Verastem, Inc. (VSTM) Earnings Call Transcript & Summary

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 KRSG12D-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 KRS-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 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; and Dr. Michael J. Kauffman, President of Development; Dr. Ting Mu, Vice President of Clinical Development; and Dr. Manuel Hidalgo, who is the Director of Gastrointestinal Cancer at NYU Langone Health and Professor of Medicine and NYU Grossman School of Medicine. And as many of you know, he's a lead medical oncologist, and he's currently also an investigator in ongoing trials. Along with our presenters, Dr. Jonathan Pachter, our CFO, 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 Gen fleet to have G12D selective agent. Everyone's been talking about Pan RAS versus G12D. And I think within the last month or so, I think folks have come to realize, Red Med 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 are a couple of key things that we really needed. We wanted it to be potent very selective, on off inhibition. And 1 of the more important things and if we go back a year or so ago, and you looked at it 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 1 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 they're 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. Well, as the data started to emerge with this molecule, I could -- I just kept running on to the field and getting penalties. So finally, I just said I better joined the team. and Dan lead me. 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 1 of my colleagues. So it is absolutely thrilling honestly 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 [indiscernible], 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 Paras 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 one o one 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 III 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 the 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 PANCRIC study, as you heard, will start by the end of this year, and we expect the lung and the colorectal Phase IIIs, 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 [indiscernible] here. There's -- this is MITT. -- it's every patient we've treated. It's the -- this is the cohort of 900-milligram pancreatic treated patients in our Phase I. 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. We 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. Five out of the 14 patients who had a 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 III trial was a recognition that this is a very, very different drug. CRs in any solid tumor, as you know, is a 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 for all of humanity. We believe it will. The patients had the standard background. It's a median of 2 priors, et cetera, et cetera. The swimmer [indiscernible] -- 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 of the antitumor activity. You can see, for example, here, we have the -- and 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 they're 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 1 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 growth 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 real 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 DraxonRassib's Phase I 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 Mark 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, including 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 2 pure second-line disease is 24% with dereconRasib. -- just came out in the FDA documents last week. We're 50% -- and -- in third line plus, best response rate, DuracoRASIb is 21% in the G12X population and highly likely to be lower than that. because we know that G12D did much worse on deraxonrasib than G12V 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 G12D, the main competitors, if you will, are Zolanasab and Insights compound. These are unconfirmed ORRs. You all -- many of you have already dug into these data and look, you know that the Insight confirmed ORR rate is 29%, not 37% confirmed rate is 29%. And -- and you know that this inds RASP is less than 30% and don't know what it is, and the data haven't been updated. Also, the durability of these agents is not known. Setagrassib, 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. Packer 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 human should do. And we wanted to be above this magical 2000 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 1 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. Oncologist 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 [indiscernible] 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 pancreata, 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 drug just can't do it. DuraxonRASIb is the strongest overall, but it's limited by its tolerability. ZoldonRashas most of the patients that are above the 50%, still not bad, but problem. And then insights drug has many patients who 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 optimists -- 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 response as 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 900 -- 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 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 that he jumped off the study before getting the first scan quit 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, 1 of these is unconfirmed -- the other is confirmed. We have this patient who's 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 we have responses. We have ongoing patients. I think I heard about another 1 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 is waterfall, 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 II trial is enrolling beautifully. And now let's switch to 600-milligram long. 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 1 patient who is continuing on the left slightly growing tumor. We don't really know why patients 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 is 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 priority 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 II 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 happened, 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 1 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 BAF data that we have varying allele frequency data here for long at the 600. Here again, we have aniolated the VAS. 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 at that were above the detection limit. But every single 1 of these has undetectable variant allele frequency. And that's consistent with our penetration to the long and the activity. Zolanashavin 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 [indiscernible] and really, that's what's happened. These are the first 8 patients, again, MITT, 1 patient came off due to a very frustrating KEYTRUDA reaction and decided to leave against medical advice and just quit the trial front line. So I don't know what happened to them. But on the denominator because they did get a singles of our drug. This is again 600 milligrams, 75% overall response rate to date. Some of these are confirmed, some of these unconfirmed -- and some of these responses are just with KEYTRUDA because the patients had high tips levels. So that, as you know, KEYTRUDA is indicated if you're PD-L1 levels above 50% contra 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 -- we and more importantly, the long key opinion leaders are thrilled about this data. the expected ORR and 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. Manny.

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. and 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 I and the Phase II colorectal, pancreatic, I'll be talking mainly about pancreatic cancer today. And we will be involved as well in the Phase III 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 1 case, 1 of the patients that I have the privilege to care for and who has been involved in the study, 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, the very simple, the outcome patients, the quality of life they're paying, everything. And then I will touch on a few points that I think are very relevant or 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 an 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 bankers with a RAS 12D 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, modify Folfirinox very intense, very toxic, not very effective. GenSitabeing ABRAXANE, in some patients, a little bit lighter but not so much. also very intense and with significant toxicity. And these patients unfortunately progressed 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 this drug came sort of age. Patients came to the clinic and he was 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 best pain that you can have. It's a pain in the upper Aptman, -- 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 morphing colleges, high dose. And the way this narcotics work is that they work for a little bit, but then when they win 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 morphing completely off morphine. I'm taking an util here and there, but my pain is completely gone. The medication causes a little bit of now 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 pill, what to take the pills with at night in the morning, midday. So a little bit of no, but it's fine. And this is doing -- it was a terrific and very impressive clinical improvement, which responses as mentioned before, an can 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's to be something that I think we will study at some point. And this patient continues to be on a study and has a very nice partial response confirm 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. Liver lesions are basically going, 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 the -- 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 outcome progression-free survival -- and survival. So 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 effects 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 combination with chemo, but we're more interested in combination with other targeted agents in patients who have co mutations and alterations in other relevant genes. So 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 brake and the accelerator at the moment you stop the cancer flares back. And now we have experience with patients who have very good CA199cleaders 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 favorite 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 was mentioned before. Of course, the PKs are super interesting. I think that worldwide when they have clean and predictable, because that when you know what you're giving, where it's getting in plasma, what is it 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 1 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 are seeing is that -- and of course, this is early data, that the patient, everything is under control, and then 1 lesion starts growing, which probably means that there are clones that are developing resistant mutations. 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 taking past progression and that by providing us the ability to then manage the disease in a more oligometastatic fashion will 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-Hui, I'm Vice President of Clinitron [indiscernible] 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 the torability data of VNN375. 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 TRE, which is quite remarkable. If you couple with the media related was intensive 97%, this is, I would say, extremely favorable compared to any class of targeted therapy. If you look at a reduction in interruption rate, they are also low. I want to point out that the interruption way is slightly higher than reduction rate, and that is by design. If you are following the story of Verastem, we have very consistent safety profile across time points. And also 1 thing that we noticed is that the safety profile of 600-milligram 900-milligram are identical. Therefore, there's no point of dose reduction because this doesn't really help with managing these AE. Rather a short interruption up to 3 to 4 days can mitigate ECaneffectively match these AEs. And these short breaks are supported by the favorable half-life as well as loan resident 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 milligrams. Another way to look at tolerability of VS-7375 is to look at the serious -- the rates of serious even as well as high-grade bands. 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 patient experienced a Grade 3 or 1 patient experienced a Grade 3 GITR -- 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 patient experience or Grade 2 GI, 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 GIEs. We noticed that these GI are not accumulated and gets better over time. Around 25% of patients started in cycle 1 without any GIE. 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 to 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 anti-medic agents later on because of consistency of these GI AE dynamics we have seen in cloning. It is very important to note that VS-7375 is highly selective to KRAS mutation. It doesn't affect any wild-type RAS or KRAS. And it doesn't have the liability of that of multi-RAS and pan-RAS inhibitors, which is outlined in this table. You can see extremely low RAS rate, and this also compares favorably even compared with other Ale-specific inhibitors highlighting the high selectivity of VS-7375. And also no medicates and sematitis are reported in this study. Together with the encouraging activity, coupled with this differentiated safety profile compared to existing paras inhibitors. I think it strengthened the narrative. That VS-7375 is emerging as the best treatment options for patients with KresaD-driven cancers. Now we know that a major AA of VS-7375 is GI disorders, but other than these 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 AE. 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 semi 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 likely tumor types such as first-line biller 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 state-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 motor therapy plus with the additional of these cetuximide classic rash. The presentation, severity and frequency of these reps are in line with what we expect for single-agent anti-EGFR agents. Inside caustic combination cohorts, we did not see significantly overlapping GI AE overlapping toxicities. And these AE can be easily managed with standard prophylax and supportive care that are associated with standard of care with syntax agents. Also importantly, we did not see an uptick of liver function test elevation or other case 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 a combination we have clear 900-milligram with anti-EGFR agents and currently going full steam for PDAC and CRC cohort in the Phase II study. That's also the same for combined with GEM Napack. We have clear 900-milligram and actively enrolling for frontline PDA for this combination. This data will be available Q1 next year. Also we have made progress in [indiscernible] to estate frontline nonsmall cell lung cancer. The excellent activity we have seen in the previous presentation, we have clear 600-milligram with the chemo IO moving to evaluating 900-milligram with the combination. Last but not least, are actively enrolling for frontline CRC combination regimen, which is anti-EGFR plus modified 4 Fox with VS-7375. This will be the go for regimen in our future frontline randomized study for CRC. So together, we have demonstrated the tolerability of VS-7375 and also the axacombinability. 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 foreign to have a well flesh out plan and continue to execute. Therefore, I will 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 1 thing Ting said that I think is amazing. 25% of patients on this drug don't have any GIAEs 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 your short of breath. 4 out of 10 patients don't have GIEs. Again, that's unbelievable if you think about it. It's really, really, really moving things 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 complementary 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 II trials, the Target D200 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 on 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 II programs are all designed for potential regulatory approval, 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 diseases, particularly in the G12 allele subpopulation. We then move to the Phase IIIs, 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 front line. You all know this is a standard practice in oncology of drugs work in refractory disease. Let's get them up from 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 along with them in the coming months as we will with the colorectal, and we expect those 2 Phase IIIs 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 type 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, we'll 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 come 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 III 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 front-runner 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 front runner 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 to response rates and talk to them about a front-runner 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 OR 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 III trial in pancreatic cancer -- which is smaller than others, gives patients 2/3 chance to get VS7375 from the get-go and allows patients to cross over immediately to Via7375 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 gold 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 to 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 -- you can't help it. It's the best we have, but you're under treating 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 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 PFS is 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 [indiscernible] 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 my last slide, just to sum up where we are here. It's just been a remarkable almost a 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; John Factor; and Dan Patterson, of course, Julia 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 multi-tumor 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're 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. I had a question on the 301 study, the frontline PDC 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 each of our antibodies and PDP, 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 a cetuximab you boost the response rates there. I won't get into more detail, but there's adequate activity. Last point, Dr. Packer and others have generated really good data. that preclinically that this is a common pathway that pancreatic cells like to use, try to get around it to get around RAS blockade and the preclinical data strongly support this.

And then you did not include FOLFIRINOX combination as an option and a 301 treatment arm. Just talk about that decision.

Yes. I have a somewhat cynical and I don't mean to be pejorative or rinotecan 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 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 and either with Genmab or we hope with just a 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 533 antagonist throughout 2 cycles. -- which is 2 months. We do see a large proportion of patients able to taper off the name agents. But this really helps the dose intensity in helping 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 1 of the distefactors that result in that differences.

Michael, keep me honest here, but that 1 patient that had Grade 3 nausea, they forgot to take their Zofran dose. And came in the hospital got it and was transient.

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

Thanks, Graig Suvannavejh. 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 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, Graig, 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 1 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 1 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 1 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. [indiscernible] -- really incredible time we have in pediatric -- I mean, a 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 1 trial versus another 1 there just seems to be so much activity.

Yes. So that's a great question and agree I mean there are so many agents out there now in development, which is a terrific opportunity for patients is also a much better situation for physicians because we can now prescribe or administer medications are better tolerated and more effective, but there is a competitive or broad landscape of how you direct patients. That action RASP is approved with a broad indication and app 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 San alias 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, PRN combinations that you have heard, are very, very interesting. I like the EGFR combo. I think that we tend to think that, that only applies to column, 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 dependent 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 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 approval. It's moving these to earlier stages. That's the real front runner. And here you have a drag that we ambition could be easily a 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 CA99, 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 IPM in tropancreatic musinosneoplasia, which is about 20%, 30% of patients with pancreas cancer come from the cystic locations in the pancreatic and we have now the tools to. So it's a complex but fascinating landscape and -- and I think the next few years are going to be quite remarkable.

Yes I'll add a point to that last we could give a talk of the RES initiative at NCI and Frank McCormick kind of is the father of the field. He's believed it in all these years. you 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 in the G12V selective that's amazingly safe and maybe 12 and everybody takes them and you prevent cancer. And that's his dream. And I think Michael will talk briefly about the alternative formulation that we're brewing in the lab that looks great in dogs get rid of the tolerability. I think our drug could be 1 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 had it on.

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 1 CA more lobbying 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.

Why are we going to turn to Eric?

Thank you, 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. that physicians wanted the patients want it. The progression is, of course, radiographic. It's not necessarily symptomatic. And I think doctors and patients generally many that they wanted -- they worry about symptoms primarily. I mean they're upset that the tumor grill. 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 lithium, 2 lesions popping up, likely reflecting there is a long that now acquire another alteration and that is bypassing. So our protocol is to biopsy dose, 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 CA125. 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 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 in blahblah,-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.