All right. Good morning, everyone. For those that don't know me, I am Julissa Viana, the Senior Vice President of Corporate Communications, Investor Relations, and Patient Advocacy. We are really excited to have you here today, and thank you for those that are listening via the live stream. Please note that this event is being recorded and will be available on our website afterwards.
This morning, we are very excited to discuss VS-7375, our best-in-class, highly selective oral KRAS G12D on/off inhibitor, which is being evaluated in multiple clinical trials. Today, we will share new clinical data from our TARGET-D 101 trial, including, for the first time, U.S. efficacy data and updated safety and tolerability results in KRAS G12D mutated pancreatic, colorectal, and lung cancers. This morning, we issued a very long press release detailing these results, along with a slide presentation that we will reference today. Both are available on our website.
Go to the next slide. Let's see. All right. I will not be reading this slide, but I do need to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. We encourage you to consult the risk factors discussed in our SEC filings for additional details. Joining me today to present the data are Dan Paterson, President and CEO, Dr. Michael G. Kauffman, President of Development, Dr. Ting Wu, Vice President of Clinical Development, and Dr. Manuel Hidalgo, who is the Director of Gastrointestinal Cancer at NYU Langone Health and Professor of Medicine at NYU Grossman School of Medicine. As many as you know, he is a leading medical oncologist, and he is currently also an investigator on ongoing trials.
Along with our presenters, Dr. Jonathan Pachter, our CSO, will also join us for Q&A. I will now turn the presentation over to Dan.
Well, good morning and welcome. We are very excited. This is, 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 has been a four-year journey where we set out and made a conscious decision working with GenFleet to have a G12D selective agent. Everyone has been talking about pan-RAS versus G12D, and I think within the last month or so, I think folks have come to realize Revolution Medicines did an amazing thing as a drug that is a leap forward for patients. But when you look at things like quality of life and tolerability, having a selective molecule matters. In order to have a selective molecule, there were a couple of key things that we really needed. We wanted it to be potent, very selective, on/off inhibition.
One of the more important things, if we go back a year or so ago and you looked at as this area was evolving, I would say Mirati BMS is probably a good example where these molecules didn't have good oral bioavailability, that's really the starting point. We have a molecule here that we can give orally. We get dose-proportional exposure. One of the things that's amazing, hopefully, you will 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 are seeing in the U.S. I think what differentiates this molecule from a lot of others in the space is you give more drug, you get higher blood levels, and you get better efficacy.
We will walk through that, I would 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 have set a new benchmark in PDAC, efficacious and safe, and we will go through that. CRC is a little earlier, but we have shown we can combine with EGFR inhibitors and are seeing early anti-tumor activity. The data set that you will see today in lung is at the 600 mg dose. Our go-forward dose is 900 mg, and we expect to see the same dose response as that data comes out. I think lastly, the favorable safety profile. What you are seeing now, it's largely Grade 1 and Grade 2 gastric AEs, and it's the pill in the gut.
There is no systemic cause here, down the road, we will do things like different formulations and stuff to even make that better. Even where we are today, we are able to deliver 97% dose intensity at the 900 mg level, and it's very combinable with the standard of care agents that will be critical to combine with in frontline. With that, I will turn it over to Michael to take us through the clinical data. Again, the picture that's emerging is what we had dreamed of four years ago. 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. Back in December, as the data started to emerge with this molecule, I just kept running onto the field and getting penalties. Finally, I just said I better join the team, and Dan let me. It has been an absolute pleasure working with him. We are going to continue to work together, and I am looking forward to working with Michael Bailey going forward. Let's switch gears now to talk about this.
I have to say, in a career that I left practicing medicine in 1995, I have never been involved in a program that could squash solid tumors this way, with the kinds of side effects that we are 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. It is absolutely thrilling, honestly, to be up here and present these data. We all know that the current therapies are very limited. Chemotherapy, we say FOLFIRINOX, it is brutal. It is like being run over by a truck.
Even Gem/Nab, which is chemo light, is not pleasant at all, and everybody gets neuropathy within months. We will talk about that towards the end, that chemotherapy is okay at the beginning. It is very unpleasant, to put it nicely. But nobody stays on the therapy because they are 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. So the durability of our molecule is what is emerging, and we will 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. 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 in oncology and other diseases, but the cetuximab, panitumumab rashes are generally much easier to treat and take care of than some of the pan-RAS rashes. Mucositis and stomatitis are big deals with chemotherapy or a pan-RAS inhibitor because you want people to be able to eat, especially with pancreatic and colorectal cancers. 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 have got to achieve a dose that hits the cancer cell. Not the bloodstream, the cancer cell. You will 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. The best chance for at least prolonged disease control with a good life for patients is to get into the frontline setting as quickly as possible. I am happy to let you know, and you have seen from the press release, that our FDA has approved our phase III trial design for frontline pancreatic cancer. It is a beautiful design, has some new elements in it that I think FDA has recognized the unique qualities of this drug. We will 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 are talking to you about single-agent and combination potential across three of the worst G12D tumors we have.
Remember that G12D is a bad prognostic factor for all of these. We are treating the worst of the worst. We already have three potential accelerated approval trials ongoing in each of these diseases that are accruing today. We expect to accrue for pancreatic and colorectal to finish by year-end, and lung cancer in the first half of next year. Our intention is to establish a beachhead in the second line. But as we say, frontline is where we all want to get to because that will address the most patients at the time when their disease is most susceptible to impact. The pancreas study, as you heard, will start by the end of this year, and we expect the lung and the colorectal phase IIIs, pardon me, frontline studies to start in the first half of next year.
Let us move now quickly to the data that we have 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. Now we are looking at things that look almost like antibiotic responses. We are 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 is no baloney here. This is MITT. It is every patient we have treated. This is the cohort of 900 mg pancreatic-treated patients in our phase I. This is it. This is everybody. There are 20 patients here.
There are two patients who did not make it to their first scan, so we do not have any waterfall data for them. But they are on the swimmer plot you will see on the next slide. MITT everybody. The second thing is that these are all confirmed responses. Remind everybody that the RECIST rules in single arm trials do not recognize a single response. They do not 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-line and fourth-line disease had confirmed response, and including a confirmed complete response and a patient who had a confirmed partial response who has their first reading of a CR.
We have every reason to believe, based on tumor markers and how the patient is doing, that that CR will go on to confirm. As far as we are aware, there have never been a report of a G12D pancreatic cancer complete remission. Part of the reason we think the FDA granted us some of the design elements in our phase III trial was a recognition that this is a very, very different drug. CRs in any solid tumor, as you know, is 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 it for all of humanity. We believe it will. The patients had the standard background. It is median of two priors, et cetera. The swimmer plot. We also try to give you guys all the data.
There is no covering up anything here. This is a combination of a swimmer and a kind of spider. 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 is surprised about that. Pancreatic cancer is a highly fibrotic, difficult to treat tumor. Not only do you have to kill it, but you have to get the macrophages and everybody else in there to clear the debris. This is a war zone. It is the patient armed with our drug fighting these tumors. You can see that most of them are ongoing.
16 out of 22 patients are ongoing, 15 of them without progression. What does that mean? What that means is we had one patient whose tumor grew 22-ish percent above their smallest tumor size. One of the unfortunate problems with RECIST is that you are blamed for having a great response. 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 4x what we would have expected for a third-line, fourth-line pancreatic cancer patient. He feels great. Interestingly, this tumor, by the way, has not grown during this time since the progression. So it grew enough to be progression, but then it stopped growing.
He continues on therapy. Really exciting for these folks. The PFS. Remember that the best data we have on progression-free survival in third-line and fourth-line pancreatic cancer is from daraxonrasib's phase I study in New England Journal. That is 4.3 months. We have crossed that. We are at 6.5 months now and increasing. We are at least two months longer than the best data in third-line 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.
Everything seems to be going along that we will be able to deliver a better disease control as well as a response rate in pancreatic cancer that has been previously treated. Running through some of the data, and of course, this is cross-trial comparison. We have to disclaim any ability to do that. I remind folks, all the doctors, Manny, and everybody else, we all do that every day. That is how we make clinical decisions. We do cross-trial comparisons. We have very little head-to-head data in oncology and other diseases. With those caveats in mind, just to remember, but in second-line disease, the best response rate in G12D so far in 2L pure second-line disease is 24% with daraxonrasib. Just came out in the FDA documents last week. We are 50%.
In third-line plus, the best response rate daraxonrasib is 21% in the G12X population and highly likely to be lower than that because we know that G12D did much worse on daraxonrasib than G12V and some of the others. We are at 36%, and it is solid. Part of the reason we have such good responses in these heavily pretreated patients is because we are a very well-tolerated drug relative to the others. When you are tolerated well, even in a frail patient, you can continue therapy. This is a constant battle for the patients. You have got to deliver the drug consistently. Ting Wu will show you some data on that. We are thrilled with the consistent use of this agent to beat up this cancer.
In the second-line plus setting where the most data are available with some of the G12Ds, the main competitors, if you will, are zoldonrasib and Incyte's compound. These are unconfirmed ORRs. Many of you have already dug into these data and looked. You know that the Incyte confirmed ORR rate is 29%, not 37%. The confirmed rate is 29%, and you know that the zoldonrasib is less than 30%, and we do not know what it is and the data have not been updated. Also, the durability of these agents is not known. Setidegrasib, we have real data, but it is not really very competitive compared to the oral agents. So we believe that this has best-in-class potential as we have said. Why is that? As Dr. Pachter likes to say all the time, it is all about getting the drug into the body and delivering it.
Most of the other drugs seem to sit in the middle lane here if you look at therapeutic windows. That is to say that you max out for most of the other competitors. Best we can estimate is that they sit in the green box. Our drug has linear PK. So 900 delivers more drug than 600, delivers better area under the curve here exposure. This was actually the goal. It is the first time in my life, honestly, that I have seen animals actually predict, mice predict what humans should do. We wanted to be above this magical 2,000 AUC, and we have done it for 80+% of the patients. We are 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 is all the same data. There is not any real subtleties here. For VS-7375, 12 out of 12 patients had at least a 50% reduction in their tumors. Not every tumor sheds, which is why we do not have 23 patients there. 12 of the tumors shed enough to pick up ctDNA, so we can use that. All 12 had at least a 50% reduction. Oncologists will tell you 50% is nice, but we really want at least a log reduction. 11 out of 12 patients delivered a log reduction. The 12th patient was at 80%, but that patient was very nice. He went and got a partial response, confirmed partial response. So even an 80% reduction here led to a confirmed PR.
We annihilated the variant allele frequency in almost 60% of the patients. It is gone. That means we penetrated the tumor sufficiently that there is no more tumor cells releasing DNA. 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 do not tell you functional. You can have a dead pancreas tumor with a lot of stroma left over and a lot of inflammation, and you will not pick it up on a CAT scan very well. 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 are all aware of. The other drugs just cannot do it.
Daraxonrasib is the strongest overall, but it is limited by its tolerability. Zoldonrasib has most of the patients that are above the 50%. Still not bad, but problem. Incyte'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. Of course, people ask us, "Where are you with Project Optimus? What do you know?" We have a dose response, just like the pharmacokinetics showed you. Up here, that 600 does not do it. It leaves half the patients below that goal line. 600 mg 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 mg , which is exactly what it should do.
We can do this because the side effect profile of 600 mg and 900 mg are virtually indistinguishable. So much so that we did not put the 600 mg data in the deck. You do not need to see it. It is basically the same. It is 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 will make, and I did not make it before, is not a single patient who had a follow-up CAT scan had a tumor that grew. That is a remarkable story. You are going to see that in CRC, and you are 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+% chance that this tumor is going to shrink on a single oral therapy after what they have been through? They are going to ask you why the heck you did not give them this drug before. Terrific for patients, and we are all thrilled to move this program as expeditiously as possible.
We will get into that at the end. Okay, let us switch gears for a minute to colorectal. Early data yet. We had to clear 600 mg+ , we will show you the dose response in a minute, and we are up at 900 mg . 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. 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 are already beyond that. We obviously want to see a response rate north of 30%. We are in that range right now early on. One of these is unconfirmed. The other is confirmed. We have this patient whose CAT scan is still waiting for the report, unfortunately. 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 will believe this.
Now, we see the same thing on dose response. This drug is extremely predictable. You go from 600 mg , where you see decent antitumor activity, certainly more competitive than what's currently available, but not the thresholds we want for accelerated approval and to get this drug to patients fast. 600 mg , 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 panc. 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 will have more updated data in a couple of months in colorectal. We are super excited about this and the phase II trial is enrolling beautifully. Now let's switch to 600 mg lung. I want to keep saying that, 600 mg. 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. We will get to that in a minute when we talk about the frontline early data. So at 600 mg, our waterfall is almost pure. We have one patient who's continuing on the left, slightly growing tumor. We don't really know why. Patient is symptomatically much improved. We see that a lot, by the way.
We see pain, shortness of breath, bloating, appetite, really remarkable on this drug getting better. In the deck that's on the web, you will see some PET scans that helps 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 are not quite there yet because they have a couple non-target lesions. All the target lesions are gone. The other thing you will notice here is we don't play games. This is the MITT cohort. This is everybody who got the drug with lung at 600. We did not exclude 1/3 of the patients who got prior taxanes. There's no reason a priori that we can think of why it should matter whether you got prior taxanes or not.
The taxane previously treated patients are in the gold bars. Great responses there. No problem treating those patients. 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 mg lung data are in an accelerated approval phase II study. This is because it's in a different division of FDA. We won't have 900 lung data to share with you, but you can do the extrapolations of what happened in pancreatic and GI. You'll also note that the 600 lung data are terrific. These responses tend to occur very quickly. All of the PRs that happened in the first scan. That's different than a GI tumor. We're penetrating the lung very well. This is pretty well known.
Lung cancer generally is more susceptible to these therapies, and every one of the PRs here are continuing. Every single one. These are durable partial responses. One of them looks like it might convert to a CR. We shall see. 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. 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 lung and the activity. Zoldonrasib, in contrast, about a quarter of the patients don't make it.
They just can't get there. Moving to frontline. The lung group has been interesting, the docs. We had a mediocre initial reception, and then it picked up. Then suddenly they said, "Well, we just want to move this to frontline. We're convinced." 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. 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 mg, 75% overall response rate to date. Some of these confirmed, some of these unconfirmed, and some of these responses are just with Keytruda because the patients had high TPS levels.
As you know, Keytruda is indicated if your PD-L1 level's above 50%, Keytruda single agent. It doesn't matter. These are fast responses. I would argue that these responses occurred primarily due to VS-7375 because Keytruda takes a while to get to a PR, and these are pretty deep PRs already. We, and more importantly, the lung key opinion leaders are thrilled about this data. The expected ORR in G12D lung cancer is on the order of 35%-40%. It is worse than the overall adenocarcinoma population with triplet chemoimmunotherapy, and that's because G12D is a bad actor. Again, very early data, but very exciting and a consistent waterfall profile. Okay. Let us turn it over to Dr. Hidalgo. Manny.
Thank you, sir. 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. I am a physician scientist. I work actually down the street at NYU, and I have been involved in the development of this agent both in the phase I and the phase II colorectal pancreatic. I will be talking mainly about pancreatic cancer today, and we will be involved as well in the phase III as soon as that is activated. This drug and the RAS inhibitors in general are changing the landscape of the way we are managing and treating this disease. I think most of the relevant points were already addressed by Michael earlier in his presentation.
What I will do is I am going to show you one case, one of the patients that I have the privilege to care for and who has been involved in the study, enrolled in the study. A patient actually who came from Europe to be enrolled in the trial. That I think it is a good example on how this medication, as a single agent, is changing the outcome of patients. Very simple, the outcome of patients, their quality of life, their pain, everything. 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. Let us get to the case. Here you have a very classic and unfortunate situation. Young male, 55 years old.
We are 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 G12D mutation. Started on multi-agent systemic chemotherapy, which is the standard of care. You have the scans of the baselines with this when he started on the trial. But prior treatment was chemotherapy, modified FOLFIRINOX, very intense, very toxic, not very effective. Gemcitabine/ABRAXANE, in some patients a little bit lighter, but not so much. Also very intense and with significant toxicity. This patient unfortunately progressed very rapidly to these two prior lines of treatment. For this patient, when he presented in the clinic, there is no standard of care, as you know. There is very little investigational agents that we know were effective before these drugs came sort of age.
Patient came to the clinic and he was a young gentleman, still with a good performance status, but with very classic and severe pancreatic cancer-related pain. That pain is horrible. It is the best pain that you can have. It is a pain in the upper abdomen. It goes to your back. You need to be sitting like this. You cannot eat. You cannot sleep because the pain is more intense at night. The patient was, of course, taking morphine, narcotics, high dose. The way these narcotics work is that they work for a little bit, but then when they wear off, the pain is back. He started on the medication and went through all the process and called me three, four days later saying, "Hey, doctor, pain is gone. I am off morphine, completely off morphine.
I am taking an Advil here and there, but my pain is completely gone. The medication causes a little bit of nausea in learning how to use it, and that is an important topic. The side effects are minimal and can be managed by the patients because they learn when to take the pills, what to take the pills with, at night, in the morning, midday. A little bit of nausea, but it is fine. This is doing the, it was a terrific and very impressive clinical improvement, which responses, as mentioned before, can come late, and we see that they continue. Symptoms improvement occurs very rapidly, which there has to be something that the drug is doing to decompressing the tumor, to affecting the tumor infiltration in the nerves. There has to be something that I think we will study at some point.
This patient continues to be on a study and has a very nice partial response confirmed, three scans. Now it is more than 50% and you can see the scans at week 12 compared to baseline and it is particularly noticeable the liver lesion, which are basically gone. The liver lesions are basically gone and he still has some peritoneal disease. Of course, as mentioned before, the RAS allele that was present is gone, is not there. That is also a very important factor that we are learning with this medication, which is that we have the ability because we know what they target to really measure the molecular response. We think that that will correlate not only with PRs but will correlate with future outcome, the progression-free survival and survival. Very good partial response.
What I think is important, as mentioned before, is the clinical improvement, the good tolerability. The tolerability allows a few things. One, of course, is great for the patients because they do not have the side effects of chemotherapy or the side effects of other medications, but allows you to do combinations. You saw the combination with cetuximab, very interesting. You have heard that there are many ongoing combinations with very high response rate, not only combinations with chemo, but we are more interested in combination with other targeted agents in patients who have co-mutations and alterations in other relevant genes. It allows you combinations. The patient takes the pill every day, and this is very important because we are learning that the moment you stop, this is like the brake and the accelerator. The moment you stop, the cancer flares back.
Now we have experience with patients who have very good CA19-9 secretors, where you can really monitor. When you stop the drugs because of toxicity, a week later, tumor marker going up. You start, it goes down. At some point, we think those on and off may actually favor resistance. The ability to take the drug every day because of tolerability is very important. The last point that I want to mention is that I think was not mentioned before. Of course, the PKs are super interesting. I think drugs work well when they have clean and predictable PKs. That is when you know what you are giving, what is getting in plasma, what is getting to the tumor, what is hitting the target, is all linear and logical. It is easy to develop drugs that way when they have these properties.
But one final point I want to make is that we're learning that these patients are progressing in a different manner. With chemotherapy, when patients progress, everything is just going up. Everything is growing. 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. That has an important clinical implication because then you can treat those patients locally 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 is appropriate. Thank you very much, and I'm going to pass the podium to Dr. Wu, who will continue the discussions. Thank you.
And thank you, Dr. Hidalgo, for sharing this remarkable case and also the insights for using RAS inhibitors. For people who don't know me, my name is Ting Wu. I'm Vice President of Clinical Development at Verastem. I'm a medical oncologist by training and have the privilege to lead the development of VS-7375 on the clinical side, and also having the privilege to share the tolerability data of VS-7375. I want to start with the consistency of patients able to stay on the 900 mg go-forward dose. And I think this is best highlighted through the dose modification statistics. If you look at the numbers of discontinuation, it's only 2%, either due to TEAE or TRAE, which is quite remarkable. If you couple with the median relative dose intensity of 97%, this is, I would say, extremely favorable compared to any class of targeted therapy.
If you look at a reduction interruption rate, they are also low. I want to point out that interruption rate is slightly higher than reduction rate, and that is by design. If you are following the story of Verastem, we have very consistent safety profile across time points. Also one thing that we noticed is that the safety profile of 600 mg and 900 mg are identical. Therefore, there's no point of dose reduction because this doesn't really help with managing these AE. Rather, a short interruption up to 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 VS-7375. Essentially no impact on activity of the drug.
Patients can resume at the same dose, continue to benefit on the high exposure, also the better activity at 900 mg. Another way to look at tolerability of VS-7375 is to look at the rates of serious event as well as at high-grade events. We did not see any Grade 4 or Grade 5 treatment-related events in the monotherapy cohort, that is important. Only 10% of patients experienced a Grade 3 treatment-related event. While the predominant AE of VS-7375 is gastrointestinal disorders, only 2% of the patients experienced a Grade 3, or one patient experienced a Grade 3 GI TRAE. If we drill down into the GI disorders, you can see the most frequent ones are nausea, diarrhea, and vomiting.
These are predominantly Grade 1, around 10%-15% of patients experienced a Grade 2 GIEE, only one patient experienced a transient Grade 3 nausea. However, this TEAE table does not tell the full story. We need to importantly understand the dynamics of these GI AE. We notice that these GI AE are not accumulated and gets better over time. Around 25% of patients started in cycle one without any GI AE, this number continued to increase to 40% six months into the study. Importantly, I think this gives us implication to manage these AEs upfront more proactively. We know that patients, after they get on through the first two cycles, they tend to get better for these AEs. So that is why we introduced the antiemetic prophylaxis for the first couple cycles. This really improves the patient experience, able to deliver high dose intensity to these patients.
Also we have seen patients who taper off these antiemetic agent later on because of consistency of these GI AE dynamics we have seen in clinic. It is very important to note that VS-7375 is highly selective to KRAS G12D mutation. It does not affect any wild type RAS or KRAS, it does not 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, this also compares favorably even compared with other allele-specific inhibitors, highlighting the high selectivity of VS-7375. Also no mucositis and stomatitis are reported in this study. Together with the encouraging activity coupled with this differentiate safety profile compared to existing pan-RAS inhibitors, I think it strengthened the narrative that VS-7375 is emerging as the best treatment options for patients with KRAS G12D-driven cancers.
Now, we know that a major AE of VS-7375 is GI disorders, but other than these GI AE, the tolerability profile is very clean. It is extremely important when it comes to combinability. We have consistently did not observe any clinical significant hematologic AE, that has been very consistent across data set we have presented earlier this year, mid-year, also in this data set. Which means that VS-7375 is highly combinable with cytotoxic agents. Similarly, we did not observe any clinically significant AST, ALT elevation in the U.S. population or ex-China population. This opens the door for combined with immune checkpoint inhibitors, which are important backbones in first-line non-small cell lung cancer, as well as selected tumor types such as first-line biliary tract cancers.
To summarize the progress we have made in these combination therapies, we believe VS-375 is highly combinable and eventually can address a very wide population with KRAS G12D-driven cancers. I want to highlight a few observations of these anti-combination therapies. Starting with anti-EGFR combination, it is highly combinable with anti-EGFR agent without any overlapping toxicity. The safety profile is essentially monotherapy plus with the addition of these cytotoxic 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. These AE can be easily managed with standard prophylaxis and supported care that are associated with standard of care with cytotoxic agents.
Also, importantly, we did not see an uptick of liver function test elevation or other concerning irAEs that is associated with immunotherapy or other older generation of RAS inhibitors when combined with checkpoint inhibitors. We continue to explore checkpoint inhibitor combination with chemo IO combination. On the left-hand side, you can see this summarize the progress we have made for combination. We have cleared 900 mg with anti-EGFR agents and currently going full steam for PDAC and CRC cohort in the phase II study. That is also the same for combined with Gem/Nab-Pac/Taxo. We have cleared 900 mg 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 the combination. Last but not least, we are actively enrolling for frontline CRC combination regimen, which is anti-EGFR plus modified FOLFOX with VS-375. This will be the go-forward regimen in our future frontline randomized study for CRC. Together, we have demonstrated the tolerability of VS-375 and also the excellent combinability. The next step is to continue to execute and bring VS-375 to a broad population with KRAS mutant-driven cancer. That being said, it is important to have a well-fleshed-out plan and continue to execute. Therefore, I will hand it to Michael to talk about future development of this agent.
Thanks, Ting. It is remarkable to present that kind of a side effect profile with the drug with that efficacy profile. Let me just reiterate one thing Ting said that I think is amazing. 25% of patients on this drug do not have any GI AEs in their first cycle. They are getting anti-tumor efficacy with almost nothing on the side effects. That is a miracle. By the time they are on for six months and the tumor is shrunk, and a lot of these AEs are worse because these tumors are pushing on abdominal organs or you are short of breath.
Four out of 10 patients do not have GI AEs. Again, that is unbelievable if you think about it. It is really moving thing very well. Let us talk about where we are. We have 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 II trials, the TARGET-D 200 series in pancreatic, lung, and colorectal that are ongoing and enrolling patients. Again, pancreatic and colorectal are expected to finish accrual to get us to the 80-ish kinds of numbers that we think will be enough to support accelerated approval if we have the good durability which will be available in the first half of next year. Lung cancer is taking a bit longer because it's only 5% of lung cancer that have G12D, but we expect that accrual to finish by middle of next year, and we'll be able to move from there.
The phase II programs are all designed for potential regulatory approval, as I mentioned, with blinded independent radiological review, as is expected, and the duration of responses will be critical there. The goal line generally is 30% ORR confirmed, which we believe we've already hit in our cancers, as well as durability north of six months. This would be unprecedented for all three of these disease, particularly in the G12 allele subpopulation. We then move to the phase III's, 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. 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 III's 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. Let me start with why. 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 2/3 of the patients will be getting the cool new small molecule. 1/3 will be getting standard chemotherapy.
We went to the FDA with the argument that it was essentially medically suboptimal for anybody in this day and age not to have at least a chance to get a RAS inhibitor if you have pancreatic cancer. It would be inappropriate given our emerging data, and this is data that we discussed with them several months ago, the data today are even better, that it would be inappropriate for them to be forced to go and get a drug either on the market or another experimental RAS inhibitor rather than our own RAS inhibitor. It is a long-winded way of saying we allow crossover. This is well published and is well known to drive compliance, especially on the control arm, because patients come into these studies, put their lives literally on the line, and they should all have the chance to get VS-7375.
2/3 chance to get it to begin with is good, but if you want to get your trial done, you have got to get patients to complete that third chemotherapy arm and get to a progression event. Unfortunately, that is how it works. We all know that. They get to cross over. Given that they all get to cross over, it becomes a study essentially of VS-7375 frontline versus second line. That makes overall survival as an endpoint very difficult to interpret. It confuses the endpoint. They agreed with this logic. For as far as we are aware, for the first time ever, the FDA has allowed a phase III randomized controlled trial for approval in frontline pancreatic cancer to move overall survival to a second endpoint, secondary endpoint.
They also, for the first time, as far as we are aware, have allowed us to include overall response rate as a co-primary endpoint. Some of you are aware of the program FDA has, the FrontRunner program, where you are allowed to potentially go to. We are allowed to go to them. They did not agree to accept it, but we go to them. We have the potential now to use program FrontRunner to use accelerated approval in frontline disease based on overall response rate of us versus chemo control and potentially win early in the trial before all of the progression events are hit. In fact, the statistical design allows for us to go to FDA after only 2/3 of the patients have been enrolled into the trial.
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 FrontRunner accelerated approval. Again, they have not agreed that they would give us the approval, but they have agreed to the statistics surrounding the ORR, and importantly, that the ORR is a co-primary endpoint. The majority of the alpha here, the power in the study, is being spent, of course, on PFS, because that is the key here. These two new design elements have allowed us to have a phase III trial in pancreatic cancer, which is smaller than others, gives patients 2/3 chance to get VS-7375 from the get-go, and allows patients to cross over immediately to VS-7375 upon 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. We expect to open it by the end of the year, as I mentioned. I want to make another comment because I think there's a little bit of misnomer or thinking that's a little bit off on the role of chemotherapy and other intensive therapies in any of the tumors that we treat. You'll pardon me, it's a little bit of an academic discussion, but I just want to remind everybody.
We start people off on very difficult levels, as Manny mentioned, very high levels of intensive chemotherapy that are extremely poorly tolerated, and we give them all the supportive care we need. If you've met anybody who've been on these kinds of combination therapies, it's very difficult for them. Often, you don't see them for a week after their infusions. People cannot tolerate chemotherapy very long. On average, approximately based on what we've been able to glean about, it's about two to three months where patients can stay on the goal chemotherapy doses. Then you have to modify the doses and reduce them.
By six months, many patients are on essentially, 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. 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 beautiful that we will have to get these patients off chemo, and they'll be very happy to be off the chemo.
We continue with VS-7375, which has excellent single-agent activity and/or in the combination with the, or I should say, with or without the combination with an anti-EGFR. 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 carboplatin and stop. Carboplatin is by far the most active drug in lung cancer. You cannot continue it more than three months.
If you want to extend the current PFSs 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 months, and it ain't chemo. 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. My last slide, just to sum up where we are here. It's just been a remarkable almost a year now since I was able to jump into this work with people like Ting Wu and the rest of the team, Nate Sanburn, our head of business, Jon Pachter, and Dan Paterson, of course, Julissa Viana, and the whole team at Verastem.
We took a drug that was just starting, and we understood that 600 mg wasn't enough. We kicked it up to 900 mg. We saw that the side effects were the same. We even have a bunch of dogs now that have a new formulation, and the dogs went from the old formulation where all the dogs throw up to all the dogs now with the new formulation absorb the drug with the same levels of the old formulation but don't throw up at all, zero. 0% vomiting. We'll see. We got to get into the species that matters, and it only has two legs. We may be able to even make this a better drug. 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've presented you the most transparent data set, I think, that we can see, and we're happy to take questions. We're actively enrolling our phase II trials, and they're going very well. There are some cohorts that are full, and we're even getting some nasty letters from people saying you got to open them up again. Then the frontline potential. We're establishing the safety of these combinations, and we are eager to get these frontline phase III studies going. 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 you, Julissa.
Sit down. If the rest of the team can join me from Verastem. Jon, please, Dr. Hidalgo, take a seat in the front.
Where am I?
Well.
Because we should have five, aren't we?
You're going to get a lot of questions.
I'm short.
Oh. Little rearranging on the stage. We will be taking questions from the room. All right. I am going to get out of the way. All right. When we call upon you, please just state your name so the folks who are listening to the live stream know who is asking questions. We have over here, Michael. God, I am like all taller than you.
Hey, thanks. It is Michael Schmidt with Guggenheim. Impressive data. Thanks for the presentation. I had a question on the 301 study, the frontline PDAC study. The cetuximab or the EGFR antibody combination is obviously a very unique aspect of this study that others are not doing. Just talk a bit more about how much data you have with EGFR antibodies and PDAC. Just curious, or how much more you may need to generate before starting the phase III. Then I have a follow-up.
Yeah, let me take the second part of that question first. We have generated sufficient data that the FDA is convinced that that is a reasonable path forward. In frontline pancreatic, we have a quiet cohort, I would call it, within our phase II accelerated approval study, which is focused, of course, on second-line disease. There is a cohort in that phase II study that actually enrolls patients in frontline with frontline pancreatic in combination with an EGFR antibody. That trial, that cohort has filled up already with 25 patients. We are strongly considering, based on some pretty aggressive pushing, that we need to open that up a bit more. So we will have a lot more data, but the early indications are that this is a very well-tolerated regimen. That all said, we have investigated this combination earlier.
I do not know that we have put it out publicly, but I do not mind saying we have had five patients at 400 mg of our drug, which is not an active dose in pancreatic cancer. This is heavily pretreated. Five patients. When you add cetuximab, we had two out of the five that converted that are PRs very quickly and very active. If you take 600 and add cetuximab, you boost the response rates there. I will not get into more detail, but there is adequate activity. Last point, Dr. Pachter and others have generated really good data preclinically that this is a common pathway that pancreatic cells like to use to try to get around it, to get around RAS blockade, and the preclinical data strongly support this.
Okay, very interesting. 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. Irinotecan has helped many people live longer, and I certainly watched its development when I was an internist. It's a very, very difficult drug. Even Grade 2 diarrhea should not be discounted, but the Grade 3 diarrhea can be life-threatening. It's very tough. We do not want to combine our very nice drug with an excellent safety profile, tolerability profile, with some of the most brutal chemotherapy around. We think we can achieve as good data or better, frankly, much better than any FOLFIRINOX combination, much better tolerability, either with Gem/Nab or we hope with just a non-chemotherapy backbone.
Okay. Just on a tolerability profile, just remind us what the prophylaxis regimen looks like now in the clinic.
Yeah. Take.
Yeah, certainly. We asked the patients to be on a 5-HT3 antagonist throughout two cycles, which is two months. We do see a large proportion of patients able to taper off the antiemetic agents. This really helps the dose intensity in helping patients to keep on treatment. That has helped 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 distinguishing factors that result into that differences.
Yeah, Michael, keep me honest here, but that one patient that had Grade 3 nausea, they forgot to take their ZOFRAN dose.
Thanks.
Came into the hospital, got it, and was transferred.
Why don't we do Graig here, and then we'll go to the side.
Thanks, Graig Suvannavejh from Mizuho, and 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 do with that, and as you think about what's next, how do you think about financing those ambitions and considerations of partnerships or not?
No, Graig, great question. The raise we did today takes us well into 2028 and gets us past the readout of the phase IIs, which is really important, and I think will be a real value-creating event. This is one of these opportunities where I think we have a true blockbuster where I've spent almost all my career in smaller companies. We can be nimble, we can be fast. We can't do things big companies can do. This is one where I truly believe partnering it makes the pie bigger.
You're 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're working alongside our partner, and we recognize how challenging it can be to be in a partnership. One of the things that I thought was quite attractive in Michael Bailey's background is he's lived these after the deal. That's many times as important as the deal itself. It is likely we'll do some kind of partnering to really accelerate this. But we felt it was the right thing for the company and for patients to push forward with all three of these indications as quickly and aggressively as possible.
Great. Thank you. Then maybe a question for Dr. Hidalgo. A 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. That's a great question, and agreed. There are so many agents out there now in development, which is a terrific opportunity for patients. It is also a much better situation for physicians because we can now prescribe or administer medications that are better tolerated and more effective. There is a competitive or broad landscape of how you direct patients. Daraxonrasib 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-specific agents tend to be better tolerated and maybe in some alleles, as in the non-comparative data, more effective. For us, the preferred is still a clinical trial if we can. That's one point. Second point, and we are very interested in non-chemo combos and in dual targeting.
PRMT5 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. Tarceva is approved. We sometimes forget that, but marginal, very small activity, but there is some EGFR dependence on these tumors that hopefully we will see that data. Many other non-chemo combinations that are very exciting. For that, you need an agent that is well-tolerated, of course. Final point is that, and I think we didn't mention that, of course, because we are now in the phase III's approval, is moving this to earlier stages. That's the real FrontRunner.
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 these responses can take more patients to surgery. That's another very important area of research. 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 19-9, really looking at what matters and being able to pivot from one to the other depending on that. Eventually, I think cancer interception and even earlier, we are doing studies with IPMN, intraductal papillary mucinous neoplasm, which is about 20%-30% of patients with pancreas cancer come from these cystic dilatations in the pancreatic and we have now the tools.
It is a complex but fascinating landscape, and I think the next few years are going to be quite remarkable.
Yeah, I'll add a point to that. Last week, I gave a talk at the RAS Initiative at NCI.
Yeah
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 G12V selective that's amazingly safe and maybe a G12C, and everybody takes them, and you prevent cancer. That's his dream. I think Michael talked briefly about the alternative formulation that we're brewing in the lab that looks great in dogs that get rid of the GI tolerability. I think our drug could be one of the most important elements of that kind of combination that everybody could take, because if it's really well-tolerated and RAS is such a bad actor, why not just head it off?
But 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 A1C hemoglobin in diabetes. When you go up,
Yeah
you know something is wrong, and then you don't need to wait for. It's dreaming, but I think we're getting there.
Yeah.
Yeah. When are we going to turn to Eric?
Thank you. Eric Schmidt at Cantor Fitzgerald. Thanks for the very comprehensive presentation, and congrats on some great data. I am intrigued by the commentary around treating post-progression. 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. We sent it in, they blessed it. The physicians want it, the patients want it. The progression is, of course, radiographic. It is not necessarily symptomatic, and I think doctors and patients generally, I think Soumen agrees.
Yeah
They worry about symptoms primarily. They are upset that the tumor grew a little. This patient was treated. I think he kept on 900 mg for a while, and then he even kicked up to 1,200 mg eventually. We saw to see if we could get it to come down again. One of the little talked about reasons for progression, because it is not very exciting, is simply drug dose. That is drug delivery to the tumor, and at least some tumors, you do not get to publish papers on it, but at least some tumors are progressing because they are just not exposed to enough anticancer therapy because they found a way to be avascular enough that they can live and grow. Oftentimes, and we have seen other cases there, where 600 mg patients are given 900 mg and that tumor that started to grow just crashes.
Localized radiotherapy will be allowed?
Yeah, we really have made a culture at Verastem of doing, and I just say this, the regulators are always open if the physicians request it and if the company support it.
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 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 reflecting there is a clone that now acquire another alteration, and that is bypassing. Our protocol is to biopsy those to learn, but also to do local regional radiation, radiofrequency ablation, resections. I think that should be allowed in protocols because it's for the benefit of the patients. You already have your PFS, your primary endpoint readout.
You're not messing with that.
When you think about where the frontline pancreatic cancer market is evolving to and your future combination with an EGFR therapy, what do you think is the likely comparator? What do you think that you need to beat in the future frontline setting for G12D therapies? What is your confidence that you are going to get there?
I think we have designed it the way it needs to be right now. I think once we get the approval, medicine will help. People like Manny will lead the revolution to use the drug properly in the combinations they want. I can imagine if we get combination approval, which we fully expect to win, many patients will start on the combo and then decide, "I do not want to get the IV anymore, and I will just keep an eye on this tumor and monitor molecularly and monitor CA 19-9. If I need to go back on an IV every couple of weeks, I will." I think the future is that, then of course, we have all these other new targeted therapies like PRMT5 inhibitors and so on.
And so on.
We are doing defactinib. We are super excited about that.
Super excited.
It has really good preclinical support. I think once we get it on the market, there may be some post-marketing studies in the future, but once we establish it as a beachhead, this will become a foundational medicine for other combos.
Last question. Breakthrough designation, where are we?
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 and with all the caveats across trial and blah, blah, and say, "We think this is highly differentiated, both on efficacy and on tolerability, and we think this deserves that," and we'll see if they agree with us.
Yeah, typically you need at least 20 patients with six months follow-up, and we want patients from the U.S. for that.
Jeet.
Jeet, go ahead.
Great. Thanks for taking the question. Jeet Mukherjee, U.S. Banc 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 III, what are your expectations for ORR, PFS, and OS for the control arm, and do you anticipate patients to receive more GnP or the modified FOLFIRINOX?
Soumen, do you?
Yeah.
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 clinical meaningful, which means that probably 1.5 months increment is not sufficient. So we want to have sufficient delta, which means probably clinical meaningful, at least three to four or five months, around that range. Of course, in the control arm, we want to be realistic, right? Because we're allowing either GnP or FOLFIRINOX. What is the PFS for those people? 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, pan-RAS, and hinted at perhaps a PRMT5 combination soon enough. Which of these combination agents do you see as most promising across the tumor types you're evaluating?
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, PRMT5 inhibitor and our G12D, and that should really have astounding control of the disease. The preclinical models, it just never grows when you treat with the combination, and really impressive data from the Tango combination with the Retinoid molecules, but we think we can make that better still. So I think that's really exciting for that subset of patients.
Yeah.
I think a lot of these are exploratory. We're looking at with Erasca's pan-RAS, we'll see if it's better. I think there might be situations where it's better and other situations where you'd rather go with our single agent or something else. But I think the more we explore these things, and I agree with Manny, there are lots of other combinations we're excited about with targeted agents that should be well-tolerated, but will find a place.
Yeah, I agree. I think PRMT5 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. Now everything that you combine with a RAS inhibitor is effective, right? If you look at the preclinical papers, there are multiple new targets claiming synergistic efficacy. I think it will be important to rapidly test those in clinical trials to make sure which ones are really promising versus other. The fact is, I think another one that there is very strong preclinical data, and a strong clinical data with G12C 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.
I think it's also important to think on combinations that you want to use at front versus combinations that may be effective at the time of resistant 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.
Jeet, the other part of the answer, we have a very active investigator-sponsored trial program. What we're talking about are things that have risen to the level of a company-sponsored trial, but we're getting a lot of proposals of novel combinations, actually from Manuel as well.
Absolutely.
We're really trying to drive some of-- That's a very cost-effective way to see is our G12D plus this agent or that really an amazing combination, and then we can promote that if it's a really exciting signal. But those are ongoing.
Yeah. Yuan?
Yuan Zhi from B. Riley Securities. Yes, great data today, and great to see almost everybody can get tumor shrinkage. Maybe a couple follow-up. I do not mean to push the limit here, but when can we expect the next data update and what will be included there? Other than the first one.
Yeah, no, we-
We will let you take that one.
Yeah, sure. Easy one. Probably by the end of the year, as Michael mentioned, we will have a little bit of updated data from the cohort of the colorectal that you saw, and a little bit of the panc 600 combo data and GnP. Then we are 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. Then I think, expect next year to be a very data catalyst-rich year at medical meetings and multiple updates from the phase II in the first half and the latter half as well, and lots of progress on our enrollment and so forth. So it will be a busy 6 months- 12 months.
Yeah. Got it. My second question is related to the combination of 900 mg VS-7375 and EGFR. I know you have some adverse event data in the back of the slides. So what are the highlight you want to share there? Do you see anything concerning about the rash, or it is just as you expected with the monotherapy EGFR inhibitor?
The rash, we also asked the investigator to further characterize the rash, and we have got really good feedback as the rash is identical to what you expect for a single agent anti-EGFR agent. In terms of the presentation, acneiform predominant. Also in terms of frequency, severity, you can see in the table that is in line with what we reported for the single agent. So no concern of overlapping toxicity.
Got it.
You're good? Yeah. We'll just give it to Josh, then we'll come back over to this side.
Hi, Josh Brewer with RBC Capital Markets. Really great data today. Congrats. Yeah, I guess one thing that I was interested in was how you guys had disclosed alignment with the FDA, but only in the PDAC indication. I was wondering whether you can give a little more color there for the other indications, are you looking at this dual ORR PFS approach there as well? Then the second question, were there any interesting patient baseline characteristics that you found correlated with deeper responses across all the indications? Yeah. Thank you.
Yeah. We're intending that the trial, the phase III be global. We've had the discussion with FDA, gotten sign-off on the. Ironically, we had our end-of-phase II meeting to agree on phase III while we were doing our phase IIs, which is always fun.
For the pancreatic, the lung and the colon meetings are scheduled, so those will be coming up. We have sent our protocols into the Europeans. The lung protocol, phase II, is being done, is including European sites. The others, phase IIs, I don't think are going to make much ex-U.S. A little bit of Australia, but they're recruiting too fast to get Europe up and running. 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 IIIs.
All right, you can grab it. You want to do Yeah, Faisal.
Great. Thank you guys so much. Faisal Khurshid from Jefferies. I appreciate you guys hosting us today and taking the questions. Two from me, one for the company, one for Dr. Hidalgo. First for the company, just if I can ask for a little bit more specificity, because it matters so much for the phase III. On the PDAC early-stage combo data sets, can I just get a little bit more granularity on what combos you expect to share and what timeframe and how many patients investors should expect?
Sure. 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. Right now, we have GnP safety is cleared in second-line treatment, so a lot of the patients already got GnP, and now they are actually enrolling people who already got GnP to GnP plus us, which tells you what investigators think of the ability of our drug, because you would never put somebody on GnP and then GnP again. They progress. People on FOLFIRINOX who blew through it and then get GnP plus us, so that will be as well. We are not doing FOLFIRINOX, as I mentioned. We are not doing it in colorectal, and we are not doing NALIRIFOX. We are just not going to deal with a grade 3 diarrhea irinotecan compound that makes people wretched.
Got it. Okay. Makes sense. Then for Dr. Hidalgo, 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, G12D with PRMT5, and G12D with EGFR?
We will need to wait for the trials. I think all of them make sense. I presume you are asking what is my expected outcomes for those?
Yeah. Just based on kind of your expertise.
Yeah
in the field, the biological hypothesis-
Yeah
the early data we have seen so far.
For the MTAP RAS mutants, I think we are seeing probably the best activity we have ever seen. Which means when you have the two targets that are relevant and you target both of them, you get the best. The others, I do not have data to compare. We will see at ESMO very prominent chemo combo datas with 12 days inhibitors. The pan-RAS, they can be combined with chemo as easy, I think the responses are a little bit lower. But likely, each one of those is killing different cell populations. 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 on ways to combine one of more of these strategies.
But the chemo versus the EGFR, I think that that will need to be, we will see.
Got it. Thank you.
Yeah.
Good morning, and thanks for taking the question. This is Kalpit Patel from Wolfe Research. I wanted to push on the choice of the first-line chemo combo strategy here. I guess we know that daraxonrasib or a pan-RAS inhibitor does better than chemo, so why not entertain a pan-RAS combo with your G12D right from the beginning? 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.
I don't know how long it'll take. We'll update you guys next year once we open it up and we'll see. I can say that accrual to our second-line pancreatic study has not taken any hit that we can discern since daraxonrasib was approved. People are coming in, and I expect they will continue to flood in, and that'll hit by the end of the year.
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 panitumumab is easier to treat. People know how to treat it. It responds better to the doxycycline, minocycline, and steroids. It doesn't carry much mucositis or stomatitis, which are a big deal. Lastly, I'd just remind you, again, cross-data comparisons, the combo data from daraxonrasib plus zoldonrasib are very exciting. But frankly, I think they had a couple CRs, we have a couple CRs. They had good response rates, we have good response rates. 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. 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. 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 pan-RAS isn't tolerated enough to maximally hit the target, you need to combine. 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. A last question from Matt, and we'll wrap it up.
Thanks, guys. Matt Venezia here from Alliance Global Partners. Thanks for taking my questions, and congrats on the impressive data this morning. 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? Can you take us through a little bit of the AEs over time?
I'll take that one.
Yeah. The trend is very consistent with what we announced last time. I think looking at these in different kind of metrics, like this time we look at patients without GI AE, I think it tells the same consistent story that these AE tend to continue over time. 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 smooth sailing after two cycles. That's how we define the timing. We use the antiemetics prophylaxis and/or associate with those practices.
Great. Thank you. Just lastly, I wanted to ask about the CA19-9 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 CA19-9, which is just consistent with the lack of symptomatic progression. 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.
Great. Thank you guys for taking the question.
Thank you.
Congrats.
All right. Well, that concludes our event and our live stream. Thank you. We'll still be here for further questions.