Next fireside chat here with Revolution Medicines. My name is Michael Schmidt, Senior Managing Director with Guggenheim. It's my great pleasure to welcome Mark Goldsmith, CEO of Revolution. Mark, welcome. Thanks for joining us.
Thanks for having us.
And so Revolution Medicines obviously is sort of at the forefront of science, developing a portfolio of first-in-class RAS inhibitors. Sort of as we kick off the year, what are some of the key focus areas for you in 2025?
Thanks for having us. Clearly, our highest priority this year is to execute an ongoing phase III trial in pancreatic cancer. This is a second-line focused trial, randomized controlled, global trial of our lead compound called daraxonrasib, or RMC- 6236. This is our RAS multi-inhibitor. That trial is underway. We began it a few months ago based on a compelling profile that I'll describe in a moment. We also expect to launch a second pivotal trial, also with daraxonrasib as monotherapy. This is in non-small cell lung cancer, also based on a compelling profile that we showed just a few months ago. We expect to initiate that sometime this quarter. We have a full year of activities. We have a very rich pipeline going beyond daraxonrasib as well. Maybe we'll get into some of that in the questions that you have.
Maybe I could just characterize, though, the daraxonrasib in pancreatic and lung cancer, just to sort of level set. We did demonstrate in monotherapy in second-line pancreatic cancer a median PFS at the 300 mg tolerated dose of daraxonrasib of 8.8 months and a median OS that was not yet determined. We haven't reached the number, but we know that at six months, the overall survival was 100%. And this compares with standard of care chemotherapy, which has numbers of around three months and six to seven months, respectively. And then in lung cancer, to level set for our expectations in the go-forward trial, we observed a median PFS of 9.8 months and a median OS of 17.7 months. And that was as compared to four to four and a half months and six to seven months. So I'm sorry, and 10 - 11 months.
That's where we are today. We're very excited about these trials. We think that patient enthusiasm and investigator enthusiasm are both quite high.
Great. Well, thanks, Mark. So yeah, perhaps just a couple of follow-up questions on daraxonrasib starting in pancreatic cancers. As you just walked through the single-agent phase II data from last year, which was obviously super impressive. Perhaps just comment on your ongoing phase III, how enrollment has been going since you initiated the study relative to your expectations. And I think in the past you suggested you might actually be able to read out data already in 2026. Yeah, so maybe just talk about how the study has been going.
Yeah, the interest in this study globally is very high. I had a chance to meet with many of the investigators on the trial just a week ago at the ASCO GI conference, and feedback is uniformly very high excitement, enthusiasm. We have now opened initial U.S. sites, which are largely the larger predominant cancer centers in the U.S., and those are enrolling well. They're meeting our expectations. We're continuing to add on to those trials to reach our larger target number of trials, and we're right on track with activating those sites in the U.S. We also received clearance from the E.U. and Japan to open sites in those regions as well, and work is underway to begin opening up those sites. They do lag behind a little bit, those initial U.S. sites, so there'll have to be some catch-up period.
but as all of these sites start to come online, I think the bolus of patients will become quite large. so we're really pleased with that. and we're very much on track with our plan. As to the timing of the readout, I can't really predict today the timing of the readout. but given the enthusiasm level, I don't think this is a long multi-year effort.
As you had us just reminded of the phase II data, I think the median OS overall was still immature, as you mentioned. Any additional plans to update the monotherapy study this year?
Yeah, there was some censoring early in the time course just because of the length of follow-up for a number of patients. We did do a second update after our first report that was a quarter later, and already most of those censor points moved to the right, so you could see as it was maturing, in fact, the median PFS actually increased. It didn't decrease, so we weren't really seeing patients coming off. We saw them staying on, so I don't think at this point there's much question about whether or not those numbers are reflective of the data set that will emerge. Of course, it is a single-arm trial, so by definition, we're not randomizing against a matched set of patients receiving standard chemotherapy, so that's what will happen in the phase III trial, and that will be a more robust test.
But we don't have any reason to believe that there will be a material difference between the patients that have enrolled in the trial so far and those that we'll see in the phase III trial.
All right. And so one big question in the investor community obviously has been, what is the path to marketing first-line PDAC? And so perhaps talk about your thoughts there and what potential registration studies could look like.
Right, so patients, maybe I'll give a little bit of the natural history. Patients who present with pancreatic cancer often have advanced cancer by the time they start to have symptoms, and they show up in a doctor's office. Pain is one of the most common initial symptoms: weight loss, nausea, anorexia, and with advanced disease. Probably 50%+ have metastatic disease at the time that they're diagnosed. Of the patients who are treated with first-line chemotherapy for metastatic disease, about half of those patients then go on to receive second-line treatment after they progress during their initial treatment, so it's a very—this takes people down. This is a terrible disease, and chemotherapy just is clearly not adequate, but you are losing patients as you move from first-line to second-line, and then again, there's another big drop-off from second-line to third-line.
If we can get into first-line, as we're optimistic that we can, we have the potential to address a larger segment of patients, and of course, there is the question of whether or not those earlier line treatment might actually have even greater anti-tumor activity or clinical benefit. We don't know that, but essentially, in every targeted therapy we know of, maybe with very few exceptions, even chemotherapy moving from later lines to earlier lines tends to carry with it improved outcomes in terms of durability. So we would assume that that would apply to daraxonrasib, but we don't have any data to address that today, so how do we get into first-line? We think we're almost ready to go, and it's a top priority for us to initiate a first-line pancreatic cancer trial this year. That's really important for me to convey. This is a high priority for us.
One of the reasons it's high priority is that once the second-line approval occurs, there will be a drug on the market, if the FDA approves it, which will make, of course, the risk that patients drop out of a chemo arm to try to go get a prescribed drug becomes higher, and that could compromise the integrity of a randomized controlled trial, so we are kind of racing the clock. We're racing against ourselves to get those patients on trial, so it is very urgent, and of course, there's the humanistic need that patients are being inadequately served with aggressive chemotherapy today and really deserve to have something better than that, so how do we do it? There is some nuance here.
If we look at the monotherapy daraxonrasib outcomes in the second-line study that I just alluded to and compare those median PFS and median OS values to chemotherapy in first-line pancreatic cancer, they are numerically superior. They're not even close. They are numerically superior, which leads us to believe that we already have some evidence, albeit single-arm data with the caveats that go with single-arm data. But we have some evidence that daraxonrasib has already shown superiority to first-line chemotherapy. Now, I put that with all the caveats that I think are important to carry with it.
But based on that and based on the fact that the biological driver of these cancers is RAS, which chemotherapy doesn't address, chemotherapy is just trying to kill cells. It's not addressing the underlying biologic driver, whereas daraxonrasib is. We think the most important thing for patients in first-line, second-line, third-line, any form of pancreatic cancer is to have a RAS(ON) inhibitor and to have it as continuously as the patient can take it, and that creates a little bit of a challenge if you're going to combine that with chemotherapy in the first line, because chemotherapy is dosed typically to MTD, maximal tolerated dose, which basically means just barely tolerated dose. I think everybody should just get their arms around that. Maximal tolerated dose doesn't mean well tolerated. It means barely tolerated.
Most patients have dose reductions or changes in their schedule that occur very early in the course of their treatment. In fact, probably 70% is the dose intensity, the median dose intensity of chemotherapy, meaning most patients only get two-thirds of the chemo that they're prescribed. Our concern is that if we allow chemotherapy effects, side effects to cause patients to stop taking daraxonrasib, that will limit the clinical benefit they might get from daraxonrasib. So we're really flipping this paradigm on its head a little bit. This is not. We're not making a commercial argument here. We're just making a biological and clinical argument that we should do everything we can to preserve patients staying on daraxonrasib because that's the thing that's going to suppress their RAS-driven cancer.
So we are looking for right now. We're dosing patients with a range of chemo regimens, either modified FOLFIRINOX-based or Gem/Abraxane-based, that are well within the standard ranges for chemotherapy that our patients receive around the world in order to optimize for that combination treatment if we are to have a combination arm. And that's our intention. We do think that we can combine chemotherapy with RMC-6236 or daraxonrasib. There's not a fundamental question of can that be done. It's can it be done in a way that makes sure that patients will continue on daraxonrasib as continuously as possible. That's what we're working on now. It just takes some time. We have to dose enough patients. It doesn't take a lot of imagination. We're not inventing new things.
We're just trying within the range of well-accepted chemo regimens that are largely accepted to be very similar to each other in terms of outcomes. And then we'll pick regimens and go forward. We haven't declared whether there will or won't be a third arm that's a combined chemo plus daraxonrasib. But of course, it would be advantageous if we could have both a monotherapy and a combination arm in the same trial. That would be the ideal solution.
All right. And so how do you make that decision process to either wait and then do the three-arm design or perhaps move ahead at this point with the monotherapy study?
Yeah, well, we're working on that, of course. And we have patients who are receiving combination chemo plus daraxonrasib now. We're monitoring them. And we'll be able to measure their dose intensity, which will be a very good single integrated measure of are they tolerating it? Are they getting daraxonrasib most importantly? And based largely on dose intensity, we'll be able to make that decision. So we're kind of pedal to the metal to get that answer. It's essentially a safety and continuity of treatment answer. And then we'll make the decision about the trial.
OK, so the next thing we hear on daraxonrasib and PDAC will be the decision on the phase III?
I think essentially, I mean, there's not really. We're moving so fast here that we need to make the decision so we can finalize the protocol, so we can get it to the FDA, so we can get it to IRBs and all the things that need to be done to get the trial up and running, and we'll catch up investors as we go along the way here. I don't know the exact timing of disclosures around that.
Right. Great. OK. So the other big opportunity for the drug is obviously in lung cancer. You did present monotherapy phase II data essentially in December. Maybe just going back to that, some folks were a little bit surprised by the selection of the lower 200 mg once a day dose there as opposed to the 300 in PDAC. So yeah, just maybe remind us, is there a logical explanation for this? And then curious to learn about next steps in non-small cell lung cancer.
Right, so in the pancreatic cancer context, we pushed the dose to make sure that we could maximize exposures in patients with pancreatic cancer because they have such an aggressive disease. We want to maximize the opportunity for every single patient to have a dose that will sufficiently cover the target, and in the pharmacokinetics that we showed previously, the 300 mg patients had, on average, a little bit higher exposure than the 200 mg patients, and it was reasonably well tolerated. We had dose intensity of around 90%, which is a pretty good marker for acceptable dosing, so that was a commitment we made in pancreatic cancer. We reset everything when we went to lung cancer and asked the same question: what's the best dose for those patients?
As an aside, this has been typically done for chemotherapy and all targeted therapies historically, that is, you pretty much try to dose optimize for each indication. As it turned out, for lung cancer patients, they didn't tolerate the 300 mg dose as well. Their dose intensity fell a little bit. But 200 mg, they tolerated well. And the dose intensity was about 90%. And the difference in exposures between 200 and 300 were not large, as I mentioned. And we decided that that was sufficient. And the efficacy data that we reported were based on the 200 mg dose. And there we saw efficacy that we felt was compelling and I think investigators believe is compelling. I mentioned a 9.8-month median PFS, which is as compared to four to four and a half months for docetaxel.
So we've essentially doubled the PFS if you're willing to make the cross-trial comparison. And the median OS was 17.7 months, which was nearly double the OS. So again, if you're willing to make a cross-trial comparison. So based on that, we don't see any logic to going to 300 mg. We don't want to dose patients to the point where they stop taking medicine. That doesn't help anybody. 200 mg seems to be a solid dose. Somebody was asking me the other day about when we first started this dose escalation, where did we begin? We actually began at 10 mg for daraxonrasib several years ago for those who weren't paying attention to us back then. We started a very low dose. And we saw activity all the way down at that level. We saw anti-tumor activity, stable disease, ctDNA reductions. It increased at 20.
It increased at 40, and we had predicted we would start seeing regressions at 80 mg. And in fact, we started seeing regressions at exactly 80 mg, so we have a wide range of doses within which daraxonrasib is active. And we just want to pick the right dose that patients can say, "I can tolerate this and continue to take it.
Right. Great. And so obviously, the monotherapy data, it does look superior also to the approved KRAS G12C selective inhibitors, right?
Right.
And then yeah, perhaps.
Do you want me to clarify that so that adagrasib and sotorasib both have accelerated approval? And they reported median PFS values of 5.5 months. So still the 9.8 months we reported, again, cross-trial comparison with the caveats, but it does suggest that it is superior.
Right. So then perhaps sort of how are you tracking towards initiating the RASolve-301 study in second-line lung cancer? And yeah.
Yeah. Well, we still expect to initiate that this quarter. We're sort of waiting to achieve FDA alignment on the final specific details of the trial design. I think I've used the analogy, our engines are revved. Everything's all lined up. Our CRO is ready to go. We just need to get to that agreement with the FDA, and then we'll launch that trial.
Right. OK. And then maybe a similar question to PDAC. So how do you think about moving into first-line non-small cell lung cancer? There are obviously a lot more combinations that are available to explore. And just curious what your latest thinking is on that front.
Yeah. So this will take a couple of minutes to explain. It's a really robust set of opportunities there. Lung cancer, of course, we now think of as being non-RAS or RAS. 70% is non-RAS, 30% is RAS. Of the 30% that is RAS, about a little more than a third of that is G12C. That's 12% of the 30% is G12C. 18% is non-G12C. G12C is now a thing of itself. It's a thing by itself because there are drugs that specifically target the G12C population. So that's why we divide into G12C and non-G12C. RMC-6236 or daraxonrasib is active against every form of RAS we've ever tested, but we've had very few G12C patients in our trial. So we don't have a lot of data expressly on G12C. Honestly, I have no concern about that because preclinically it's an extremely active compound.
But nonetheless, we don't have much data on G12C. The trial design for first-line trial has to be based on whether you're focused on the G12C or the non-G12C because there are different options for how we could treat those. For the G12C subset, we could use our G12C inhibitor called RMC-6291 or elironrasib. We could use daraxonrasib. We could use either of those in combination with Pembro, or we could use either of those in combination with Pembro plus chemo. Or we could combine two RAS inhibitors like daraxonrasib, elironrasib combination, which we believe is the most robust way to suppress G12C RAS signaling. And we've shown that now as a clinically meaningful combination in colorectal cancer, albeit a small study just a few months ago.
We believe putting together two RAS inhibitors, we call it a RAS(ON) inhibito r doublet, may give us the opportunity to have a chemo sparing regimen, meaning no platinum-based chemotherapy, two RAS(ON) inhibitor s plus Pembro in first line, which would then push platinum-based chemo to second line, which would then push docetaxel to third line. And that really could stack up to be very significant benefit for patients if we push chemo down the line but reserve those to be used later. That could result in much longer OS impact and certainly quality of life impact. So those are all possibilities. We're working to sort of sort them out and decide, do we study them all? Do we study a subset? If we're studying them all, do we study them all in the same study or do we break that into more than one study?
It becomes a little bit of logistics, and it's a little bit of strategy that we have to think through.
Right. So yeah, as you mentioned, we have seen some early combination data in December with Pembro with the dual RAS combination and I think another Pembro RAS combination. So yeah, how far along in this exploration are you at this point? And yeah, help us sort of if you were to map out the path to first-line lung cancer, what are sort of the stepping stones this year that you could cross, I suppose?
Right. So first, let me just say combining with Pembro has not been easy in the RAS field. We know that most compounds have had difficulty doing so. Some have pushed through. Some companies have pushed through and said, we don't care. We're going to combine it. Others have said, we can't combine. We've seen very good tolerability and safety from both daraxonrasib and elironrasib with Pembrolizumab so far. So we don't believe that there's going to be a toxicity barrier to moving forward, which I think in and of itself justifies moving into first line with that drug because that may be a well-tolerated regimen. But sorting through these other options is a little bit complicated. And I think one thing people are looking for is, does the data that we see that we saw in colorectal cancer translate in lung cancer? That's a question I'm often asked.
We expect that it will. The tricky part of it, though, is that each of those monotherapies is already active in lung cancer. We know that. We have plenty of patients who have received the monotherapy. So in asking, does the combinatorial effect translate from colorectal to lung? It's a little bit harder to prove experimentally, but we're working on that. And so I think that's one question that if we answer that clearly, that would help prioritize that combination into first line based on activity, not based on safety, but based on anti-tumor activity. So that's among the things that we're working on. And I just have to ask for everybody's patience while we sort through it. We have so many different studies going on. We want to sort of report them out when we have meaningful data and meaningful interpretations of them.
So it sounds like if I interpret your comments, the sort of preference in the G12C subset would be the dual RAS plus Pembro combination?
Yeah. It's a scientific preference. I mean, it's not, of course, commercially, it would be attractive to do that too, but it's not really driven by a commercial desire. It's driven by our desire to do what's best for patients. And if a combination of two RAS inhibitors that are reasonably well tolerated allows somebody to avoid platinum-based chemotherapy in first line and, as I said, reserve that for later lines of treatment, that will translate into a real benefit for patients. That would really move the needle. So we're ambitious about potential impact for patients. We want to achieve it. And we think the doublet has the highest chance of doing that. But it's not the only option. If we don't do that, we could do singlets with chemo plus Pembro. There are various other things that we could do.
And we're just keeping them all in play while we sort that out. And maybe we'd like to have all of those regimens available for patients. The more ways in which doctors can prescribe the drug, the more likely patients will benefit.
Right. And so for the non-G12C subset, what is your current?
Right, so there we don't have a doublet because we only have one compound that hits all these different forms of RAS, and so the most likely scenario for that would be combining it with PD-1, potentially in PD-L1 highs, or with chemo plus PD-1 antibody in the lows and highs, and so that's a narrower set of options, and we're certainly excited about that too.
OK. Great. So I made it about halfway through my questions.
Terrific.
But we have to wrap up here, unfortunately. So perhaps next time. So thank you much.