Thanks, everybody, for coming. I'm very excited to be able to update on a couple of really important programs for us. I think that's really impactful. We've got a couple of important things today we want to talk about. One is opportunity-based research. This is a really fascinating combination of research that's been done in Connecticut and purchasing data that's been very exciting to have folks here to go through that today. As you know, I see a lot of familiar faces in the room. You're familiar with our story. We're really focused on RAS/MAPK-driven cancers. Within our own portfolio, we've got the RAF/MEK inhibitor, avutometinib, defactinib, which is our FAK inhibitor, and then the G12D inhibitor. In addition to that, we do have two other targets as part of our GenFleet collaboration that we haven't disclosed.
Both within our own portfolio and then combining with things outside our portfolio, we think we have a lot of different options to really directions to go in. I will not go through the guiding principles here, but really what we are trying to do is develop treatments for cancers with high unmet need. AVMAPKI FAKZYNJA CO-PACK, which is the brand name of the drug that just got approved. It was approved on May 8, almost two months early. Very excited. The data in low-grade serous ovarian cancer, a 44% overall response rate with durability, is really unprecedented. The fact that we can offer really an oral therapy for patients is just wonderful. What we are going to do today is I have got Dr. Prakosi here really to talk about the pancreatic studies, the RAMP 205. John Pachter will talk a little bit about some of the preclinical information.
Dr. Hung is here to talk about the G12D inhibitor. Then John Hayslip will talk us through really our development program going forward for those. Dr. Prakosi, we're happy to have him here. He's the Director of the Pancreobiliary Program at Virginia Mason and really a real expert in this disease. We're just honored to have him here to give some background. Thanks.
Thank you. I appreciate the kind introduction, Dan, and it's a pleasure to be before all of you today. My task is to update you on the pancreas cancer field in general and in specific how the RAMP 205 study fits into that. Just by means of introduction, pancreatic cancer is actually a continuously increasing disease both in the United States and worldwide. Here you see the incidence in several major countries. The most current numbers are actually somewhat higher than this. The expected incidence of pancreas cancer in the U.S. this year is about 66,000 and over 500,000 worldwide. You see the difficulty with survival. The five-year survival of all pancreas cancer is 13.3%. If one takes adenocarcinoma, which is what we're focusing on today, it's actually less than 8% even now. In its most fundamental sense, the disease has a biological abnormal substrate.
Foremost among the abnormalities seen in pancreas cancer are mutations in KRAS. You can think of KRAS as like the on/off switch for pancreas cancer growth. When it's mutated, it's permanently on. The vast majority of people with pancreas cancer will have KRAS mutations. Here you see they're listed in order of frequency, with KRAS G12D mutation the most frequent, followed by V, then R, and a variety of others. About 10% of people are what we call so-called KRAS wild type. They don't have a readily demonstrable mutation. Currently, this is how we treat people with pancreas cancer. They divide into two groups. About half of people have disease that is confined to the pancreas visibly. About half of people have disease that's visibly spread, local and metastatic.
Although it turns out that literally almost everybody has metastatic spread in a way that you either can see or can't see. People operated on, if they received no additional treatment, will recur 90% of the time. The way I think of it, everybody has metastatic disease. It's just you can't see it in some people. This is how we treat people with the more advanced forms of pancreatic cancer. There are multiple standard regimens that are used, which really there's no consensus on in terms of which is best. I think the truthful answer is different regimens are best for different people. Generally, if one of those regimens fails, you try as a second therapy something else. FOLFOX maybe has been substituted for by NALIRIFOX, which is actually the only approved regimen in second-line pancreas cancer.
Below that, you see the survival, the rates of response and survival still far from what we'd like to see. More importantly, what the patients would like to see. In that environment comes drugs that intend to block the RAS/RAF pathway. The first drug in the combination we're going to discuss today is a drug called avutometinib. Avutometinib, as you see from the diagram, blocks the RAS/RAF pathway and thus inhibits the effect of KRAS. You also see there's a second pathway that's very essential to tumor growth and development, which is referred to sometimes as the FAK pathway. A FAK inhibitor drug, defactinib, which is the second experimental drug in the combination I'm going to discuss, inhibits that pathway. When the first pathway is inhibited, more activity switches to the second.
An important theme of this discussion is the duality and synergy of both of these drugs together. It turns out the drugs also have other effects, in particular the FAK inhibitor, which induces a decrease in the stroma, which is the cellular surround of the cancer, both in terms of collagen and fiber structure as well as cells. This reduction in the stromal density may play a role in therapy, including drug penetration and penetration of immune cells. The point is that it's a broader concept of how drugs work. Typically now in pancreas cancer, we think not just of the effect of the drugs on the cancer itself, but also the surrounding environment, what we refer to as the TME, the tumor microenvironment.
Furthermore, if we explore the combination of avutometinib and defactinib in conjunction with chemotherapy, you can begin to see, at least in a preclinical setting, the synergy I was talking about. The slide on the left relates to frequency or degree of tumor regression. You can see that there's some tumor regression by using standard chemotherapies, much more by using the two investigational agents. The biggest gain of all comes when all four agents are used together. On the right-hand side, you see the development of liver metastases. Again, you see some effect when you add either defactinib or avutometinib to chemotherapy. It's the combination of the four drugs that almost completely abrogates the development of liver metastases, which is actually directly related to the cause of death of many people with pancreatic cancer.
This is an overview of the RAMP 205 study. It looked at patients who had untreated, pathologically proven metastatic pancreas cancer that could be readily assessed radiographically with what we call a performance status or a level of function that permits chemotherapy. The first part of the study, part A, looked at different doses of the four drugs in the experimental design or the experimental group to try to find what would be the best combination and doses of drugs to move forward into the second part of the study, which is to look in more detail at that most successful combination. It turned out that there were five different dose combinations examined.
As you will see in a moment, the one out of the total of 60 patients, 12 in each group, that ended up being the most successful, and you'll understand why in a sec, was actually the very first level tested. Here you see the doses of the four drugs and their schedule over time. You can see that most of the other combinations look at different adjustments in doses and scheduling of the different drugs. Here is the response of dose level one. Out of the 12-patient study, you can see that 10 of the 12 actually had evidence of what would be considered a response radiographically. To put that in some context, a typical treatment for metastatic pancreas cancer might show a radiographic response of about 30%. Here it was 10 out of 12 or 83%.
On the right of the slide, you see some of the more detailed data in terms of what's been confirmed and unconfirmed. I actually think almost as equally important is the absence of progressive disease. About 25% of people with metastatic pancreas cancer will progress despite therapy in the first two months. In this early experience, there wasn't any. You will see even more as we examine all five dose levels. A very high response and what we call the dose control rate, which means absence of progression after four cycles of therapy, was a very robust 92%, again, based on a literature comparator that's much lower than that. This is called a swimmer's plot or a swim plot of the patients. You can see that many of the patients remain on therapy.
The red dotted line indicates the historical length of time that patients remain on just gemcitabine and Abraxane. You can see that, first of all, many of the patients remain unstudied. It will turn out that a vastly significantly greater percentage of patients will, in fact, have therapy extended beyond what would be the normal amount of time using gemcitabine and Abraxane. With that, presumed better outcomes in terms of response. In the corner there, you see some comparator data from two very significant trials in pancreas cancer that's metastatic, the MPACT trial, which looked at gemcitabine and Abraxane, and the NAPOLI-3 trial, which also used gemcitabine and Abraxane as one of its arms. You can see the literature is very consistent in terms of the median progression-free survival. This is a CT scan from a patient who was treated with dose level one.
I think even to the relatively untrained eye, and I include myself in that, my wife is a radiologist. She cautions me never to look at X-rays because I'm not a radiologist. I get even because when my kids get sick, they tell my wife, "We want to go see a real doctor like Dad." You can see there's an obvious regression of the cancer in the liver, particularly in the bottom set of slides. I think that the CT scan doesn't really tell the true story. It turns out the very last patient I saw before I came to ASCO is a man in his 60s who is one of the patients at this dose level.
When he started this treatment, he was in a lot of pain, very limited in terms of his lifestyle because of that, and actually even wondered if he wanted to take treatment at all and continue to live. Now here we are eight months later. As I say, he was the very last person I saw before coming here. He had just gotten back from a trip to Cancun. He was snorkeling and eating what he calls gourmet Mexican food every day. He asked me if he could move to Cancun and get his treatment there. I said, "No, I don't think we can do that. But you can have another vacation if you want." The toxicities of the treatment are actually similar to what you see in general with other treatment regimens. There was not anything that was previously unknown that was detected.
Most of the toxicities were relatively mild. As I've said, they are characteristic of what's been known in the past. Probably the big issues relate to hematological toxicity, as is characteristic of gemcitabine and Abraxane, and GI toxicity. The avutometinib also has a peculiar auxiliary toxicity. Patients are managed by serial visits with an ophthalmologist. Overall, it's quite doable. Here you see actually the responses of all five cohorts. You see that there were significant responses at every dose level. There were many more at dose level one, which was a big factor in the choice. To me, again, almost as significant is the number of lines pointing significantly downward or the absence of lines pointing upward. In a typical pancreas cancer regimen in this setting, about 25% of these bars would be going up instead of down.
If you look at dose level one, there are not any bars going up. They are all going down. To me, that speaks as much about the activity as the magnitude of the response. Many of the patients also in all five dose levels remain on treatment. Again, the dose level one seems to be the one that is the best. The conclusions that have been drawn to date by the study team are that the toxicity of this regimen is certainly manageable and has a very impressive response rate, particularly at dose level one. Thus, that was chosen as the recommended phase two dose. The response rate to date, which is again early, but what the further experimentation is going to be based on, was 83%. Optimizing dose intensity, particularly with respect to Abraxane, may be important.
The vast majority of the patients are expected to do better than what would be expected historically. The enrollment of additional patients, additional 17 up to 29, is already underway. In fact, we have one patient as a part of that now. Thanks very much for your attention. I'd be happy to answer any questions you got. Yes, sir.
What is unique about dose level one? Why does this similar—thank you. This is support on for the.
Jeff from RBC Capital Markets.
Okay.
Yeah.
Let me try that one. I think that's not entirely clear because of the sample size. If you look at dose level one, it's the one that has the highest overall dose intensity of all the drugs, particularly the Abraxane.
A related question. Why do you think the 2.5 milligram dose for avutometinib works better than 3.2 that's been used for LGSOC? I guess, do you think there's perhaps an additional dose optimization that could help identify potential differences in terms of efficacy between different tumor indications?
I don't have an exact answer for that. I think, first of all, your questions are very sophisticated. Thank you. The way I would think of it is that I would think of the drugs not individually, but collectively. It's like cooking. In a particular dish, more of one spice as opposed to another may be better or not. There probably are differences between the cancers. In this particular cancer, that particular set of concentrations may come to the best result.
I think we'll do a Q&A at the end. We'll save the rest of the questions until the end of the session.
Okay. Sorry about that.
No, that's fine.
Good questions. Thank you.
Thanks, Vince. I'm John Pachter. I'm Chief Scientific Officer at Verastem. Ted Durbin, if you can advance the slide. Oh, I guess I can advance. Sorry. Now we're going to change topics to our KRAS G12D on-off inhibitor VS-7375, which we developed in collaboration with GenFleet Therapeutics. I have about five slides to convince you why I think it's a best-in-class molecule. Let's see if you agree. One of the key things, as you can see on the lower right of this slide, is that it binds both the GTP on-state and the GDP off-state with low single-digit nanomolar affinity. I think being a dual on-off inhibitor is important.
To talk through that a little bit, if you look at an on-only inhibitor such as RMC-6236, which is Revolution Medicines' RAS multi, there has been some elegant work from Piro Lito which shows that it can induce GTP hydrolysis and convert the on-state to the off-state. RMC-6236, as an example, is not covalent. By definition, it is going to come off. It cannot bind to the off-state. Our molecule can bind regardless of where the KRAS lives, on-state or off-state. Theoretically, at least, there should be a pool of the off-state that could build up and be ready to come back and signal. We think it is an advantage to be able to occupy no matter whether it is in the on-state or the off-state. I will show you some preclinical data where we have compared directly to the on-only inhibitors.
We feel that there's really exciting in vivo data that shows that difference. Just quickly, we've looked here at the selectivity of our G12D inhibitor versus a couple of others. What we're doing on the right side of the slide, if you look at the table, we're looking at 3D proliferation of a number of tumor cell lines, those with G12D mutation, those with other KRAS mutations, or KRAS wild-type cell lines. You can see that 7375 is potent against and inhibiting proliferation of all of the G12D cell lines and very selective relative to the other KRAS mutant cell lines or the KRAS wild-type cell lines. That's in contrast, for example, to 9805, which does not hit a couple of the G12D cell lines very well, but does hit a number of the other KRAS mutations. It does seem to be selective relative to wild-type.
The Mirati molecule is less potent in these experiments. I think this is probably the most important slide that convinced me, other than the theoretical, that our dual on-off mechanism of our G12D inhibitor is really advantageous. What we did here is we looked at a comparison of VS-7375 as a G12D on-off inhibitor to a couple of on-only inhibitors, one Revolution Medicines' 9805, their G12D, and the other Revolution Medicines' 6236, which is their RAS multi. We compared in a couple of ways. We used typically the highest concentration that Revolution Medicines has used in their in vivo models for each of the two agents to give it the best chance of full activity. On the left is KP4, which is a KRAS G12D pancreatic cancer model. You can see that we treated with 7375 compared to 9805 or 6236.
For the first nine or so days, the agents looked similar. We continued dosing all of the agents. The RevMed agents let go, so less durable response. Whereas with VS-7375, it's really striking to me that it's able to maintain for quite a while the anti-tumor efficacy. We're currently doing some RNA-seq and other translational studies to better understand why the RevMed compounds are letting go as ours is holding on to the tumor growth inhibition. Similarly, on the right side of the slide, you see a G12D colorectal model. In the bar graph on the right, you see individual animals. You can see, for example, where it says maximal dose. We used 100 mg per kg of 7375, which is the highest we go with that agent. We used maximal doses of 9805 or 6236 from RevMed.
You see really deep regressions with 7375 in this model, which are really impressive relative to what the on-only inhibitors do. I'm very excited to see, as the clinical data play out, whether we can see that efficacy advantage relative to the on-only inhibitors and also the off-only inhibitors. This slide I'm showing mainly to set up how we should think about the clinical PK that Dr. Hung will talk about in a moment. What we did here is we ran four different xenograft models, two pancreatic and two colorectal. We're looking at different doses. You can see in green at 30 milligrams per kilogram orally, 7375 gives strong tumor regressions in all the models we've tested.
Impressively, in pink at 100 milligrams per kilogram, we see partial responses, if you will, 30% or more reduction in every mouse in every model we've run. We had thought this is before we had seen any of the clinical data from the China trial that was presented today. We thought if we can get essentially the equivalent of green or the 30 milligram per kilogram dose we're doing well, if we can get the equivalent exposure to the pink, we're doing extremely well. What we found in the China trial was that when we correct for protein binding, we get the equivalent exposure of the 100 milligram per kilogram dose that's giving these very strong responses. As you know, Mirati Bristol Myers Squibb's G12D fell out for lack of oral bioavailability. These are relatively large molecules, 650 molecular weight or higher.
It was really a challenge as we selected this particular compound with GenFleet to make sure we had really excellent oral availability across species. I think this might be my final slide. This is a colorectal model where we're looking at the combination of VS-7375 with anti-EGFR, cetuximab. I've been running preclinical models my whole career. I get less and less impressed with them as time goes on. This one really did impress me. You can see that all eight mice had a complete response with the combination of cetuximab and VS-7375. We stopped dosing on day 28. The complete responses persisted. We will move in our clinical program very quickly for colorectal to the combination with cetuximab. With that, it's my great pleasure to introduce Dr. David Hung. I can't think of anyone better to represent the RAS inhibitor space. Dr.
Hung is Deputy Chair of the Department of Investigational Cancer Therapeutics, the phase one program at MD Anderson Cancer Center. David.
All right. Thank you, guys. Thanks for coming. All right. Let's go through this. The KRAS space is pretty big. We enrolled 1,500 patients last year in phase one trials. I would say 35% of my patients have some kind of RAS. And somebody asked me, you have a lot of RAS trials up going. I don't have enough RAS studies going because I have so many patients. If you look at D itself, the most common mutant allele, you can see here in pancreatic, it's 37%, colorectal 12.5%, endometrial 8%, non-small cell lung 4.9%. But there are other rarer tumor types that are not listed here, like jejunal, small bowel, cholangio. There are subsets of head and neck that are almost 100% D. If you take all those together, that's 61,000 patients a year. It's a lot of patients. You all saw the GenFleet data.
I think when the abstract came out, it wasn't a whole lot of initial patients. I think it was 11 in non-small cell lung and 11 in PDAC. You see the data now. It's definitely impressive. I mean, especially the PDAC data, 23 patients, confirmed response rate of about 52%. You can see here, based on the different dose levels, all the way from 300 b.i.d., 600 daily, and 400 daily. I think they're moving forward with the 600 daily here. It looks good. I'm sure I'll get questions about comparisons, et cetera. That's always hard to do. You can see here in the list here on the very bottom, the number of prior therapies. There are patients up to four prior lines of therapy, et cetera, all looking like they're having a relatively robust response.
Too early to figure out PFS yet, right? That is an important metric, right? Too early to obviously have a cutoff for overall survival. That is an important metric. We will see that this initial response rate looks very encouraging. The adverse events here, one, obviously, contrast to what has been out there, particularly RevMed's 6236, is you do not see rash. There is no real rash. There are other what are probably expected side effects with these pan-on-off inhibitors, which are the GI side effects, some diarrhea, nausea, vomiting, et cetera. Some of you guys have asked me this question. How much of this is related to the actual class of drug versus some of it may be pharmacological, whether it is pill burden, whether it is certain types of coating on these pills? I am sure we will figure this out as these trials advance a little bit more.
What's a little bit more interesting here is the neutrophil. They did see some neutrophil, grade 3 neutrophils. Neutropenia is not something that we don't know how to manage. We all know how to manage. Oncologists, we all know that's standard fare in oncology. Here's the PK. I think the one thing that we learned from Mirati's 1133 is PK matters. PK matters because I will tell you, I had many, many preclinical scientists tell me when they were running these trials with Mirati 1133, you're going to cure patients, David. You're going to cure all these pancreatic patients. This drug is amazing in preclinical models. I put it in patients. We didn't cure anybody, nor did we really see any significant responses. The fact that they can actually get this in human, this is human data. This is human data, I'm assuming, not animal data.
That's important. You see the steady state effect here, which is way above this phospholuric IC50. You see that in the CMAX, CMAX trough, which we think is probably a very important metric. You see the AUC, likely compatible with once-a-day dosing. Patients love once-a-day dosing. They hate taking their pills more than once a day. All this suggests that the 600 milligrams q.d., which was recommended by, will go. We will see. There may be some differences in an Asian and Western population. We will see how this goes. OK, here is the trial design. Very simple, straightforward. Let's try to move this as fast as we can. Full disclosure, I'm actually involved in the trial. We just activated today. Boom. We're going to get patients on this month.
You can see here, dose level 1, 2, 3, move from 400, which they saw activity in, up to maybe 900, then move forward very quickly to second line and second line non-small cell lung patients, and then move into the combination, which I think will be important because we do not know yet whether or not RevMed can actually combine it with cetuximab. I am not involved in those trials. We will see what hopefully they can. We do not know. I mean, we will see where this all goes. This is a good, straightforward, simple forward design. We will accrue rapidly. I know I will. There is a high met on me. I want to reemphasize this again. 61,000 patients a year, just in the United States, KRAS G12D diagnosed, not just in pancreatic, lung, colorectal, other solid tumor types. Unmet need, huge market.
The initial phase one is very encouraging. The pharmacokinetics, the responses, et cetera, proof of concept. Part of the reason I'm also involved with them is because I know they're thinking of combinations beyond just single agent, beyond just the standard of care. You saw the data from the RAMP. I mean, there's clearly, I mean, there's clear rationale to combine it with FAK inhibitors. There's clear rationale to maybe combine LTRIPL. We'll see. That is important. There are some key questions we talked about. I think I've talked about to some of you all. This shows proof of concept that these on-off inhibitors can work. In the world of kind of RAS development right now, there are these pure off inhibitors, on-off inhibitors, and these pure on inhibitors. The on-off inhibitors are right now the most frequent type of RAS inhibitors in development.
They're all still in dose escalation. If this GenFleet data is, I'm assuming it's real, then it really shows that these on-off inhibitors can work. One question that we do not know yet of any of these RAS inhibitors, because they have not done the experiments, is how brain penetrant are they? That is going to be an important question in lung. You talk with any lung doctor, after they see a response, they'll ask you, does this go to the brain? About 40% of those patients, 45% of those patients will get brain metastases. Hopefully this thing will. I'm sure you guys will at some point see what activity it is and then maybe have a cohort that allows for untreated brain metastases. We'll see where that goes.
OK, that's me. Thank you.
Thank you, Dr. Hung and Dr. Prakosi, for sharing those data with us this morning and, importantly, for providing your insights and interpretation. My name is John Hayslip. I'm the Chief Medical Officer at Verastem Oncology. I'll review with you now our clinical development plans and timelines. Acknowledging that we're earlier in our journey in pancreas cancer than we are in low-grade serous ovarian cancer, for example. I believe avutometinib and defactinib is showing the potential to reshape the expectations in metastatic pancreas cancer. Today, most patients with metastatic pancreas cancer do not expect to achieve deep and durable responses to their treatment. With the data that Dr. Prakosi shared with us today, I see that there is potential to reshape expectations for patients with metastatic disease. Our clinical focus right now is in moving forward rapidly in the RAMP 205 trial. Dr.
Prakosi, I think, reviewed with us that we've expanded at dose level 1. We're focused on enrolling additional patients to expand that cohort out to 29 patients in total. Our team is planning now for a randomized trial to initiate in 2026. We're excited about the potential to evaluate at least two different indications of metastatic pancreas cancer, of course, newly diagnosed patients with metastatic pancreas cancer, and also, importantly, the potential to see what we can bring to patients with borderline resectable pancreas cancer. There may be no indication more in need of a new novel therapy with high rates of deep response in advanced pancreas cancer. We're planning and working on further regulatory interactions to align these plans. I'll look forward to sharing more about that in the future.
As also mentioned, we will continue to evaluate additional novel combinations to bring forward in pancreas cancer in the future. Based on the results shared this morning by GenFleet Therapeutics and reviewed for us by Dr. Hung, I am incredibly excited by the high rates of objective response that was presented for the 7375, our KRAS G12D on and off inhibitor. Also impressed by the non-clinical or preclinical findings regarding depth of response and how that translated to durability of response in those models. I am very excited to see updating clinical data throughout the year. Our focus here at Verastem Oncology is on activating the study in the phase 1, phase 2A trial. Very happy to announce that we have actually initiated three sites here at the end of May. Those sites are actively screening patients right now.
We're initiating the trial at the 400 milligram dose level on the 7375 study. The 400 milligram dose level is a dose level that was just shared this morning with a monotherapy activity for patients with heavily pretreated recurrent resistant metastatic cancer. As reviewed, we have planned expansion cohorts in pancreas cancer, non-small cell lung cancer, and the combination with cetuximab in colorectal cancer previously treated, which Dr. Pachter reviewed with us, has shown complete responses in all of the mice tested to date. Additionally, our team is evaluating more cohorts for potential activation in the future. We're actively targeting newly diagnosed pancreas cancer, newly diagnosed lung cancer, and additional indications such as our KRAS G12D mutated, such as endometrial cancer, building on our strong focus in gynecologic oncology. I thank you for your attention. I'll turn back over to Dan Paterson, our CEO.
Thanks, John. As you can see, some very exciting data today to build on our recent launch. Exciting year for us, really, I'd say a transformative year for Verastem in 2025. With that, I will leave it. We can take a few questions. I think we've got a little time for any of the panelists. We'll start here because I know you had your question before.
Thanks, Michael Schmidt with Guggenheim. I had one for Dr. Hung, actually. I know you've presented the 9805 data for RevMed last year. Yeah, I'm just curious how you think the 7375 data compares. Do you think the tolerability can be managed at this 400 milligram q.d. dose?
Of this drug?
Yeah.
I think both drugs look pretty good. It's hard to do. The number one thing that all clinical trials will tell you, it's hard to do cross-trial comparisons. That's what I'm going to say. Both drugs look good. I'm not going to dismiss 9805 results because obviously, you know the results. It looks like the 400 seems tolerable. I mean, we'll see what happens. There could be some differences between Asian and Western populations. I don't expect necessarily any change. Both drugs look good. John and I have talked about how do they and they have an opportunity, I think, to move very quickly. They have an opportunity to do combinations that RevMed doesn't have. They don't have a FAK inhibitor. They don't have these other things. We'll see what happens.
Right. Yeah, I mean, the drug is obviously very selective, perhaps more selective than other D inhibitors. I think because of that, some of us were a little bit surprised by the GIAs. I know they were mostly grade 1 and 2. Is it just idiosyncratic, as Dr. Hung mentioned, perhaps? Is there something?
I think maybe John can come on to that. I think GI toxicities can be very difficult to tease out exactly what are the causes. There can be related to the actual mechanism, which I will probably say, I'm just going to say, all oral agents to some extent, whether RAS or what other therapy, have some GI toxicities, mostly diarrhea, mostly nausea, vomiting. Some of that, though, is complicated by, especially during the trial, things like pill burden. Like Mirati's Adagrasib, for example, before they reformulated it, they had a lot of nausea, vomiting. It was because somebody was taking 12 pills a day in one sitting. I do not know what the exact pill burden on this is. There are also other aspects of the actual pill, not necessarily the mechanism, such as you can enteric coat a pill, which makes it much more tolerable.
All these things kind of come into play. I guess John can comment on it also. I do not necessarily think it is just purely the RAS inhibition.
Yeah, what I was going to say is when I think about side effects, but particularly GI side effects, I think not just about the drug, but the disease and the patient. For example, some patients have had pancreatic duodenectomies. Some patients have other GI pathology. Some patients have other issues that are important symptoms that require management. It is a very complicated thing to associate a particular symptom with just one factor. It is often multifactorial.
I was just going to add that the switch tube binders have a common kind of structural component. I think you're going to see some things. I don't think that KRAS G12D is expressed in normal tissues that's mediating what you're seeing. It is structural based rather than target based. I think the similarities to Adagrasib make sense from that point of view.
We have already discussed some strategies in the phase I to mitigate that that might be different than how the patients were treated in China.
I can speak to that. Thank Dr. Hung reviewed. In this trial, we'll be testing patients with food. So they'll take their medicine with food. The data presented, of course, this morning comes from the first in human study of this medicine. In the initial patients dosed, all patients were treated in a fasted state. They did not know when they initiated the trial whether there would be really any nausea or diarrhea. The results that we reviewed this morning come from patients who had not received any prophylaxis or prevention. Also remember, when you read an adverse event table, it's showing you the table as to whether patients had any adverse event even for one day. A patient who had nausea for a day and then does not the next day still is counted as a person with nausea.
This has not been a reason for discontinuation. The drug has been, to our appearance, it looks to be tolerable in that study. We're optimistic that by evaluating in the fed state, evaluating by patients who initiate, they start the treatment with some nausea prevention with the opportunity to come off of that if they're doing well. We may see an even improved adverse event profile in the future. We're excited to see what we can see.
Yeah, most oral agents, when you give it in the fed state, the nausea usually gets better. That's my experience.
This is Clara Dunn for Kelly Xi from Jefferies. My question is on G12D. From the ASCO presentation, we saw there were a few colorectal patients enrolled in the China phase 1. I do not see the CRC activity data specifically broken down, so I am just wondering if you maybe can qualitatively comment on what you see to support you moving forward with the CRC eGFR combo study besides the preclinical combo data you presented.
I'd say first and foremost, that amazing preclinical data. I don't know if John or John, you want to comment on.
Yeah, I can say a bit. I mean, I think that we just had an approval of our FAK inhibitor, which doesn't show a lot of single agent activity. But combined with avutometinib, it's clear that the two together really got over the finish line and the FDA accepted the contribution of parts. I mean, that's an example of in colorectal, I think it's been a real challenge for KRAS inhibition alone to be sufficient. Across the MAPK kinase pathway, BRAF inhibitors, et cetera, are there examples. Also, G12C inhibitors previously where combining with anti-EGFR greatly increases. I don't think that you need a huge response rate in colorectal as a single agent to predict that you could have success when you combine with an anti-EGFR.
Yeah, I mean, most of the, even with these are the reported data from 6236, response rate with the PanRAS inhibitor is probably around 9% in single agent in colorectal. They did not have a whole lot of patients either. I do not think any of us, especially GI docs, really expect more than single digit response rates in either the PanRAS or even the D specific cohorts with these molecules unless you combine it with cetuximab or with panitumumab. The fact that they do not have any rash is key because you are going to have with a PanRAS inhibitor like dexonrasev, the big question is, can you dose combination to the full dose of cetuximab and to dexonrasev without really threatening that therapeutic window? We do not know yet.
Thank you. Also, just wondering if you could elaborate a little bit more on the 400 milligram daily dose you start in the U.S. phase 1 trial because I also just want to confirm, are you sticking to only 400 milligram dose because you presented both 400 and 600 milligram for efficacy and safety?
The 400 is the starting point for dose escalation. The advantage of having the Chinese data is we did not have to go back to 100 to start. We are starting in an effective dose range and escalating from there. Now, one of the things we will explore is there are probably differences in how the regulators look at your chosen dose given Project Optimus. We are going to have to make sure we nail that before we move on.
Great. Jeet Mukherjee, BTIG, thanks for taking the question. Obviously, just still on the topic of the adverse event profile we're seeing with the various agents here, let's just say, assuming equivalent efficacy, what adverse events from these agents becomes a non-starter or a limiting factor for you in the clinic?
Of the current profile?
Current profile.
Really nothing. I mean, like nausea, diarrhea. I mean, the neutropenia rate was very, very low. I doubt, and I don't recall exactly at what dose levels they had the higher levels of neutropenia. These are standard toxicities that, because you're not really talking to me, you're talking about the community oncologist who's going to prescribe this thing. These are standard side effects that community oncologists all know how to deal with.
Understood. Helpful. At least among the lung cancer patients presented today, did any of them have brain mets or were they excluded from the trial?
I don't know.
John, do you know?
My guess is most phase 1s, we exclude essentially the eligibility criteria. Most phase 1s is that they either cannot have brain mets or they have to have treated brain mets. That means they get XRT, and then they have to be stable for a period of at least four weeks before they get enrolled. By definition, that tumor is dead. Most of the, at least the trials that I've run, most of the phase 1 RAS studies have excluded brain mets at this time. They usually do that experiment at a later time because they do not want to, if you have, even if you have a small brain met, it can rapidly grow. You do not want to have these patients fall off in the middle of the dose-limiting toxicity window.
My guess is that at some point, we'll probably, in the expansion, we'll probably try to see if that's the case.
Got it. Helpful. Just lastly, to the frontline PANC data, same standard of care provides about 5.5 months MPFS. What improvement or delta on PFS would be considered clinically meaningful here?
OK. I wanted to comment a little bit on the first question you asked. That is to emphasize two things. One is that, as Dr. Hung mentions, managing GI toxicity to a GI oncologist is one of the, if not the most, aspects of supportive care that they're most experienced with. I also wanted to add that you have to remember this from the patient's point of view. These patients have desperate prognoses. Many times they're willing to do darn near anything if they can prolong their life. There is a greater tolerance for this sort of thing than there are in many others of oncology. Now, with respect to the PFS question, actually, oncologists look more at overall survival than progression-free survival. The reason for that is that progression-free survival is sometimes hard to gauge.
Radiographic, such as CT, indications of response are infrequent given the natural disease and somewhat difficult to assess. It turned out there was a study done some years ago that was presented at the ASCO GI that looked at 20 years' worth of studies in pancreas cancer. There was a very low correlation coefficient between PFS and OS. A good example would be the Panova 3 trial I presented on Saturday, where there was not a clear benefit in PFS or local PFS seen, but there was a clear benefit in OS. Again, oncologists look more at OS than PFS.
Yep. Prakesh Patel, B Reilly Securities. Maybe one for the KOL. There has been some ongoing discussion about patients who are diagnosed as locally advanced versus metastatic and what their prognosis is like over time. We saw here that almost all of the patients were metastatic at diagnosis, whereas Revolution Medicines' data, about half were locally advanced and half were metastatic. I'm curious, does it matter after you have a median of two priors your outcomes or your response to these therapies in the advanced setting?
Do you want to start?
OK, I'll start. As you go through different lines of therapies for incurable pancreatic cancer, I think the difference between locally advanced and metastatic narrow. Still, patients with locally advanced disease would have some survival superiority over metastatic disease. Therefore, when I read trials, the percentage of patients that are locally advanced versus metastatic does matter. That would be my answer. Dr. Hung?
I mean, locally advanced is pretty bad still.
Yeah.
I mean, as you mentioned.
Between adverse, right.
As you mentioned, these patients are locally advanced tumors. That means you can't resect them with a Whipple, et cetera. Invariably, I mean, a CT scan, if you think about it, is a very blunt instrument. It's not like we can, on a CT scan, I cannot see usually a lesion that is bigger than a centimeter. These patients, a lot of these patients locally advanced will probably have seeding on the perineum that we cannot see by CT scan. Locally advanced is, he's the pancreatic expert. Locally advanced is pretty bad.
Yeah, actually, locally advanced patients, if they're not laparoscopically staged, meaning literally you go in the abdomen and look, will have occult metastatic disease about a third of the time. There is overlap between the two. Thank you. I think we had one more over here.
Thanks. Eric Schmidt at Cantor. Maybe two questions. I'm curious about your decision to dose escalate from 400. I know it's not your data, but when you look at the China data, it looks like the PK for 400 and 600 is overlapping. And then you're way above phosphoric inhibition levels at CMAX and CMIN. So why not go lower? That's number one. I know Dr. Hung thinks PK matters. And then two, could you explain the two grade 3 liver dysfunction abnormalities that were observed in phase 1, again, knowing it's not your data? Thanks.
Yeah. So glad to take that. Thank you. Regarding the first question, the data shared today represent the data as of the data cut on May 16. The data shared today will include some additional observations beyond the data I believe GenFleet had in hand at the time they decided to expand at the 600 milligram dose. I will not speak for them. The data have evolved. There is more data than what they had when they made that choice. I think as Dan mentioned, and it is important just to be clear about where we stand at Verastem. We are developing VS-7375 outside of China. We have United States, Europe, and other locations. We will continue the development program and work to evaluate what is the optimized dose and schedule of VS-7375.
Regarding the design of this trial, this is an oral agent. We are excited to boldly initiate this study. We are treating patients at a dose that we have seen clear efficacy in the study coming out of China. In addition to, of course, the more blunt dose level evaluations of efficacy and safety, we will be doing all the standard exposure response, exposure response for safety, exposure response for efficacy. If the data lead us to suggest that other dose levels would be appropriate, we will be right there to do that.
The grade 3.
Liver.
Grade 3 liver.
As you mentioned, that's not my data nor my study. I would say, I think what I can share is that both of those cases we regard as highly confounded and do not impact our starting doses or how we will be evaluating in our trial.
I know we had one question from online. Maybe I can give to the KOLs here. Can you put the RAMP 205 data in context with other data at ASCO for experimental agents looking at first line PDEC?
OK. I think that's an excellent question. I would say the data is actually very competitive. For example, in part of the GI oral session, there was an examination of a GSK3B inhibitor in association with Abraxane. The data that is being displayed here with the avutometinib and the defactinib combination is going to be significantly superior to that, for example.
All right. I think we'll wrap it up. Thanks, everybody, for your attention.
Thank you.
Thank you very much.