Verastem Oncology VS-7375 R&D Update - VERASTEM INC

Good morning, everyone. For those that don't know me, I'm Julissa Vianna, 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 VS7375, 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 D101 trial, including, for the first time, U.S. efficacy data and updated safety and tolerability results in KRS-G12-D-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. Let's go to the next slide. 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 patterson president and ceo dr michael g kaufman president of development dr ting wu vice president of clinical development and dr manuel hildago 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. You know, 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 four-year journey, where we set out and made a conscious decision working with Genfleet to have a G12D selective agent. You know, everyone's been talking about Panras versus G12B. And I think, you know, within the last month or so, you know, I think folks have come to realize, you know, RedMed 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, you know, having a selective molecule matters. And in order to have a selective molecule, there were a couple of key things that we really needed. You know, 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 as this area was evolving, you know, 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 this 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 anti-tumor 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 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 with in 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 four 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 onto the field in getting penalties. So finally, I just said, I 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 full Firanox, it is brutal. It is like being run over by a truck. We even Gemnab, 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 and second line disease, even that is difficult. People have rashes. These are very tough to treat rashes, People do get rashes from other drugs and oncology and other diseases, but the cetuximab, panetumumab 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-rass 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 cells. 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 control with a 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 three trial design for frontline pancreatic cancer it's a 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 but 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 three of the worst G12D tumors we have. Remember that G12B is a bad prognostic factor for all of these. So we're treating the worst of the worst. We've already have three 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, front line 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 IIs, IIIs, pardon me, front-line studies to start in the first half. of next year. Okay, so let's move now quickly to the data that we've all been waiting for. 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 the best we had. And now we're looking of 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. This is MITT. It's every patient we've treated. This isthe cohort of 900 milligram pancreatic treated patients in our phase one. This is it. Thisis everybody. There are 20 patients here. Thereare two 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 resist 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, four out of the eight patients who had second-line pancreatic cancer had confirmed responses. Five 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's doing, that that CR will go want 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 three trial was a recognition that this is a very, very different drug. CRs in any solid tumor, as you know, is remarkable. Two 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 median of two priors, et cetera, et zebra. The swimmer plot. We also try to give you guys all the data. There's no covering up anything here. This is a combination of a swimmer and a kind of spider. So the size of the circles for each patient represents the anti-tumor activity of the drug. The bigger the circle, the more the anti tumor 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 two scans to get to the response. That means it takes 12 weeks. Nobody's surprised about that. Pancreatic cancer is a highly fibrotic, difficult-to-treat tumor. Not only do you have to kill it, but you have the macrophages and everybody else in there to clear the debris. This is a war zone. It's the patient 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 resist is that you are blamed for having a great response. So if your tumor 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 four times 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 Drax and Rassib's phase one 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 a least two months longer than the best beta in third- and fourth-line, at least two-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 pancreatics and 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 Derax and RAS. It just came out in the FDA documents last week. We're 50%. In third-line plus, the best response rate, Durex and Rassib, is 21% in the G12X population and highly likely to be lower than that because we know that G12D did much worse on DureX and RASSIB 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 G12Ds, the main competitors, if you will, are Zoldanrasib and Insights Compound. These are unconfirmed ORRs. Many of you have already dug into these data and looked. You know that the insight-confirmed ORR rate is 29%, not 37%. The confirmed rate is 99%, and you know that Dazoldon RACIB 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. Cetagracib, 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 others and the other competitors, best we can estimate, is that they sit in a 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 2000 AUC, and we've done it for 80 plus percent of the patients. And we're not bad on the other three 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 VS7375, 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. Twelve of the tumors shed enough to pick up ctDNA, so we can use that. But all 12 had at last a 50 percent reduction. Oncologists will tell you 50 percent's 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 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 CA-19-9 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. Deraxanracib is the strongest overall, but it's limited by its tolerability. Zoldanracid has most of the patients that are above the 50%, still not bad, but problem. And then Insight's drug has many patients whose 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. 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 them 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, and 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 four patients are too early. You have five patients on the graph. One is missing. Why is 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 five out of six, but the denominator is six, 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. 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 anti-tumor 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 Pank. 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 two 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 ain't 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 front line 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 seen 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 target lesions, but all the non-target 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 has everybody who got the drug with lung at 600. We did not exclude one-third 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 a accelerated approval phase two 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 one of thePRs 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, varying 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 five. 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 varying allele frequency. And that's consistent with our penetration to the lung and the activity. Zoldan and Rouse have been contrast. About a quarter of the patients don't make it. They just can't get there. They just cannot get there, moving to front line. 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 eight 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 eight 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 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, Keytrude is indicated if your PD-L1 level is above 50%, Keytruder is a single agent. It doesn't matter. These are fast responses. I would argue that these responses occurred primarily due to 7-3-7-5 because Keytruda takes a while to get to a PR, and these are pretty deep PRs already. We and, more importantly, the long-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. Manny? 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, 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 1 and the phase 2 colorectal pancreatic. I'll be talking mainly about pancreatal cancer today and we will be involved as well in the face 3 as soon as that is activated. it. 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 will 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 involved in the study, enrolled in 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. They're very simple, the outcome of patience, their 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 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 RAS 12D mutation. Started on multi-aging 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 fulfirinox, Very intense, very toxic, not very effective. The incitabine abraxin, 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 two 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 of age. Patient came to the clinic, and he was a young gentleman, still with a good performing 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 abdomen. It goes to your back. You need to be sitting like this. You can't eat. You can 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 was back. So he started on the medication. And, you know, went through all the process. And called me three, four days later saying, hey, doctor, pain is gone. I'm off morphine, completely off morphines. I'm taking an alveol 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 their pills with at night, in the morning, midday. So a little bit of nausea, 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 to decompressing the tumor to affecting the tumor infiltration in the in the nerves there there's to be something that I think we will study at some point and this this patient is It continues to be on study and has a very nice partial response, confirmed, three 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 RAST allele that was present is gone, is not there. And that's also a very important factor that we're learning with these medications, which is that we have the ability, because we know what they 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, 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're 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 brake and the accelerator. The moment you start, the cancer flares back. And now we have experience with patients who have very good CA-199 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's when you know what you're giving, what is getting in plasma, what is getting to the tumor, what is hitting the target, is all linear and logical. And 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 mutations. We don't know what they are yet. We're investigating those. So that has an important clinical implication because then you can treat those patients local regionally 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. Wood, who will continue the discussion. 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 Veristem. I am a medical oncologist by training and have the privilege to lead the development of VSMV75 on the clinical side. And also having the privilege to share the tolerability data of VSM375. I want to start with the consistency of patients able to stay on the 900 milligram GO4 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 median related dose intensity of 97%, and 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 interruption weight is slightly higher than reduction rate, and that is by design. If you are following the story of Veriston, we have very consistent safety profile across time points, and also one thing that we notice is that the safety profile of 600 milligram and 900 milligram are identical. Therefore, there is no point of dose reduction because this doesn't really help with managing these AE. Rather, a short interruption up to three to four days can mitigate these AE and effectively manage these AEs. And these short breaks are supported by the favorable half-life as well as long resident time of VSF-375. 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 VSM-PRED-75 is to look the rates of serious event as well as 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 VSM-175 is gastrointestinal disorders, only 2% of the patient experience a grade 3 or 1 patient experience a grade 2 GITR-AE. 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 experience a grade 2 GIAE, and only one patient experienced a transient grade 3 nausea. However, this tapey table does not tell the full story. We need to importantly understand the dynamics of these GIAEs. We noticed that these GIEs are not accumulated and gets better over time. Around 25% of the patients started in cycle 1 without any GIAe, and this number continues to increase to 40% six months into the study. Importantly, I think this gives us implication to manage these AEs up front more proactively. We know that patients, after they've gone through the first two cycles, they tend to get better for these Aes. So that's why we introduced the anti-emetic prophylaxis for the first couple 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 see in the clinic. It is very important to note that VSM375 is highly selective to KRAS GTOD 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 rash rate, and this also compares favorably even compared with other allele-specific inhibitors. Highlighting the high selectivity of ESM275. And also, nomicocytase and somatitis 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 VSM-375 is emerging as the best treatment options for patients with KRAS-GOD-driven cancers. Now, we know that a major A.E. of VSM375 is GI disorders, but other than these G.I.A.E., 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 it earlier this year, mid-year, and also in this data set, which means that VSM3-Symbio is highly combinable with cytotoxic agents. Similarly, we did not absorb any clinically significant AST-ALT elevation in the U.S. population or ex-China population. This opens the door for combining 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 VSM-375 is highly combinable and eventually can address a very wide population with KRAS-street-home-D-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 additional of these cetoxyamide 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 supported care that are associated with standard care with cytotaxy 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 summarizes 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 two study. That's also the same for combining with GEM, NADPAC, and EXO. We've cleared 900 milligrams 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 mg with the chemo IO and moving to evaluating 900 mg with a combination. Last but not least, we are actively enrolling for a frontline CRC combination regimen, which is an anti-EGFR plus modified Fofox with VSM375. This will be the go-forward regimen in our future front-line randomized study for CRC. So together, we have demonstrated the durability of VSM375 and also the excellent combinability. The next step is to continue to execute and bring VSM375 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. you. 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 a 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 GIAs in their first cycle. They're getting anti-tumor efficacy with almost nothing on the side effects. That's a miracle. By the time they're on for six months and the tumor shrunk, and a lot of these AEs are worse because these tumors are pushing on abdominal organs and they're short of breath. Four out of ten patients don't have GAIAs. Again, that's unbelievable if you think about it. It's a 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 three cancers here. We have, as I mentioned, ongoing phase two trials, the target D200 series in pancreatic, lung, and colorectal that are ongoing and enrolling patients. Again, pancreatics and colarectal 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 longer because it's only 5% of lung cancer that have G12D, but we expect that accrual to finish by the 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 blind and 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 six months. Okay, this would be unprecedented for all three of these disease, particularly in the G12 allele subpopulation. We then move to the phase threes, 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 frontline, 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 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 303 colorectal, and we expect those two phase 3s to start in the first half of next year. I think there are two 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 one cycle of chemotherapy or whatever therapy they're going to get in order to have their G12D typed and confirmed. It's a three-arm trial, one-to-one-to one. So two-thirds of the patients will be getting the cool new small molecule. One-third 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 been 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 this is well published and is well known to drive compliance especially on the control arm because patients coming to these studies put their lives literally on the line and they should all have the chance to get 7-3-7-5 two-thirds chance to Get It To Begin With is good but if you if you want to get your trial done you've got to get patients to complete that third chemotherapy arm and 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 7-3-7-5 front line 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 three 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 then. 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 two-thirds 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 two new design elements have allowed us to have a phase three trial in pancreatic cancer, which is smaller than others, gives patients two-thirds 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 мы 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 bit off on the role of chemotherapy and other intensive therapies in 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 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 is about two to three months where patients can stay on the goal chemotherapy doses and then you have to modify the doses and reduce them and by six 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 anti-tumor activity especially for a disease that's seen the same chemotherapy now for six months and is probably becoming resistant to it after all the pfs expected is around six months in the control arm here so you basically under 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 7-3-7-5 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 three months. It's four cycles of carbop platin and stop. Carboplatins by far the most active drug in lung cancer. You cannot continue it more than three months if you want to extend the current PFS is beyond eight months or nine or 10 months with G12D lung cancer, you better have a drug that continues well beyond eight or nine or 10 month, and it ain't 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 two and three years for the first time ever in the history of medicine. so at my last slide just to sum up where we are here I it's 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 John Pachter and Dan Patterson of course Julissa and the whole team at Veristem 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 dog's now with the new formulation absorbed the drug with the same levels of the old formation but don't throw up at all zero zero percent vomiting we'll see we got to get into the species that matters and it only has two legs but we we may be able to even make this a better drug, but this is an 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 two 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 мы are eager to get these frontline phase three 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. So if the rest of the team can join me from Veristem, John, please. Dr. Hidalgo, take a seat in the front. Where am I? Because we should have five, weren't we? You're going to get a lot of questions. And I'm short. A little rearranging on the stage. so we'll be taking questions from the room all right I'm going to get out of the way all right so when we call upon you please just state your name so the folks who are listening to live stream know who is asking questions or any we have over here Michael I'm like all taller than you hey thanks 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 each of our 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 PDAC or how much more you may need to generate before starting the phase 3 yeah 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, we have a quiet cohort, I would call it, within our phase two accelerated approval study, which is focused, of course, on second-line disease. But there is a cohort in that phase two study that actually enrolls patients in frontline with frontline pancreatic in combination with an AGFR 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 five patients at 400 milligrams of our drug, which is not an active dose in pancreatic cancer. This is heavily pre-treated. Five patients, when you add cetuximab, we had two out of the five that converted that are PRs very quickly and very active. And if you take 600 and add cetoximab 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 pre-clinically that this is a common pathway that pancreatics 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. Yeah, I have a somewhat cynical, and I don't mean to be pejorative, orinotecan 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 And even grade two diarrhea should not be discounted, but the grade three 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 Fulfironox combination, much better tolerability either with Gemnab 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 like now in the clinic. Certainly. So we asked patients to be on a 5-H3-3 antagonist throughout two cycles, which is two months. We do see a large proportion of patients able to taper off the antibiotic 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 one of the disadvantageous factors that result into that differences. Yeah, and Michael, keep me honest here, but that one patient that had grade 3 nausea, they forgot to take their Zofran dose. And came in the hospital, got it, and was transferred. So why don't we do Greg here, and then we'll go to the side. Thanks, Greg. Thank you for the presentation. Just a couple of questions. One, you seem to have a really great drug here. There's a lot that you can do. I know you announced 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 what your current financing provides for, what you can doing with that, and as you kind of think about what's next, How do you think about financing those ambitions and considerations of partnerships or not? No, great question. You know, the raise we did today takes us well into 28 and gets us past the readout of the phase twos, 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, you know, I've spent almost all my career in smaller companies. We can be nimble. We can be fast. We cannot do things big companies can do. This is one where I truly believe partnering it makes the pie bigger. You are not just bringing in financial resources, but expertise and scale. We are likely to do some kind of partnering in an ideal deal. We keep upside and we are working alongside our partner. We recognize how challenging it can be to be in a partnership. And, you know, one of the things that I thought was quite attractive in Michael Bailey's background is he's lived these after the deal. And, You know, 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, You Know, we felt it was the right thing for the company and for patients to push forward with all three of these indications as quickly and aggressively as possible. Great, thank you. And then maybe a question for Dr. Hidalgo. Really incredible time we have in 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? Yeah, so that's a great question. and agree that 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 can now prescribe or administer medications that are better tolerated and more effective, but there is a competitive or broad landscape of how you direct patients. that Axon RACIP is approved with a broad indication and is 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 non-comparative data, more effective. So for us, the preferred is still a clinical trial, if we can. But there are, so that's one point. Second point, we're very interested in non-chemo combos. And in dual targeting, PRNT5 combinations, as you have heard, are very, very interesting. I like the EGFR combo. I think that we tend to think that that only applies to colon, but the reality is that pancreas is also dependent on that. Tarsiva is a proof. 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 well-tolerated, of course. And then the final point is that, and I think we didn't mention that, of course, because we're now sort of in the phase three's approval, is moving this to earlier stages. That's the real front runner. And here you have a drug that we envision could be easily studied 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 if these responses can take more patients to surgery. That's another very important area of research. And two 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 CA-199, really looking at what matters and being able to pivot from one 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 these cystic dilatations in the pancreatic. And we have now the tools. So it's a complex but fascinating landscape. And I think the next few years are going to be quite remarkable. I'll add a point to that. Last week, I gave a talk at the RAS initiative at NCI. And Frank McCormick kind of is the father of the field. He's believed in it 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 G 12V selective that is amazingly safe and maybe a G-12C, and everybody takes them, and you prevent cancer. And that's his dream. And I think, you know, Mike will talk briefly about the alternative formulation that we're brewing in the lab that looks great in dogs to 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 sometime from now there will be good enough cell-free DNA test, quantitative test, that will be monitoring like your 1CA hemoglobin in diabetes. is 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 we're getting there. When are we going to turn to Eric? Thank you, Eric Schmidt at Cantor. Thanks for the very comprehensive presentation, and 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? Yeah, 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, but progression is, of course, radiographic. It's not necessarily symptomatic, and I think doctors and patients generally, I don't know how many, agree that they worry about symptoms primarily. I mean they're upset that the tumor grew a little. So this patient was treated. I think he kept on 900 for a while, and then he even kicked up to 1,200 eventually, so we saw, 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 som tumors are progressing because they're just not exposed to enough anti-cancer therapy, because they found a way to be avascular enough that they They can live and grow. And oftentimes, and we've seen other cases there where 600 patients are given 900, and that tumor that started to grow just crashes. And localized radiotherapy will be allowed? Yeah, you can do... I mean, we do what's... We really have made a culture at Veristem of doing... And I'll just say this. There's always... The regulators are always open if the physicians request it and the company is supportive. If I may, I hope that as studies are designed based on ORR, PFS, hopefully molecular responses, and that's 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 one lesion, two lesions popping up, likely refracting. 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 need to beat in the future front line 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, you know, 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 CA-125. 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. You know, 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 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 with all the caveats of Croft's trial and blah, blah, blah and say we think this is highly differentiated both on efficacy and on tolerability and we think that this deserves that and we'll see if they agree with us. Typically, you need at least 20 patients with six months follow-up and we want patients from the U.S. for that. Jeet, again. Great. Thanks for taking the question, 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 frontline PDAC phase 3, 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 full farinox? 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 one and a half months kind of increment is not sufficient so we want to have like sufficient delta which means probably clinically meaningful at least like three to four or five months around that range of course in the control arm we want it to be realistic right what is the Because we're allowing either GMP or forferonox, what is the kind of the PFS for those people's studies in the past were used 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, PanRAS, 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? Yeah, 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 two targeted agents, pure MT5 inhibitor and our G12B, 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 Redmond molecules, 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 Erasca's Panras, we'll see if it's better. I think there might be situations where it's besser 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 with targeted agents that should be well-tolerated, but we'll find a place. Yeah, I agree. I think PRNP5 and EGFR are probably the two that we have more clinical data, and they're very exciting. But you need to have the dual target. I don't know. There are another 10, 15. This is like Pembrolizumab days. Like now everything that you combine with a RAS inhibitor is effective, right? So 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 others. The fact is, I think, another one that there is very strong preclinical data, but strong clinical data 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 want to use up front versus combinations that may be effective at the time of resistance and progression. This may be the same, may be different. There may be patients that 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 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 a company-sponzored 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 of that. That's a very cost-effective way to see, is our D12D 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. Yeah, go on. Yuanzhi from B-Ride has great data today and great to see almost everybody can get tumor shrinkage. Maybe a couple of follow-up. I don't mean to push the limit here, but when can we expect the next data update and what will be included? there. We'll let you take that one. Sure, easy one. Probably by the end of the year, 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 Pank 600 combo data and GMP. 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 I think expect next year to be a very data catalyst-rich year at medical meetings and multiple updates from the phase two and the first half and the latter half as well, and lots of progress on our enrollment and so forth. So it'll be a busy six to 12 months. Got it, got it. And my second question is related to the combination of 900 milligram 7375 and EGFR. I know you have some data, adverse event data, in the back of the slides. So what other highlight you want to share there? you know do you see anything concerning about the rash or it's just as you expected with the monotherapy ejfr inhibitor okay the rash what we also asked the investigator to further like characterize the rash and we have got like really good feedback as the rash is identical to what do you expect for single agent and each of our agent in terms of the presentation acting form predominant and also in terms on frequency severity you can see in the table that's in line with what we reported for the single agent so no concern of overlapping toxicity got it are you good yeah we'll just give it to josh and then we'll come back over to this side uh hi uh josh brewer with rbc capital markets um really great data today congrats um yeah so i i guess one thing that i was interested in was uh how you guys had um 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, you know, 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, you Know, across all the indications? Thank you. Yeah. So we're intending that the trial, the phase three, be global. We've had the discussion with FDA, gotten sign-off on the, ironically, we had our end-of-phase-two meeting to agree on phase three while we were doing our phase twos, 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 in to the Europeans. The lung protocol phase two is being done, is including European sites. The others, phase twos, I don't think are going to make much ex-US. 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 international phase threes. All right, you can grab it. You want to do? Yeah, Faisal. Great. Thank you guys so much. Faisel Shade from Jefferies. I appreciate you guys hosting us today and taking the questions. Two for me, one for the company, one 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 three. On the PDAC early stage combo data sets. Can I just get a little bit more granularity on what combos you expect to share and what time frame and how many patients investors should expect? Yeah, sure. As we told you in June when we weren't ready to show you these data and we asked 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 want to get some durability because I think everyone agrees these RAS inhibitors are active, so you need to see duration. 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'll include the first line data set as well, possibly. Got it. And that's both chemo combo and the EGFR combo? Yeah, with GNP, right. I mean, 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 GMP to GMP Plus Us, which tells you what investigators think of the ability of our drug because you would never put somebody on GMP and then GMP again. They've progressed. And people on Fulfirinox who blew through it and then get GMP plus Us, so that'll be as well. We're not doing fulferinox, as I mentioned. We're doing it in colorectal, and we're not doing niliferox. We're just not going to deal with a grade 3 diarrhea erinotecan compound that makes people wretched. Got it. OK, 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 four approaches, chemo and RAS combinations, G12D with multi-RAS, G12DE with PRMD5, and G12ED with EGFR? So we need to wait for the trials. I think all of them make sense. I presume you're asking what is my expected outcomes for those? Yeah, 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 mutants, I think we're seeing probably the best activity we have ever seen. And so, which means when you have the two 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 datas with 12Ds inhibitors. The PAN-RAS, they can be combined with chemo as easy, so I think the responses are a little bit lower. But likely, each one 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 one or more of these strategies. But the chemo versus the EGFR, I thin that that will need to be, we'll see. Got it, thank you. Yeah, good morning, and thanks for taking the question. This is Kalpa Patel from Wolf Research. I wanted to push on the choice of the first-line chemo combo strategy here. I guess we know that Deraxon or a pan-RAS inhibitor does better than chemo, so why not entertain a pan RAS 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? Thank you. Yeah, 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 Deraxon 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. And as far as why not combine with a pan-RAS, frankly, to be blunt, we think our EGFR combo will do at least as well, if not better, and will be better tolerated. The rash from cetuximab and panetumumab 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 Durax plus Zoldon are very exciting. But frankly, I think, you know, they had a couple CRs. We have a couple KRs. They had good response rates. We have good response rights. 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 want a different mechanism. We think that'll give the best chance for not only great responses, but most importantly, durable disease suppression. Yeah, a lot of these combinations might kind of speak to weaknesses of the individual drugs. I mean, if your G12D selective can't get good enough exposure to maximally hit the target, you might need something else that's a similar drug. If your Panras isn't tolerated enough to maximaly hit the target you need to combine. So I think that we're interested in the Pan-RAS combination because those drugs are more different, but I think those can often be just kind of showing the weaknesses of the individual drugs, the need to put two very similar drugs together. All right, our last question from Matt, and we'll wrap it up. Thanks, guys. Matt Venezia here from Alliance School Partners. Thanks for taking my questions, and congrats on the impressive data this morning. So first, I wanted to ask the pan-RAS 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 one cycle. Did you see this trend continue after two, three, four cycles and can you take us through a little bit of the AES over time? I mean the trend is very consistent with what we announced last time I think, like, looking at these in different kind of metrics, like this time we look at, like. Patients without GIE, I think that tells the same, like consistent story that these AEs tend to attenuate over time. And that's also very consistent what we have heard from our investigators, that the first two cycles is where you need to more practically manage, whereas after that it's like soon selling after two cycles. And that is how we define the timing. We use the anti-emetics, prophylaxis, and all associated with those practices. Great. Thank you. And then just lastly, I wanted to ask about the CA-19-9 trend over time as compared to your last data update in June. Yeah, we chose not to present it today just because of the abundance. It looks like last time, only longer. In fact, even the patient who had radiographic progression didn't have a bump in his CA-18-9, which is just consistent with the lack of symptomatic progression. But it's very stable. there are a few signs at this point that these diseases are starting to progress across most patients we'll have to see 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 guys for taking the question that concludes our event and our live stream So thank you. We'll still be here for further questions.