+F. Really appreciate the color on sort of how you see the commercial strategy evolving. But I guess I'm curious if you could provide more details on how you'll actually affect those changes. I mean is there a different way the sales force is going to message? Are the promotional materials going to be different? Are the regions going to shift? I guess how do you actually drive towards those goals that you laid out?

No, that's a great question. And the short answer is I'll accept the last one. So we did add 2 additional sales positions, and that was really driven by the fact that 2 of the regions were just too big. And so we said all along we were going to rightsize the launch. We were in the process of doing a deep dive. We're about 6 months in when we got to the end of the year. We had that seasonal issue, which frankly, impacted refills more than initial scripts, and it was reauthorizations and things like that, that would push things from January into February We actually had some patients we had to put on free drug for a month until things got sorted out.

And so when I -- when we talk about the focus for 2026, some of it was just additional training. Some of it is making sure that we're putting the right amount of effort into the visits after the first prescription and not putting all our effort into getting a prescription. And then implemented a number of different steps with information flow between the specialty pharmacy and really our integrated force, which is both the sales team and the med affairs team to make sure that when there's a delay, and we increased the number of calls to patients so that we are in touch with what's going on with the patient. But also a very deliberate link where if there's a dose delay, somebody is calling on the practice, whether it's med affairs or the sales rep to both find out what's going on and then reinforce the messaging that came out of the SGO meeting recently.

We had 2 big events at the SGO meeting, which that and IGCS tend to be our 2 big meetings of the year. We had the long-term update to RAMP-201, which showed durability and no increase in side effects with cumulative use over a long period of time. But also, we had a poster on the importance of dose intensity. And one of the things that you're able to do in a clinical trial when you're interacting in a very regular basis is make sure you're reinforcing the protocol rules, which is if there's a side effect, you delay the dose and you restart at full dose.

That works really well with this drug. I think we were finding with MedOncs in particular, who are used to the dynamics for chemotherapy are a little different where you may get a response earlier and side effects are cumulative, where with this treatment, you tend to get early side effects, and they tend to be predictable things and things that the patient knows they're coming can be dealt with and then the response becomes later. And so really reinforcing the messaging and really the sharing of data on how important it is to get the patient through that first 3 months or so, so they get the benefit of the treatment. And then we talked about the new campaign that we rolled out.

That's something that had been in the works for a little over 6 months. When you launch with accelerated approval, you're limited in what you can talk about in the early days. And so this was really our next wave of the promotional campaign that had been planned from the beginning and really reinforces the importance of getting on this treatment early. I think there's another dynamic going on is also at SGO, there was an early report of a frontline LGSOC study that compared platinum-containing chemotherapy followed by as part of the same regimen, an AI versus an AI only. And the combination won out. And I think you're going to start seeing patients as standard of care based on the data that just came out that will get the platinum-based chemotherapy followed by AI as frontline therapy. And I think that really sets us up very nicely to be the next therapy that patients get after that.

Our next question comes from Graig Suvannavejh with Mizuho.

This is Sam on for Graig. Congrats on the quarter. Maybe one on 7375. So how should we be thinking about the cadence in terms of the timing of readouts? Is there a specific program or indication that you see as, I guess, the most likely path for successful registration-enabled readout and data?

Sam, thanks for the question. I'll start, and then I'll turn it over to Julissa to give more specifics on what we'll have when. We believe all 3 of those indications are important for patients and places where our drug, we believe, will work quite well based on preclinical data. So they're all moving forward in parallel. Our goal is to have those Phase II studies largely accrued by the end of this year and then move forward as quickly as possible. Obviously, there's a lot of movement in PDAC. We're going to have to monitor.

We are in an enviable position as a company of our size that we have multiple programs in PDAC, and we're going to have to see how both of those develop to make some decisions on how best to prioritize things while staying right on top of what's going on in the competitive space because obviously, there's a lot going on in PDAC. And then for CRC and lung cancer, again, the preclinical data is really exciting. If you look at the GenFleet data in second-line lung cancer, 50 -- or 69% response rate we're seeing unprecedented response rates as a single agent. We're starting to see that we can combine nicely with other agents. And so we've got a lot of choices to make around the frontline path in a very short period of time. But while we do that, and we will be doing frontline Phase III studies, we will continue to push forward very aggressively on those potential accelerated approval paths.

I'll just add just with that. Yes. I think just to reiterate what we said on the call about the timing, again, the update in the first half will show progress on enrollment. We'll share some more mature safety profile data since the one that we provided back in March. And we'll provide some patient cases so that you can get a sense of the efficacy that we're seeing. And then in the latter half of the year, again, the goal is more comprehensive data set, double-digit patient numbers across the tumor types, ideally at the go-forward dose, looking both at mono and combo data sets. So we can make some decisions at that point, looking at all of the variables that were just mentioned.

Yes. In the first half data release, we'll have much -- we'll have more data on PK. And as Michael mentioned during his prepared remarks, this is the first time we've disclosed that in the U.S., we are seeing better PK at 900 than 600. And that's both AUC, which is kind of, I guess, the standard measure folks would normally use. But because of the residence time or time on target, being about 24 hours, we actually think Cmax matters a lot. So it can come out of the blood and still be actively blocking the target, and Jon Pachter presented some really elegant work at AACR last meeting recently. And so we think by seeing that PK going up with the dose, we think it just further strengthens the case for pushing that 900-milligram dose, especially since we are seeing that it's tolerable.

Our next question comes from Andres Maldonado with H.C. Wainwright.

Congrats on the progress. Two for me for 7375. First, so in the non-small cell lung cancer, you're including an asymptomatic untreated brain metastases cohort. So curious there, is the goal mainly to show systemic activity in a difficult subgroup? Or is there potential to -- do you guys think you have enough CNS exposure to support a differentiated intracranial profile that extends beyond that tissue type? And then second question, kind of a macro question. So earlier this quarter, we saw a pan-RAS program report a Grade 5 pneumonitis given the historical trends also seen with approved G12C, how should we be thinking about these events through the lens of an on-off G12D or other strategies targeting G12D?

Michael, do you want to take those?

Sure. So first on the question of the brain mets. The systemic activity of the drug will be in lung cancer generally is being evaluated now at 600 in the ongoing Phase I, and we will be doing the 900 in the Phase II, as you see, as you saw from the deck that we had along with the prepared remarks. There is a separate cohort because, obviously, when you're trying to ascertain the value of the drug, systemically, you tend not to pick patients with metastatic brain disease. That said, lung cancer frequently goes to the brain, unlike colorectal and unlike pancreatic cancer. And so in lung, it's especially important to try to see if there's substantial brain activity. The drug does penetrate the brain.

I believe GenFleet reported that 2 out of the 5 patients that they had who had asymptomatic brain mets had systemic responses to the drug. We haven't been able to ascertain exactly how much the brain mets may have shrunk, but the brain mets clearly did not progress because they wouldn't have been responsive if they had. So this cohort of about 25 patients will be treated at 900, which is a higher dose than GenFleet is able to obtain to see if we can control the brain mets. And you all know about avutometinib and some of the other amazing therapies that also cross the blood-brain barrier and really can help these patients do very well over time by preventing or treating brain mets. So that's a starting point for potential for this drug that may differentiate it from others.

And to reemphasize what Dan said, the fact that we're able to deliver such good systemic levels that are very tolerable so far with the 900 gives us a good shot at being able to drive enough of the drug into the brain and do something about this. As far as pneumonitis is concerned, we have not seen any cases of pneumonitis that were believed to be caused by the drug. I believe that they -- that we may have a treatment unrelated pneumonitis case in a patient who already received radiation and it was thought to be a radiation associated, but it was grade 1, and it had 0 impact at all on anything we've seen. We've certainly not seen any kind of pulmonary symptoms with our drug that give us any pause.

That said, we'll be treating a large number of patients with previously treated lung cancer, many of whom have received chest field radiation, many of whom have had one or more infections, all of which predispose you to downstream lung events. We're obviously hopeful we're not going to see that. And lastly, we do not believe, based on our tox studies, there's any drug-related risk of pneumonitis, but that remains to be seen, but nothing important so far.

And just to amplify Michael's comments about pneumonitis, we do have access to the entire PV database at GenFleet. And when we heard these events with some of the other drugs, we did a deep dive. And so his comments are informed by that work that's been done.

Our next question comes from Yuan Zhi with B. Riley.

Maybe one question on the combination of 7375 plus EGFR inhibitors in the PDAC indication. So with this incremental addition of EGFR inhibitor, which normally patients cannot get because of baseline KRAS mutation, what kind of incremental efficacy you guys are looking to justify the addition of this agent considering the safety liability with this EGFR inhibitor?

Michael, do you want to take that one?

Sure. There's 2 components to this. One is the overall response rate, of course. And the second very important one is durability. It is -- we do believe, and we have some early data that could support that hypothesis that we could deliver a higher response rate. We -- it's too early yet to say whether we would have an increased durability of response. That said, the mechanism of action of cetuximab is to block -- specifically block not only a growth pathway. It's an accessory growth pathway for sure, for RAS-driven cancers. It's not the primary one.

But when you block RAS in these cancers, including pancreatic and colorectal and probably some of the other gastrointestinal tumors, the EGFR pathway becomes much more important and blockade of that can be helpful, again, upfront, but also to prevent the development of resistance and running growth pathways through the EGFR pathway. So this could have impact on both sides of this. We will know fairly soon what kind of incremental we'll have. I can't give you a real number. I think what we'd like to do is say that if there are probably patients who would benefit from cetuximab from the get-go. We don't know who they are.

And there'll be other patients who might benefit from down the road after, say, 8 or 9 or 12 months on our drug, if they started to develop resistance, one could imagine adding cetuximab. We think that this development plan that we expect could support accelerated approvals could lead to availability of this combination regimen, maybe not upfront in everybody, but certainly as an option for patients if they start to see progression of their tumor as well as for some patients upfront. So I think this provides a lot of flexibility. This is not an option for most of the pan-RAS inhibitors because the strong concerns about added rash here. And I think for the 40% of patients who have PDAC that's G12D and the 20% of patients that have colorectal cancer that's G12D that this could be a really important addition either upfront or down the road.

Our next question comes from Jeet Mukherjee from BTIG.

Two for me. You certainly mentioned that 900 mg is looking like a very suitable go-forward dose. But I was just wondering if you could elaborate a bit further on why this hits the sweet spot. It looks like 1,200 mg is certainly still under evaluation. Was there some limiting factor with that dose perhaps? And then the second question was just related to the target studies. I think you've definitely mentioned that these are designed to be supportive of approval. Have you reached some degree of alignment with the agency on what the bar for approval is? It looks like ORR is a primary endpoint across several of the studies. Is there some threshold you need to exceed? Any details there would be helpful.

Michael, do you want to take those?

Sure. So just to be really -- it's a simple answer for 1,200. The capsules that we have right now -- I'm sorry, the pills that we have right now are 100-milligram pills. Asking patients to take 9 of these to give you 900 mg is the upper limit of what they can really handle in one swallow, if you will, or one session, if you will. For the 1,200, we're going to a split session of 6 and 6 split by about 30 minutes because we ask people to take it with food and plenty of water and so on to make sure it gets down there and everything. So it's just impractical to go much above 1,200 with the current pill size.

That said, we are certainly in the midst of constructing larger pills, which we'll update you guys on when we have that to a point where we think it's real. And hopefully, we won't be -- we don't expect to be marketing this as 100-milligram pills. We expect to be marketing it with higher pill sizes so that we don't have to give people that much. So it's pretty simple and straightforward. Once we have the larger pills, depending on what we see with 1,200, we may consider going higher. But right now, 1,200 is it.

As far as FDA's threshold, I mean, we have not had any discussions with them specifically about what this is. But thankfully, and I think the oncology division of the FDA has been superb about this, particularly for molecularly defined subsets of cancers. They have routinely approved drugs as low as 25%. Typically, the 25% to 30% ORR range is what's approvable as a single-arm study, provided there is sufficient durability. If you go to ASCO, most experts will tell you they want to see at least 6 months duration of response. You all keep in mind that, that's 6 months plus the 1.5 months minimum, it takes to get to a response. So you're talking 7.5 to 8 months at least on the drug, which for these kinds of tumors is pretty impressive, particularly in heavily pretreated patients. I think those are kind of the thresholds you should be thinking about 30% on the ORR number and 6 months durability, but those are general numbers, and it's always a review issue with the FDA.

And our final question comes from James Molloy with Alliance Global Partners.

This is Matt on for Jim today. Just 2 from us. In terms of the launch for A&F, the reimbursement for KRAS undefined and KRAS wild type, is that continuing at similar rates from previous quarters?

Yes, we've seen no change.

Okay. Excellent. And then do you guys have any anecdotes from treating doctors whose patients have been on treatment for over 8 or 9 months at this point? And if you could share, that would be very helpful.

Sure. I mean it's anecdotal at this point, given the fact we've only been out for just a year now. But there are patients that have done quite well that are both wild-type and mutant. And we also continue to interact with the sites on RAMP-201. And I recently spent some time with a patient that's been -- never achieved a PR with stable disease, but had a really transformational change in her ability to do things. She went from not being able to vacuum or living room to running a 5k and has been on our drug for, I believe, 3 to almost 4 years now.

And so we do have a lot of anecdotal information, even going back to the FRAME study, we had a number of patients staying on for a long time. So we do think when it's the right patient that we'll recapitulate what we saw in the clinical trial. As you may recall, in RAMP-201, we had patients from anywhere from 1 prior therapy to 10 prior therapies. And it tends to be less, I think -- of course, the more prior therapies you have, the more challenged the patient has. But I think the big difference in the real world versus the clinical trial will be performance status.

In most clinical trials, you're limited to performance status 01. And obviously, in the commercial setting, you take anybody who wants to come on the drug. And even though we did hear instances of patients going on cycle and coming off and then you can say, well, they probably shouldn't have gone on the therapy. We've also heard anecdotal stories of patients that were pulled out of hospice put on the drug and did well for a number of months and got a number of months with good quality of life they wouldn't otherwise wouldn't have had. And so those are great stories to hear, and we continue to monitor those. And we're very excited about the franchise. I think we've uncovered some things from seasonality, plus you learn as you go through the launch, and I think we've made some course corrections that it may take a couple of months to see the full benefit of. But I will say with confidence, we already are sure that we will see an increase from Q1 to Q2 that was bigger than the Q4 to Q1.

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

Good afternoon, and welcome to Verastem Oncology's Fourth Quarter and Full Year 2025 Earnings Conference Call. My name is Desiree, and I will be your call operator today. Please note this event is being recorded. [Operator Instructions]

I will now turn the call over to Julissa Viana, Vice President of Corporate Communications, Investor Relations and Patient Advocacy at Verastem Oncology. Please go ahead.

Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss Verastem's Fourth Quarter and Full Year 2025 financial results and recent business updates. This afternoon, we issued a press release detailing these results along with a slide presentation that we will reference during our call today. Both are available on the Investor Relations section of our website.

Before we begin, let me point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional detail.

Additionally, today, we will be discussing certain non-GAAP financial measures. Reconciliations to the most directly comparable GAAP measures are provided in the press release we issued today.

Joining me on today's call to deliver prepared remarks and take your questions are Dan Paterson, President and Chief Executive Officer; Mike Crowther, Chief Commercial Officer; Dr. Michael Kauffman, President of Development; and Dan Calkins, Chief Financial Officer.

I will now turn the call over to Dan.

Thank you, Julissa. Good afternoon, and thanks for joining our call today. 2025 was a truly transformative year for Verastem as we transition to a commercial stage company following our FDA approval of the first treatment specifically for KRAS-mutated recurrent low-grade serous ovarian cancer, nearly two months ahead of our PDUFA date. For the launch period of May through December 2025, we delivered $30.9 million of net product revenue and $17.5 million for the fourth quarter. I'm pleased to report that the strategies we put in place to guide our commercial launch continue to yield meaningful results. We continue to see steady growth driven by consistent adoption among both academic centers and community oncologists.

Before I continue, I want to address the updated NCCN ovarian cancer guidelines that were released last week and mentioned in our press release today. The guidelines did not expand the recommendation for avutometinib plus defactinib to include patients with the recurrent LGSOC, without a KRAS mutation. This does not change our launch trajectory. Everything we've been doing for the launch has been based on the guidelines that include the combination as a category 2A recommendation for KRAS-mutated recurrent LGSOC. We're disappointed for the patients with KRAS wild-type recurrent LGSOC, who currently have no targeted FDA-approved treatment options specifically for their disease and face a particularly poor prognosis.

Across three separate clinical trials, the FRAME study, RAMP 201 and RAMP 201J, we've observed what we believe are robust objective response rates for patients with recurrent LGSOC, with and without KRAS mutations. We remain committed to advancing the clinical evidence through longer-term follow-up analyses from the RAMP 201 study in 2026 and completing our ongoing confirmatory RAMP 301 Phase III clinical trial, which includes patients with and without KRAS mutations and look forward to sharing these data next year with the NCCN and the medical community to support future guideline consideration.

This clinical conviction and our confidence in our data is what underpins our commercial execution. As Mike will share with you shortly, we have an opportunity to continue to drive more growth through the expansion of our prescriber base and increasing their comfort to use AVMAPKI FAKZYNJA CO-PACK at first recurrence. With this approval, we've proven that precision targeting of RAS/MAPK pathway with the combination of avutometinib and plus defactinib can deliver meaningful outcomes for patients.

Cancer is highly dependent on this pathway for its growth and approaches [ that block ] just a single node in this pathway are generally insufficient for deep and durable anticancer activity. The cancer will compensate by activating other signaling proteins within the RAS pathway or in parallel pathways. This is what differentiates avutometinib plus defactinib and is defining our success in the market in the clinic.

The team's execution through the early phases of the launch has enabled us to quickly deliver this medicine to patients living with a rare ovarian cancer who previously had no approved treatment options specifically for their disease. Likewise, our R&D team has made great strides in advancing key strategic clinical trials. As with LGSOC, the combination of avutometinib plus defactinib has shown promising antitumor activity in pancreatic cancer, a highly KRAS-driven cancer and our RAMP 205 trial in first-line metastatic pancreatic cancer where combining avutometinib and defactinib with standard of care chemotherapy to improve response rates and other outcomes. Avutometinib can help to inhibit tumor growth while defactinib works to inhibit FAP to reduce the stromal density in the pancreatic cancer tumor and address adaptive resistance to avutometinib. The updated data we shared at ASCO last year demonstrates the potential for this combination in treating one of the most challenging cancers.

In addition to the avutometinib defactinib combination, we're targeting RAS-driven cancers with other novel therapies. This includes our other exciting pipeline program VS-7375 which has the potential best-in-class oral KRAS G12D ON/OFF inhibitor. Building on the unprecedented data from our partner in China, we moved VS-7375 into the clinic last year with a multi-indication trial strategy. Recent feedback from the FDA has given us a clear strategic path forward for clinical development. As a result, we'll be amending our existing VS-7375-101 trial protocol and separating our disease-specific Phase II registration-directed trials. This added clarity will help us move this program towards a potential accelerated approval pathway. Given the early results, we believe VS-7375 has the strong potential to be the preferred agent in treating KRAS G12D driven cancers on pancreatic, lung and colorectal. Michael will provide a more fulsome update shortly.

With all our clinical studies, we've made disciplined data-driven decisions to prioritize those with the greatest potential impact for patients living with RAS-driven cancers. This was demonstrated in our decision to accelerate the VS-7375 program towards registration-directed studies and with the discontinuation of avutometinib plus defactinib program in lung cancer in light of an evolving treatment like landscape despite an interesting clinical signal.

We have a wealth of opportunity but limits to our resources, and we'll continue to prioritize the opportunities with the highest value. We'll continue to closely manage our expenses and with our last financing and the exercise of the remaining cash warrants, we've extended our cash runway into the first half of 2027, giving us what we need to advance our near-term milestones. In fact, we believe the LGSOC franchise will be self-sustaining in the second half of this year with CO-PACK revenues funding both the commercial operations and any ongoing clinical trials for [ A+D ]. Our focus remains on identifying value-creating non-dilutive opportunities in this challenging environment as we advance our clinical programs and deliver for patients and shareholders alike.

With that, I'll turn the call over to Mike. Mike?

Thank you, Dan. I'll cover our commercial performance for the quarter, our launch progress in 2025 since our FDA approval in May and some perspective on how we see the launch progressing in 2026. As we have shared, a diagnosis of LGSOC is a life-changing event. LGSOC can affect women as young as in their 20s and the vast majority of these women about 80% to 90% experienced recurrence highlighting the urgent need for more effective therapies. In May of 2025, AVMAPKI FAKZYNJA CO-PACK became the first ever treatment specifically approved for KRAS-mutated recurrent LGSOC, forever changing the treatment landscape for this disease. Let me give you an example of the impact of the CO-PACK therapy.

Recently, we learned of a patient in her early 40s who had been diagnosed with LGSOC at age 30 and for several years, tried other systemic therapies, including chemotherapy. Following her second recurrence 4 months ago, she started in the CO-PACK and her most recent scans has shown a complete response to treatment. This incredible outcome underscores the benefit of using the CO-PACK. This is just one of many stories we are hearing from physicians treating people with this disease when other treatments were ineffective or a patient who experienced a recurrence, the doctor would give the difficult news that they have no other treatment to offer. This has all changed with the introduction of AVMAPKI FAKZYNJA CO-PACK.

For the fourth quarter, we delivered a solid finish to 2025. The steady growth momentum since our launch speaks to the demand we continue to see. The team is executing well against all 3 key strategic launch imperatives, effectively reaching health care providers, ensuring seamless access to coverage and engaging and supporting patients throughout the journey. Consistent with Q3, we saw encouraging signals in Q4 in both the breadth and depth of prescribing. The number of active prescribers continues to expand. And through February, there have been nearly 300 prescribers of the CO-PACK. Let me walk you through some of the launch dynamics we saw in the fourth quarter and have continued so far through the first quarter.

More than half of total prescriptions are coming from the academic setting, and we are seeing repeat prescribers write scripts for new patients. We are making good progress with our top accounts. Our top target institutions include both academic and community centers, about 75% of these organizations have either introduced or adopted AVMAPKI FAKZYNJA CO-PACK into their ecosystems, reflecting growing penetration across prescribers. The split of prescriptions between GynOncs and MedOncs remains roughly at 60-40 consistent with previous quarters. Our GPO accounts have started to incorporate the therapy second-line use into their internal EMR pathways, and we are actively partnering with their leadership on data analytics to find eligible patients within their networks. Payer coverage continues to be strong across all LGSOC prescribed patients regardless of mutational status. The tactical prescriptions continues to be in the range of 12 to 14 days due to rapid prior authorization approval and our payer mix remains consistent with previous quarters.

Our Verastem Cares program has been effective in helping patients manage through insurance processes. Approximately 60% of commercially eligible patients are using our co-pay program.

In our medical educational efforts, our medical science liaisons and oncology nurse educators have engaged in approximately 1,800 scientific exchanges and well over 700 educational engagements with health care providers through year-end. We saw high participation in multiple expert-led educational programs we supported for physicians to improve physicians' understanding of our treatment in the disease state. We provided a variety of tools to side effect management to help both prescribers and patients stay on the treatment and realize the benefits of the CO-PACK. This includes providing more education to prescribers as they gain experience and get more comfortable with the treatment. These resources are especially important where many community-based medical oncologists may see relatively few patients of LGSOC and appreciate support for patient management.

From a patient perspective, we continue to see high engagement in our branded website. Patients are opting in to receive more information about the CO-PACK to facilitate further discussions with their doctor.

This brings me to our plans for 2026. As the first company to develop and launch a treatment specifically for KRAS-mutated recurrent LGSOC, there were no well-established support systems in place for these patients and we have been working to build these systems, including providing education about the disease, increased awareness of our Verastem Cares program for insurance support and supporting patients as they learn about this new treatment option. As expected, while many physician's first experience with the CO-PACK is often in later lines, we will continue to focus on driving use of first recurrence that patients can receive the full benefits of AVMAPKI FAKZYNJA CO-PACK.

In the next quarter, we will be launching a new promotional campaign to offer physicians and patients to help them reimagine how this disease can be treated. The campaign will be supported by a comprehensive digital ad campaign to generate awareness about the availability of first ever treatment specifically for KRAS-mutated recurrent LGSOC and drive traffic to our product website to access more tools.

We are expanding our educational plans with additional peer-to-peer programs, including a new program that directly connects physicians with an expert in LGSOC to feel confident caring for patients with LGSOC and driving optimal outcomes. In addition, we will share support tools designed to increase depth within our active accounts while continuing to expand our reach in new patient starts. We are deploying our sales reps and those educators whenever a doctor prescribes the therapy to help them understand what to expect and use the tools we have created to manage through any adverse events. We have been focused on a fit-for-purpose launch, and as such, we've added a few additional field staff, including some sales reps, nurse educates and MSLs.

Due to the nature of this disease as a slow-growing cancer where patients stay on their first treatment for several years, we know it will take time to achieve peak share of first recurrence. We remain focused on our core launch priorities and sustaining steady growth. We're encouraged by the progress we have made, and we will continue building on our momentum throughout the year.

I'll now turn the call over to Michael.

Thank you, Mike. When I moved from Lead Director on the Board to Head of Development at Verastem last year, it was because I see significant promise in our pipeline and specifically believe that what we're building here with VS-7375 as the potential to significantly change outcomes for people living with KRAS-C12D-driven cancers. I'm proud of the progress our team has made in such a short amount of time. Let me start by recapping where we ended the year with avutometinib plus defactinib because 2025 was a defining year across our portfolio.

Our team completed enrollment ahead of schedule in our two avutometinib and defactinib clinical trials, RAMP 301 in LGSOC and RAMP 205 in pancreatic cancer. This positions us well for the catalysts ahead. On RAMP 301, because we completed enrollment early, we expect to report the top line primary analysis in mid-2027. As a reminder, this is our randomized international Phase III trial of avutometinib plus defactinib against standard therapy in recurrent LGSOC, with or without a KRAS mutation. It will serve as a confirmatory study for the initial indication and has the potential to expand the indication regardless of KRAS mutational status and to support future regulatory filings outside of the United States.

Turning now to some of our progress. For our Japan-specific RAMP 201J study in LGSOC, in collaboration with Japan's GOG, we shared an update of all 16 patients enrolled by investigator assessment that demonstrated a 57% overall response rate with KRAS mutant and a 22% overall response rate with KRAS wild-type recurrent LGSOC. This is the first ever study conducted in Japan for this disease. We look forward to sharing more data from that trial in the future.

And in Europe, we received growth in drug designation in ovarian cancer last year from the European Commission. We continue working through the steps needed for our future regulatory application once we have the RAMP 301 results in hand. For RAMP 205, our first-line metastatic pancreatic cancer study of avutometinib plus defactinib in combination with [ GEM ABRAXANE ]. At ASCO last year, recall we reported a confirmed response rate in 10 of 12 patients for an overall response of 83%. We completed enrollment of the expansion cohort and expect to share an update on the additional patients enrolled in the trial in Q2 of this year. We're excited with the progress we've made with our avutometinib plus defactinib combination trials which we believe has the potential to expand the franchise into new and larger markets.

Now turning to VS-7375. We moved quickly after licensing the product to secure FDA IND clearance and Fast Track designation, and we dosed our first patient in June of 2025, following the very promising early results from our partner in their trial in China and we've continued to build momentum since. Here's why the program matters so much.

KRAS G12D is an important mutation in pancreatic, colorectal and lung cancers along with lower prevalences in a variety of other difficult-to-treat cancers. There are no FDA-approved therapies targeting this mutation. We have taken a broad approach to generate data not only in these larger tumor types but also across other KRAS G12D cancers, such as biliary tract cancer.

We've made some exciting progress in a short time. We recently cleared the oral dose of 900 milligrams once daily in our dose escalation phase, and we're evaluating the 1,200-milligram daily dose. Our partner GenFleet selected the 600-milligram daily dose as their go-forward dose in China due to a strong efficacy signal. While we are advancing some of our cohorts using the 600-milligram dose, we're continuing on our dose escalation to the 1,200-milligram dose level to further interrogate the dose range and characterize the safety, tolerability and efficacy profile of our agent.

In addition, based on a preclinical synergy with dual RAS EGFR blockade, we are evaluating the combination of VS-7375 with cetuximab. We recently cleared 600-milligram daily dose level in combination with [ secure ] dose cetuximab, and we'll continue to evaluate higher doses in this combination.

I'm also pleased to share that the FDA recently provided feedback on our Phase I/II protocol. Per the agency's request, we are changing our initial Phase I/II trial, which had multiple expansion cohorts and breaking out several disease-specific Phase II registration-directed trials for KRAS G12D mutated cancers, including second-line pancreatic ductal carcinoma, second and third-line non-small cell lung cancer and with VS-7375 in combination with cetuximab in second line plus colorectal cancer.

Now let me move to discuss our recent PK analysis that we did. Doses of 600-milligrams daily and above with feeding and antiemetic prophylaxis yielded similar exposures to that observed in China with faster patients. And exposures achieved cover the exposures to preclinical models necessary for maximal antitumor efficacy.

From a safety perspective, we continue to be pleased with the profile we see emerging. We have the benefit of hindsight of our partners' trials in China, and we adjusted our protocols to directly address some of the tolerability issues that our partner has seen early on. As noted, the overall tolerability of VS-7375 in the United States appears to be better than that which was observed in China as we're able to escalate beyond 600-milligrams and now beyond 900-milligrams.

No drug-related liver function test abnormalities have been reported in any patient across any of the dose levels to date. No drug-related neutropenia in Grade 2 has been reported. And we included in the protocol strong recommendations for standard prophylactic anti-nausea agents and rapid institution of over-the-counter antidiarrheal agents as needed.

As a result, rates of nausea, vomiting and diarrhea are lower than those reported by our partner in China. The differentiation we are seeing from the data and our partner in China as well as early signals from our own trial give us strong confidence that potential of this asset to treat multiple difficult-to-treat cancers where there's a high end of medical need with a highly targeted once-a-day oral agent.

Looking ahead to this year, our goal is to generate a meaningful data set in each of these tumor types, both as single agents as well as in selective cancers in combination with other treatments. Initially, we plan to share an update on preliminary data in the first half of 2026. But as I said, because of our success to date, we're able to continue with the dose escalation and also enrollment into our various tumor cohorts. And this is really important, getting the optimal dose, of course, matters greatly. We plan to share a more fulsome data at our go-forward dose in the second half of this year.

Now I'll turn the call over to Dan Calkins.

Thank you, Michael. Our full financial results are included in our press release, so I'll focus on the highlights here. I'm also pleased to reiterate that we reported $17.5 million in net product revenue for the fourth quarter of 2025 and $30.9 million for the full year, which includes the launch period of May through December. Cost of sales were $2.6 million for the fourth quarter of 2025 and $4.6 million for the full year 2025 period. Cost of sales increased in the fourth quarter in line with the increase in net product revenue for the quarter. As we've previously communicated, we're not providing detail on gross to net other than to say that expectations should be consistent with other oncology small molecule therapeutics.

Turning to Research and Development expenses. They were $31.7 million for the fourth quarter of 2025 and $114.6 million for the full year. R&D expenses were driven by both the ongoing global confirmatory Phase III or RAMP 301 clinical trial and the ongoing VS-7375 Phase I/II clinical trial as well as higher costs associated with drug substance production activities related to 7375. SG&A expenses were $24.4 million for the fourth quarter and $81.1 million for the full year. The expenses were driven by commercial activities and operations, including personnel-related costs to support the ongoing CO-PACK launch. Directionally, for 2026, we would expect SG&A expenses to remain roughly the same on a quarterly basis as we continue to be disciplined in our expense management, making the right investments at the right time to support the ongoing commercial launch efforts while simultaneously advancing our pipeline.

For the fourth quarter of 2025, non-GAAP adjusted net loss was $39.8 million or $0.48 per share diluted compared to non-GAAP adjusted net loss of $29.3 million or $0.60 per share diluted for the fourth quarter of 2024. For the full year, non-GAAP adjusted net loss in 2025 was $163.1 million or $2.35 per share diluted compared to non-GAAP adjusted net loss in 2024 of $107.4 million or $3.01 per share diluted. Please see our press release for a full reconciliation of GAAP to non-GAAP measures.

Moving to the balance sheet. We ended the fourth quarter of 2025 with cash, cash equivalents and investments of $205 million including the proceeds of the expiring cash warrants, which were exercised in January of 2026, our pro forma cash balance as of December 2025 was $234.4 million. We believe our current cash, combined with the future revenues from AVMAPKI FAKZYNJA CO-PACK sales will provide cash runway into the first half of 2027. We are very encouraged by the initial launch and look forward to building on the CO-PACK growth into 2026. Given our current trajectory, I'm pleased to reiterate that we believe the LGSOC franchise will be self-sustaining in the second half of the year, with CO-PACK revenues funding both the commercial operations and any of our avutometinib plus defactinib clinical trials.

With that, let me turn the call back over to Dan.

Thanks, Dan. Before we open the call to Q&A, I'll spend a few minutes on 2026 priorities. 2025 has given us a solid foundation for the remainder of 2026, we'll stay laser-focused on 4 key strategies: first, maximize the commercial launch execution of AVMAPKI FAKZYNJA CO-PACK for broad adoption. Second, generate monotherapy and combination data with VS-7375 to expedite the execution of our registration path in major KRAS G12D solid tumors. Third, continued execution of the RAMP 301 confirmatory Phase III trial in recurrent LGSOC. And fourth, maintain prudent capital management through our key catalysts and a strong balance sheet. In support of these strategies, we set several goals in which to measure our success.

We want to maximize adoption of the CO-PACK to ensure every appropriate patient benefits from this novel treatment at their first reoccurrence. For our first-line PDAC study, RAMP 205, we plan to share an update on the expansion cohort in Q2. Finally, as we push to accelerate our VS-7375 trial, we expect to further demonstrate the breadth of our RAS/MAPK pathway driven approach and lay the path for expansion of our commercial product line. We plan to share an update on the 101 trial in the first half of this year. With the FDA's feedback in hand, we are creating Phase II registration-directed protocols for pancreatic, lung and colorectal cancers. Enrollment in the 101 trial is going well, and we anticipate being able to enroll the Phase II trials quickly. Our goal is to move forward quickly and efficiently to hopefully bring this treatment to patients who currently have no FDA-approved treatments to their KRAS G12D mutated cancers.

But having said that, while speed is important, we're always cognizant that bringing the best therapy to market is more important. We're privileged to have a commercial product with growing revenue and a robust clinical pipeline that addresses larger market opportunities. We're building a sustainable multi-asset oncology company to address important unmet needs in RAS/MAPK driven cancers. As we enter 2026, we're well positioned to continue to deliver on our milestones.

With that, we'll open up the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Eric Schmidt with Cantor.

Congrats on all the progress. Maybe on the NCCN non update, do you guys have any visibility into the thought process behind why wild-type patients weren't included? And then if you could comment on your confidence that wild-type patients can continue to gain reimbursement? I know they've been a meaningful cohort for you in the commercial setting to date.

Eric, thanks for your question. Look, we were -- it was disappointing, and we're a little surprised. We've not gotten any direct feedback. We're not really going to speculate. We suspect it might have had something to do with the imminent Phase III readout coming. We know they don't like to change things once they do add something. We don't see any difference to how we've been running our business and to the trajectory. I've said a number of times, it would be nice to have NCCN because it's kind of like air coverage and we're fighting a ground war right now on the reimbursement side. But our team has been doing a wonderful job securing reimbursement regardless of KRAS mutation status, and we'll continue to do the same thing.

So our message to our team to physicians and to patients is we're going to continue to do what we've been doing before. Ultimate adoption likely to be very much driven by the results of the confirmatory study because then we can actively promote, which even with the NCCN guidelines, we can't actively promote although we are allowed to share the publications that we have and both the FRAME study and the RAMP 201 study have results in both wild-type and mutated that we believe show benefit to patients, and we'll continue to share those publications.

The next question comes from the line of Michael Schmidt with Guggenheim Partners.

I had a couple on 7375. Obviously, the safety now looks very good in the U.S. study based on the detailed table that's included in the slide deck this quarter. Could you comment on what you've seen or if you have seen any dose modifications or perhaps discontinuations? So I'm just curious if you've seen any of those?

And then question on how you're approaching dose selection. I believe you've been enrolling patients and expansion cohorts at 600 mg QD, but obviously escalating further up to 1,200 now. So how do you think about dose selection for these planned Phase II studies?

And then lastly, just thinking about your combination strategy, maybe just comment on how you're thinking about the longer-term positioning of 7375 in the landscape -- in the RAS space. I know you've planned combination cohorts with approved center of care and various indications, but would it make sense perhaps to also consider combining with other novel agents, for example, pan-RAS inhibitors or other agents that are out there?

Michael, thanks for your question. I'll let Michael Kauffman address the questions for you.

Sure. I'll try to remember all of them and come back to me if I missed something. I think -- first of all, the number of dose modifications is low and slower than typically that I expect in various trials. And remember, these are heavily pretreated refractory tumors and the patients are doing well, the drug. So the tolerability is consistent with the data you saw on the table and then consistent with any modifications, the dropout rate is very low for the patients. So we're really pleased with what we're seeing. And that includes both the 600 and the 900-milligram cohort.

The second issue is how we think about escalation and evaluation of these doses because what we're really doing is kind of a 2-dimensional matrix here with dose escalation where we're increasing the dose now up to 900 and now beyond that. At the same time, we have to determine longer-term tolerability because that's the name of the game now with chronic cancer medicines and longer-term disease control and responses where we're looking for durable antitumor responses. So it's a 2-dimensional matrix for sure. We believe we can identify the proper doses evaluating 10 to 15 patients in each of these areas. And this is not going to be a long-term commitment. I mean these drugs tend to work quickly. Our drug, in particular, works quickly. and we're able to discern a lot of this stuff in several months.

But the other -- just to remember, it does take -- it still takes at least two CT scans to determine if someone has a confirmed response and sometimes the responses take more than the first CT scan. So we'll be looking at multiple months.

The last point on that is that the important achievements really are after 6 months because in all cases, we need to see prolonged disease control. And as you all know, thankfully, the minimum kind of numbers that we all want to see now even in these difficult-to-treat tumors is north of 6 months. So that's -- it will just take 6 months at least to affect this and understand it better, but we think we're going to be there in the not-too-distant future.

The last bit is the combination strategy. Yes, I mean, there's two goals here. One is regulatory, clearly, and the second goal is where is the puck going to sort of -- Wayne Gretzky quote of how to predict the future. And we'll be looking at both. But the primary goal here is to move these drugs initially into the second and third-line setting through these accelerated approval pathways, which the FDA has helped pave the way aggressively with us to do that and then to run into frontline studies with standard of care so that we can achieve regulatory approvals but then to start to investigate -- probably through investigator-sponsored trials, some of the novel combinations.

Our next question comes from the line of Clara Dong with Jefferies.

Congrats on all the progress. Just on the NCCN guideline update, do you have any plan to maybe reengage with the NCCN in the future with longer term data, maybe RAMP 301 data or on additional Japan data as well. And then for the FDA feedback at G12D, can you walk us through what specifically trigger feedback to separate the study into disease-specific and registration directive Phase II trials for the three indications?

Clara, thanks for your questions. I'll take the NCCN one and then turn it over to Michael for the FDA question. Yes, we intend to continue to develop evidence on the use of this molecule in both wild-type and mutated. We have a number of activities ongoing that I won't get into details on right now. And then, obviously, as I mentioned, when we have the readout from 301, that's kind of the penultimate randomized readout that will help with both NCCN and hopefully, with the label expansion at the FDA.

Michael, do you want to address the question on 7375?

Sure. We modified our protocol, our initial 101 protocol based on initial results that we were quite pleased with to expand the cohorts in each of the three major diseases as well as in a sort of tumor-agnostic cohort basically taking a page from the playbook of KEYTRUDA, where they use the Phase I trial to expand into lots of different places. The FDA since then, since the KEYTRUDA really has split the solid tumor divisions into multiple divisions. And based on that, pretty much was the driver for the FDA is saying, "Hey, we like your plan. But in general, cohorts that are going to be used for marketing authorization should be included in separate protocols." We didn't explicitly ask them for the marketing authorization, but we got the answer very clear in black and white, which was really gratifying. I mean they knew what we were trying to do. And when you put 80 to 100 patients in an expansion cohort, they know where you're going with this. And I think they were extremely supportive with us and excited about the kinds of data that we have provided both from China and the initial safety data from the U.S.

The next question comes from the line of Graig Suvannavejh with Mizuho.

Congrats on continued progress. I was hoping to get maybe some color on -- a little bit more color just on the prescribing dynamics for CO-PACK right now? I might have missed it in your prepared remarks, but usage between -- in the academic center versus the community setting and color on refills?

And then the second question, if I could, is just a question on financing and I'm wondering with things at your disposal, how are you thinking about future financing for the company to extend the cash runway beyond first half of 2027?

Yes, Graig. Thanks for your question. I'll take the second one first and then ask Mike to address your question on uptake. As we've said, and we think this is really important. We believe that launch for the [ A+F ] franchise will be self-sustaining by the second half of the year and won't require additional fundraising. So any additional capital that we have to access will be based on good data coming out of the G12D program.

We're looking very carefully at prioritizing what we need to do, looking at different vehicles to raise money. Obviously, going out and doing straight equity raises, creates dilution, and we like to avoid that as much as possible, especially at current stock prices and are looking at a number of different ways to stage things over time to make sure we've got enough runway, but we're being prudent in how we raise that money. Non-dilutive approaches are ones we're spending a lot of time looking at. We have had a lot of strategic interest, not saying that there's anything imminent or that we're going to go ahead and out-license the program, but there's a lot of flexibility when you have a lot of interest from folks. And I think there is a growing consensus that this is probably a best-in-class molecule, and I think that gives us a lot of degrees of freedom. And so we'll continue to look at different ways to fund it, and we'll be prudent in doing it over time.

Mike, maybe if you want to address the other part of the question?

Sure, Dan. Thanks for the question. We're not giving specific guidance on patient numbers or refill rate yet since we're still early in the launch. But I can certainly give some color about the prescribers and some other factors.

So we've continued to grow the number of new prescribers through February. There have been nearly 300 total new prescribers. Month over month, our field team is making some really good headway with our top accounts. Our top institutions include both academic and community centers and around 75% of these organizations have either introduced or adopted the CO-PACK reflecting growing penetration across the providers. The split of prescriptions remains roughly 60-40 between GynOncs and MedOncs, which is consistent with our previous reports. More than half the prescriptions are coming from the academic center. We expect that split to be consistent with the community over time.

And importantly, as we talked about our Verastem Cares program, has continued to perform incredibly well with short times for reimbursement and fills between 12 to 14 days and about 60% of our commercially eligible patients are using our co-pay program.

The next question comes from the line of Leonid Timashev with RBC Capital Markets.

I want to ask on 7375's safety. Just to ask you guys to elaborate a little bit more on that. I've got three questions, but hopefully, they're all related. I guess the new cut of data looked quite encouraging, but I was just trying to better understand how much we can lean on that versus what we saw coming out of China. I guess if you have any insights into what might be different across those two populations to lead to such a different safety profile. And then if you could also remind us on the kinetics of when some of these events might occur, particularly via the heme events or the liver signals just given that these patients have been followed for just -- only about 1.6 months, I think, it said.

And then lastly, I know you guys were also working at some point on some potential formulation improvements that you were going to effect later on. I'm just curious how much further those could potentially improve some of the GI tolerability?

Michael, do you want to address those questions?

Sure. The data that we provided to you that are all in the database and cleaned and all that, pretty clean, they're not completely clean, but they're representative for sure. and they're very consistent with what we're hearing ongoing now even -- these data were with a date cut off more than a month ago. So I think we've not heard of anything new and the drug is behaving very well, including at the higher dose of 900 milligrams.

The cadence of these side effects are pretty straightforward. The nausea and diarrhea and vomiting, as you know, are all pretty fast, and we've really taken them down to pretty much Grade 1 and a lot of the Grade 1 goes away over the first week or two with the proper use of antinausea agents like standard Zofran or palonosetron or one of the other 5-HT3 agents. And sometimes, patients which is typical of any drug if they don't have complete cessation of nausea. I mean, nobody wants to have any nausea, then we'll -- the docs will add a second agent and really cleans it up. So those issues have been largely dealt with diarrhea is we don't prophylax against it, but we absolutely come in and the docs have been requested to come in very quickly with over-the-counter drugs to counter that, and it's very easy to get under control.

We don't expect to see much in the way of emergent heme tox. We've not seen it. We have similar entry criteria to what they required in China to get onto the trial. So I don't think this is a baseline bone marrow, I should say, baseline to cell count issue. It's probably a health of the bone marrow issue. I suspect that we're using a lot more growth factors here in America than they do in China. And so when the patients who all got chemotherapy at least once and usually multiple times coming on to our trial are probably having better bone marrow support coming in. I suspect that's the major reason.

I don't expect to see much in the way of liver function abnormalities. We haven't seen that. We are aware, and I think probably everybody is aware that patients in China tend to use a lot of natural products and a very inconsistent quality that have all kinds of liver abnormalities as well as other abnormalities associated with them. And we've really tried to make sure that our patients here tell their docs about any organic or general nutrition center kind of supplements they're using and really to limit all of that. So I don't know if that's the reason we're not seeing the liver signals, but we're really very comfortable with how this drug is behaving.

Lastly, as far as formulation is concerned, we are looking into whether something like enteric coating could be helpful here or not. It's really important for us to get -- obviously figure out which dose we're going to use. And my gut feel is we're going to end up at the 900, but that's just a, no pun intended, my gut feel. Once we figure out the dose and we understand better the side effect profile in the setting of standard antinausea agents, we'll be able to make some decisions on formulation. But I think there is some room for a formulation to help things.

The next question comes from the line of Yuan Zhi with B.Riley Securities.

Can you expand on the impact of this protocol update on your clinical development? What's the real impact or change there? Was it narrowed patient enrollment criteria or fewer doses to be tested there?

Thanks for the question. I I'll let Michael elaborate, but it's essentially an administrative change where we're just breaking out into separate protocols and working to streamline things to get the new protocols in place at our current institutions. Anything more you want to say, Michael?

No, that's -- I don't think there's going to be a significant time line hit. We're going to be going -- we'll be sending the protocols in with a cover letter that basically explains is, as Dan said, this is administrative, there's no new safety change. There's no informed consent change. It's just a different protocol basically so that each of these can go to the proper part of the FDA.

Got it. On the dose selection part, do you see a possibility to do maybe a [ titration ] meaning starting at 900 or 1200 milligrams and then using 600-milligram as maintenance dose if needed?

Michael, do you want to address that?

Sure. Look, it's -- one thing we've learned about most cancer therapies, not all, but most, over the years is that starting high and blasting the tumor because it's really a vicious war, getting it under control and shrinking it. And as you suggest, which is sort of an induction, if you will, followed by maintenance is probably okay. Honestly, we have any reason to believe yet that we're going to need to lower the dose. It's fairly early with our U.S. experience. And I'll remind folks that in China, they were not able to get to 900 milligrams. So we have a number of patients ongoing now with 900 milligrams over many, many weeks and there doesn't seem to be a major issue. That said, of course, there will be time for patients to reduce their dose. But I'm not sure it doesn't seem like it at this point that we're going to need to reduce the dose.

[Operator Instructions] And we'll take our last question. It comes from the line of James Molloy with AGP, Alliance Global Partners.

Matt on for Jim today. Congrats again on the continued progress. So firstly, I wanted to ask about the RAMP 201J trial. The updated data look positive to us. But can you just take us through the next steps in Japan for the [ A+D ] combo?

Sure. There's a couple of things going on in parallel. One is all of the institutions that participated in the 201J study have now been converted over to the confirmatory study. Although we've completed accrual in the rest of the world, we do want to have enough Japanese patients on there so that we can have final approval in Japan. But the intent is to meet with the PMDA and discuss using the bridging study for conditional approval. And steps are underway for that right now. And I think we've guided that we'll probably file early next year when we have enough follow-up.

Got it. And then in terms of the U.S. launch, is there any specific insight into the payer coverage of KRAS wild-type patients? Do you have any number or like ballpark of how many of these cases have been covered since launch?

We don't have specific numbers on the number of cases. What I will say is our most common group of patients are of the KRAS mutant. The second biggest group is KRAS unspecified. We're seeing a lot of prior [ auths ] put in, where they're not putting the status, and those seems to be going through pretty smoothly. And then the third group is the KRAS wild type, where we've said a number of times, we're having really good success getting those paid for too. And I think it's an indication of the high unmet need.

And then if you look at the totality of the data in the publications that we use and submit to the payers, these patients do appear to be benefiting where we have gotten some tightening in the last quarter or so is what I would call the totally off-label. So brain, lung, PDAC, we have seen a little pushback from payers on those. And that's not to be unexpected. I think in the early days, you sometimes get a bit of a honeymoon period. And in PDAC, we're talking the data set of 12 patients. And then in -- some of these other diseases that it was slipping through really not a lot of support. And so we're very pleased with what we're seeing to date. I think our specialty pharmacy and our hub are doing a great job, and we're hoping to see that continue.

That concludes the question-and-answer session. Thank you all for joining in. You may now disconnect. Everyone, have a great day.

Good morning, and welcome to Verastem Oncology's Third Quarter 2025 Earnings Conference Call. My name is Liz, and I'll be your call operator for today. Please note, this event is being recorded. [Operator Instructions] I will now turn the call over to Julissa Viana, Vice President of Corporate Communications, Investor Relations and Patient Advocacy at Verastem Oncology. Please go ahead.

Thank you, operator. Welcome, everyone, and thank you for joining us today to discuss Verastem's Third Quarter 2025 Financial Results and recent business updates. This morning, we issued a press release detailing our financial results for the quarter and year-to-date. This release, along with the slide presentation that we will reference during our call today, are available on our website. Before we begin, I would like to remind you that any statements made during this call are not historical and are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent annual report on Form 10-K filed with the SEC on March 20, 2025, and the current report on Form 10-Q that will be filed later today as well as other reports filed with the SEC. Any forward-looking statements we make represent Verastem's views as of today, and we disclaim any obligations or responsibility to update. Joining me on today's call are Dan Paterson, President and Chief Executive Officer of Verastem, who will provide opening remarks and recap key highlights from the quarter. Matt Ros, Chief Operating Officer; and Mike Crowther, Chief Commercial Officer, who will walk through the continued progress of the AVMAPKI FAKZYNJA CO-PACK commercial launch; and Dan Calkins, Chief Financial Officer, who will provide an overview of our financial results. I will now turn the call over to Dan.

Thank you, Julissa. Good morning, and thank you for joining us today to discuss our third quarter financial results and business update. In Q2, we shared our excitement about achieving FDA approval for AVMAPKI FAKZYNJA CO-PACK in KRAS-mutated recurrent low-grade serous ovarian cancer, or LGSOC, and reported our first 6 weeks of commercial performance. Today, I'm pleased to share that the strength we saw in those initial weeks has accelerated. With a full quarter of commercial operations now complete, the fundamentals we put in place to guide our commercial launch are translating into meaningful results.

Our third quarter net product revenue of $11.2 million surpassed our expectations and was driven by consistent adoption among both academic centers and community oncologists. We set 3 key objectives to support our commercial execution and drive sustainable growth. Physician engagement, patient initiation and retention and streamlined reimbursement, all 3 are trending positively. We're simultaneously advancing our broader strategic priorities, specifically expanding the opportunity set for AVMAPKI FAKZYNJA CO-PACK and accelerating the clinical path of VS-7375, our KRAS G12D (ON/OFF) inhibitor program. Let me highlight a few achievements.

We completed the enrollment of our expansion cohort in RAMP-205, our first-line pancreatic cancer trial evaluating avutometinib plus defactinib and standard of care chemotherapy. We completed the planned enrollment of our confirmatory Phase III clinical trial, RAMP-301 in recurrent LGSOC, and we'll be making a modest increase in enrollment per the IDMC's recommendation. This does not have a meaningful impact on our expected time lines. We shared initial safety and tolerability data from our G12D program with VS-7375. We cleared 2 monotherapy doses with no dose-limiting toxicities. We reported that we did not observe nausea, vomiting or diarrhea above Grade 1. Importantly, these dose levels included the Phase II go-forward dose that was chosen by our partner in China.

We're now moving ahead of opening the combination cohort with cetuximab. These are exciting developments that add to our continued success. In the fourth quarter, we remain focused on our 3 key launch objectives and maintaining our execution discipline across all commercial, clinical and operational functions. Let me now turn the call over to Matt to review some specific highlights from the third quarter.

Thank you, Dan. The strong AVMAPKI FAKZYNJA CO-PACK growth reflects the high unmet medical need and physician enthusiasm for this first-ever treatment option. The team has achieved significant results since our May approval, and we continue to execute well against all 3 strategic launch imperatives. Dan touched upon these, and they are: first, to effectively reach health care providers, remembering that the top 100 commercial health care organizations comprise about 50% of the sales opportunity. Second, to engage and support patients throughout their journey as we know that as patients progress through other therapies, many will be ready for a new treatment option. And third, to ensure seamless access so we can support patients and ensure any barriers to reimbursement are removed.

Our approach is highly targeted, and we're utilizing a deliberate mix of one-on-one meetings, group discussions and conference engagements to maximize the impact of every interaction in this rare disease market. Thus far, each element of this approach has proven to be successful. As Dan shared, we generated $11.2 million in net product revenue in the third quarter, which was our first full quarter of launch. We've leveraged the momentum from the first 6 weeks of launch and uptake has been strong. With 133 prescribers of that AVMAPKI FAKZYNJA CO-PACK, physician excitement is palpable and our field teams continue to do an excellent job in engaging with health care providers to ensure they understand the unique benefits of the CO-PACK and how to administer.

Consistent with Q2, we continue to see prescriptions generated by gynecological oncologists and medical oncologists. This well-rounded base of prescribers reinforces the touch points our teams are making across our top 100 organizations and Tier 1 and Tier 2 targets. We are experiencing high levels of engagement within community practices that are either large affiliated practices or are associated with group purchasing organizations. We are directly contracting with the GPOs and conducting educational programming. We are also having meaningful success in accounts that are typically closed to sales representatives. We continue to engage and support patients with outreach efforts to help educate them about the treatment and support their conversations with their doctors.

And while we won't be speaking to future trends or prescriptions at this time, we are encouraged by specific insights following our first full quarter of launch. Approximately 65% of prescriptions written have been generated by our top 100 organizations. What's great about this is that we are making strong headway in our Tier 1 and Tier 2 accounts, but we are also seeing prescriptions coming from other accounts as well. We believe that speaks to the strength of the data and brand awareness. More than half of total prescriptions are coming from the academic setting, and we expect the split to be consistent between the community and academic setting providers over time. 60% of the prescriptions written are coming from GYN oncologists and 40% written from medical oncology.

Our specialty distributors are now fully on board, and we see a good mix between the 2 specialty pharmacies onboarded in Q2 and the 4 specialty distributors we added this quarter. The initial orders across our specialty distributors were managed closely and have been consistent with the initial orders from our 2 specialty pharmacies at launch. For these reasons, we believe inventory stocking has been minimized, and we plan to continue to manage this closely through year-end. Lastly, reimbursement has not been a barrier to any access, and Mike will provide more specifics in that regard shortly. Looking at the fourth quarter, we aim to continue to build on our momentum while staying laser-focused on our strategic imperatives to ensure every appropriate patient benefits from this novel treatment.

The key opinion leader community continues to reinforce our thesis that every KRAS-mutated LGSOC patient should not only receive this treatment, but should do so at their first recurrence. Given our early achievements, our team's effective execution and the high unmet need in this rare form of ovarian cancer, we believe we are well positioned for continued growth. Now I will turn the call over to Mike to speak further about the launch dynamics. Mike?

Thanks, Matt. Let's get right into the specifics of our AVMAPKI FAKZYNJA CO-PACK launch. I'm extremely pleased with how well the launch is going as net product revenue growth accelerated in the third quarter. While we consider ourselves still in the early days of launch, the underpinning of success is built upon the breadth and reach of our field engagement to raise awareness of the availability of the first-ever treatment, specifically for people living with KRAS-mutated recurrent LGSOC. These impressive results are driven by a few key factors: high unmet need, increased engagement with both academic and community oncology practices, expanding reach and removing barriers to access through specialty distributors and their GPO partners and continued efforts to ensure seamless access.

From an engagement standpoint in the third quarter, we have had high engagement among our top 100 organizations and top 100 offices, which includes a mix of academics and community providers. These efforts have resulted in approximately 65% of prescriptions coming from them and specifically within our Tier 1 and Tier 2 accounts. We continue to see both repeat prescriptions from physicians prescribing to multiple patients and refill for patients given the CO-PACK's favorable safety profile. An important insight we have gained is that HCPs treating LGSOC have a good understanding of where their patients are in the treatment journey and are keeping CO-PACK top of mind for when the patient's current therapy fails due to either intolerability or clinical progression. Doctors continue to share that they are actively assessing and identifying patients that may become appropriate candidates for this targeted combination therapy, demonstrating that our efforts with HCPs are creating visibility into new patients becoming available for treatment.

Additionally, the awareness about AVMAPKI FAKZYNJA CO-PACK is high. Our medical science liaisons and oncology nurse educators have engaged in 800 scientific exchanges and well over 100 educational forums with health care providers within this quarter alone. We believe payers are acknowledging the unmet need that can now be addressed by the CO-PACK as well as the clinical value of the combination therapy. The payer coverage continues to be broad and the time to fill prescriptions has been fast within approximately 12 to 14 days. We can also confidently share that covered lives has now exceeded 80% and that the payer mix for our combination therapy is about half commercial and half Medicare. From a patient perspective, we continue to see high engagement in our branded website.

Our digital campaign is effectively driving traffic to this resource and patients are downloading our patient brochure and opting in to receive more details associated with how the CO-PACK can be appropriate for them. To close, we strongly believe that the AVMAPKI FAKZYNJA CO-PACK combination therapy has the potential to make a significant impact on the lives of patients who previously had no treatment options specific to their disease. With several months now under our belt, the team is executing well against all our launch objectives. We continue to believe a steady adoption will occur over time, and our early observations post approval support this perspective. I look forward to sharing more in the coming quarters as we progress through the launch and gain more experience and insights. With that, I'll turn the call over to Dan Calkins to provide an update on our financials.

Thank you, Mike. We issued a press release before the call today with the full financial results so I'll focus on the highlights for the third quarter. In our first full quarter of launch, I'm also pleased to report $11.2 million of net product revenue for the third quarter. Cost of sales were $1.7 million for the third quarter of 2025 and did not include a significant amount of product costs as inventory produced prior to FDA approval was fully expensed at the time of production. Currently, we're not providing guidance on gross to net other than to say that expectations should be consistent with other oncology small molecule therapeutics. Turning to research and development expenses. They were $29.0 million for the third quarter of 2025. R&D expenses were driven by both the ongoing global confirmatory Phase III RAMP-301 clinical trial and the ongoing BS-7375 Phase I/IIa clinical trial as well as higher costs associated with drug substance production activities related to BS-7375.

SG&A expenses were $21.0 million for the third quarter. The expenses were driven by commercial activities and operations, which included personnel-related costs to support the ongoing CO-PACK launch. We continue to be prudent in our expense management, making the right investments at the right time to support the ongoing commercial launch efforts while simultaneously advancing our pipeline. For the third quarter of 2025, non-GAAP adjusted net loss was $39.4 million or $0.54 per share diluted compared to non-GAAP adjusted net loss of $35.3 million or $0.88 per share diluted for the 2024 quarter. Please refer to our press release for a reconciliation of GAAP to non-GAAP measures.

Moving to the balance sheet. We ended the third quarter of 2025 with cash, cash equivalents and investments of $137.7 million. We believe our current cash, combined with future revenues from AVMAPKI FAKZYNJA CO-PACK sales and the exercise of the outstanding cash warrants provides runway into the second half of 2026. We had a solid first full quarter as a commercial company. We have sufficient capital to fund our ongoing commercial launch in the U.S. and continue advancing our current clinical development plans. With that, I'll turn the call back over to Dan.

Thanks, Dan. Before we open the call to Q&A, I'll share a few final remarks to close out today's presentation. We've seen another strong quarter of execution at Verastem as we continue to deliver on all our strategic priorities, meeting our key milestones and delivering a strong commercial launch. As we're in the final quarter of 2025 and look to 2026, I want to reaffirm our strong confidence in our growth trajectory and the significant value creation opportunities ahead for our company and shareholders. Commercial execution remains a top priority. The fundamentals are driving AVMAPKI FAKZYNJA CO-PACK adoption and the launch is progressing as planned. Our clinical pipeline continues to advance on multiple fronts. We expect several important data readouts in the first half of 2026 that will further demonstrate the breadth of our RAS/MAPK pathway-driven approach.

We expect to share safety and efficacy results from our RAMP-205 expansion cohort in first-line advanced pancreatic cancer in the first half of 2026. We also plan to share initial results from our Phase I/IIa trial evaluating VS-7375 and advanced G12D mutant solid tumors in the first half of 2026. We'll continue to advance our trial of VS-7375 in both monotherapy and combination expansion cohorts in pancreatic, lung and colorectal cancers. Importantly, we believe VS-7375 has demonstrated significant and best-in-class potential among KRAS G12D inhibitors to date in both advanced pancreatic cancer and lung cancer. And we're committed to moving quickly to registration-enabling studies in these and other high potential priority indications. This is an active area of focus for the company, and we plan to engage with the FDA in the first half of 2026 to discuss our path forward.

This would include seeking their input on how to harmonize the abundance of existing data generated by our partner in China to advance the program efficiently on behalf of patients who currently have no FDA-approved treatments for their KRAS G12D mutated cancers. We now have a commercial product generating growing revenue and a robust clinical pipeline with multiple near-term catalysts that will determine the future development plans. We are building a sustainable multi-asset oncology company to address important unmet needs in RAS/MAPK Pathway-Driven cancers. With that, we'll open up the call for questions. Operator?

[Operator Instructions] Your first question comes from the line of Michael Schmidt with Guggenheim Securities.

On the LGSOC launch, yes, just wondering if you could provide a few more comments on how the product is being used in the market in terms of patients having had prior lines of therapy. I'm just thinking about some of the market dynamics around incidence of new patients that relapse versus that sort of existing prevalence pool. How is the product being utilized in that context? And what are you seeing in terms of KRAS mutant versus wild-type use?

Yes. I mean we're early in the launch. So you do end up seeing some patients with later lines of therapy, but we're also seeing patients that are first recurrence, and it is a mix of wild-type and mutant as well as some just off-label totally. We don't have exact numbers on that. Again, we don't see total visibility of that through the distribution channel that goes through the distributors as opposed to specialty pharmacy. And we don't always have a good view in the total number of lines of therapy. I don't know, Mike, if you wanted to give a little more color.

Sure, Dan. I mean, consistent with what you've said, we've seen a variety of patients across a range of lines of therapy. We're not always giving the information about what prior therapies they've been on, but obviously, they've seen most of the classical mix of chemotherapy, AI, bevacizumab plus or minus a MEK inhibitor. Since we're promoting just on label, the vast majority of our patients that we've seen so far are KRAS mutant LGSOC.

Great. And then a question on the RAMP-301 study update. Just curious if you could comment on what type of analysis the IDMC did? Was this just looking at event rates and adjusting for event rates? Or did they perhaps look at additional information in terms of effect size? Any comments there would be helpful.

Yes, great question. I mean, to be clear, we're blinded by what the IDMC did. And we had put this interim analysis in place because -- and we've mentioned this before, there wasn't perfect information on the comparators. There weren't prior studies with prospectively broken out KRAS mutant and wild-type. And we tried to keep the sample size as low as possible, but also have the ability to be able to upsize that if needed. I'm optimistic because the number of recommended additional patients was relatively small, about 30. It was across both wild-type and mutant, which, again, I think speaks to them being within the range. And what I was told is because the study accrued faster than we had projected, there were less events than one normally would have had. And I think part of the reason for adding a couple more patients is there just aren't enough events yet really to draw any definitive conclusion, and we want to make sure we're -- we have enough patients to be in the range.

And congrats again on a great quarter.

Your next question comes from the line of Justin Zelin with BTIG.

Congrats on the strong quarter. I wanted to ask about the NCCN committee review in October, if you had heard back on a recommendation for the labels to be expanded to include KRAS wild-type patients? And I have some follow-ups.

Yes, that's a great question. And to be clear, had we heard, we would have told people, we don't know. We know the committee met. We don't know the outcome of that yet.

Got it. Do you have an expectation on any time lines on when you might expect to hear back?

We actually don't. We've heard it can be as long as early next year, could be earlier. I think different committees operate differently. We've not been given a lot of guidance. It's a relatively opaque and what I would say, secret process, and they've all signed NDAs and things. And so as much as I would love to know the outcome of the meeting, we just don't know yet.

Understood. And maybe just one additional question just on the commercial launch. Do you have any color on new patient starts versus patients who are refilling prescriptions as far as contribution to your strong quarter?

Matt, do you want to take that one?

Yes, sure. Great question. We aren't providing that level of detail or specificity on new to Rx refills. However, we are continuing to see significant new prescriptions come in for patients and patients that have started on therapy, particularly in the beginning of the third quarter have continued to receive refills. So we are seeing the dynamic in the marketplace, but providing that level of granularity at this point is a bit too premature for us. We wanted to see another full quarter or 2 underneath our belts before we provide that level of detail.

[Operator Instructions] your next question comes from the line of Sean Lee with H.C. Wainwright.

Congrats on a good quarter. I just have 2 quick ones. First, on the LGSOC market. I was wondering whether you could provide some details on what are you seeing in terms of patient retention. Correct me if I'm wrong, I think on the clinical study, the average treatment duration was about 10 months. So it's still a little bit early for that. Maybe if you can provide some color on the patient dropout rates, has that been in line with what you expect?

Yes. I would say it's really early to tell. And actually, average duration was about 18 months in the clinical trial. I don't know, Matt or Mike, if you want to provide any more color. It is really too early to tell.

Yes. I mean it's a great question. Dan is right. The performance of the CO-PACK in the clinical program, the DOR was around 18 months. We're seeing patients that are coming in at first recurrence. And so we would expect if they're coming in, in an earlier line of treatment that the benefit would be prolonged, but it is still fairly early to provide specific commentary.

I see. My second question is on the VS-7375 study. I was wondering whether there are any significant differences between how you're treating the patients compared to the study that your partners running in China? Because I think I recall that you were discussing some prophylactic antiemetics and such. Are there any notable differences?

Yes. Thanks, Sean. That was a great question. Yes, one of the things that we've said we were doing differently is -- and this was based on experience with the G12C inhibitors being developed and a number of our investigators participated in those studies is really the differences where the patients in China were fasted. This first couple of cohorts we treated in the U.S. were fed. They were also mandated to have prophylactic antiemetics, which is not a part of the protocol in China. And part of the reason we released the information on the first 2 cohorts is, a, we thought it was important that we cleared those first 2 cohorts, which included the recommended Phase II dose in China without any DLTs. But also the early data that we're seeing is that those interventions are making a difference. And as we said earlier, we didn't see any GI toxicities, nausea, vomiting, diarrhea that were greater than grade 1, which we were very happy to see, and we hope that carries forward.

Your next question comes from the line of Yuan Zhi with B. Riley Securities.

Congratulations on the commercial launch. And maybe my first question is for your confirmatory trial, can you remind us what was the enrollment plan for the KRAS mutant patient population and the KRAS wild-type patient population separately?

So the total enrollment was planned for 270, and there were guardrails to set up to keep the amount somewhere between 1/2 and 1/3 KRAS mutant to mirror the population. And so this accrual has come out that way. And as I mentioned, the data monitoring committee recommended that we put a couple more patients on both of those groups. And so we were glad to see, a, that it was a small number of patients that actually could have gone up quite a bit and that it was both arms, which tells us that we're in play with both of them.

Got it. My second question is, what is your next step or priority in the commercial launch? Do you plan to target more prescribers or just make sure a higher number of prescription per doctor?

I would say both. We're not going to change what we're doing. We feel that between our direct calling on individual doctors, the programmatic work we're doing with the organizations and our digital work as well as reaching out to patients that we're covering the waterfront. So we're not planning on changing what we're doing, but it's really a matter of making sure existing prescribers continue to prescribe. New prescribers come on because in any launch, you've got early adopters, mid-adopters, late adopters, and we're working through that chain. And then importantly, that when patients go on, they stay on.

Got it. Maybe before I jump back to the queue, my last question is on the patient's journey. So let's say a patient got their prescription, how long do they have to refill? And how often do they have to visit the doctors to check either symptoms or any side effects? Additional color will be very helpful.

Yes, Mike, do you want to take that one?

Sure. So prescription is for a month supply, 3 weeks out of 4. And in terms of doctors' visits, there is a small amount of visits to begin with just to make sure they're being monitored closely for early toxicities, but that rapidly goes down to every 3 to 6 months.

Your next question comes from the line of Eric Schmidt with Cantor Fitzgerald.

Apologies, I hopped on a little bit late. But with regard to the RAMP-301 IDMC recommendation to moderately upsize the study, can you talk about what the potential outcomes could have been through that look and what data the committee had access to in order to make the decision?

Yes. So the committee had the full data set and the outcomes could have ranged from everything from futility adding, I believe, up to 100 patients to they could have added none. Again, we're blinded to the actual results, but our understanding was there were less events than one would have anticipated given the rapid accrual and that may have led to the small number of patients being added on, but they are being added on to both KRAS wild-type and mutant and it's about 30 across the 2 groups.

So that's helpful. There wasn't any prespecified criteria for adding the 30-ish, 27 patients -- sorry, 29 patients. It was just what the IDMC chose to do, that number?

My understanding is it was within their purview and they made a recommendation to us and we followed it. And again, we don't have full transparency into exactly what they were doing.

And then maybe switching to the 7675, the G12D in your ongoing study. We're very clear that GI tolerability was good in the first dose with no more than grade 1 cases of GI issues. Were there any other side effects to report in that initial cohort? Anything at all of grade 2 or 3?

Well, I believe there were some grade 2 or 3 in very, very small numbers, but nothing -- no signal that we had not expected based on the Chinese data. I think the only thing that was really different was the level of GI tox. And we'll give a more full release of the full efficacy once we've got a few more patients on. I think we've guided early next year, we'll give an update on both efficacy and safety.

Your next question comes from the line of James Molloy with Alliance Global Partners.

I was wondering, could you share any sort of anecdotal updates from the launch, talking to the usage and potential off-label usage on the wild-type versus mutant and sort of any feedback you're getting early stages of the launch? And then I have a couple of other questions as well.

Sure. Mike, Matt, you guys want to give a little more color?

Sure. I mean I think as we shared in our scripted remarks and an earlier question, we're promoting obviously, our labeled indication. So the vast majority of use we've seen thus far has been within the KRAS mutant LGSOC population. That doesn't mean there haven't been wild-type patients because they have, and those have also been seeing coverage through the payers as well thus far.

Okay. Great. Then maybe a follow-up, looks like there's been some M&A in the oncology space recently. You guys are obviously off to an excellent launch here. Any thoughts -- care to discuss any inbound interest you may or may not have from other partners?

I mean obviously, we wouldn't talk about any specifics. But given the launch trajectory to date, and I'd say even more so the excitement around G12D and how the molecules perform both preclinically and clinically. We do get a fair amount of inbound interest and entertain those discussions all the time. We've got some very exciting plans to take these forward, but we're always evaluating could we do more with more resources.

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