Revolution Medicines, Inc. (RVMD) Earnings Call Transcript & Summary

We're very committed to patients with pancreatic cancer. We believe, based on feedback from leading authorities in pancreatic cancer that daraxonrasib has delivered so far really unprecedented benefit for patients in the single-arm trials. And so we are interested in all the indications for pancreatic cancer. They're all driven by RAS and therefore, the treatment with a RAS(ON) -- effective RAS(ON) inhibitor should be similar across all of these. We announced 2 additional pivotal trials beyond the RASolute 302 trial. One of them is for patients with adjuvant disease or -- for adjuvant treatment of resectable disease. That trial we announced a few weeks ago has initiated. Those patients received surgery and perioperative chemotherapy according to standards of care and get randomized either to observation or daraxonrasib monotherapy for a period of 2 years and will follow a disease-free survival for those patients. So that study has been initiated. The study you just alluded to, which is called RASolute 303 is the first of our first-line studies in pancreatic cancer, our global Phase III first-line studies. It is a study with a 3-arm trial design, as you mentioned, that is comparing standard of care cytotoxic chemotherapy versus daraxonrasib monotherapy versus a combination of daraxonrasib plus chemotherapy. So those are the 3 arms. It's a very attractive trial design for patients. It means everybody has a 2 out of 3 chance of receiving daraxonrasib. They have a 2 out of 3 chance of receiving chemotherapy as well. We had indicated we expected to initiate that trial in the fourth quarter of this year. I'm also pleased to announce today that we have, in fact, initiated that trial as well. So we're now running 3 global Phase III trials in pancreatic cancer. We're looking to cover every possible indication in pancreatic cancer, and we'll continue to build on that with additional trials.

So maybe just a little bit more on the frontline pancreatic cancer trial. So you do have this monotherapy arm and also [indiscernible] chemo combo arm. So when we look at your early phase monotherapy data, it's, in fact, already very highly encouraging as a monotherapy even in the context of frontline. So how should we think about in the frontline monotherapy versus chemo combo under what scenario you think monotherapy might have a shot as well?

Well, pancreatic cancer is a RAS-driven disease. And it turns out if you treat it with a really good RAS inhibitor, you can modulate that disease. So the data you just alluded to were that in the second-line monotherapy trial that we performed previously, the PFS and OS outcomes were not only superior with daraxonrasib to standard of care in second line, they were also superior to standard of care in first-line pancreatic cancer. I think that's the point you were just making. We also reported a cohort of first-line patients treated with daraxonrasib monotherapy, and those patients also showed very good outcomes. From a response rate perspective, we've not yet reported durability from those, but we expect that to be durable also. So I think the evidence supports the biology that pancreatic cancer is a RAS-driven disease and daraxonrasib is very active against that disease. So why bothered with cytotoxic chemotherapy? Well, the question has been changed. It used to be why are we running monotherapy. That was before we reported the monotherapy data. And now the question is why bother with cytotoxic chemotherapy. And it really comes down to just our philosophy that we're trying to find the most effective regimens for patients with RAS-driven diseases. And it is conceivable that cytotoxic chemotherapy combined with a targeted RAS agent will simply deliver the greatest effect. We don't really know that. In the cohort I mentioned of first-line patients, we actually compared monotherapy with cytotoxic chemotherapy as a combination. So we compared mono versus the doublet. And the response rate for the monotherapy patients was 47% and the response rate for those with GEM/abraxane plus daraxonrasib was 55%. Are those different? We don't really know. This is not a randomized controlled trial of the size that would answer that question. But it certainly is a trend towards a possible difference. And in preclinical work, we've seen that a cytotoxic agent combined with daraxonrasib does deliver greater at least initial efficacy. And so it makes sense for us to evaluate that in the clinic. And the best way to answer the question is simply do the experiment. It may turn out that different patients will prefer monotherapy versus the combination with cytotoxic chemotherapy. A 45-year-old robust patient might say, "Doc, I want to receive the most aggressive therapy you have available, give me the strongest chemotherapy and give me daraxonrasib." A less robust 85-year-old might say, "I don't think I can handle chemotherapy, but I can certainly take a daily once-a-day pill. And so I'd rather have monotherapy." I think in this world today, especially with such a devastating disease, creating options for patients and their physicians is really the best way to go.

That's fair. And then in terms of the frontline response rate you just alluded to, should we expect an update on that data in the near term?

We do expect at some point to report out durability data from the treatment arms that I just mentioned, the monotherapy and the combination with cytotoxic chemotherapy. Those data are maturing. We tend not to report durability until we have stable numbers that we think can hold up for the long term. We prefer that instead of getting out ahead of ourselves. So we'll report it when we have stable enough information to share.

Great. And then I just want to quickly touch on the adjuvant opportunity as well. I mean, in this setting, maybe people are less familiar in terms of how large exactly is the opportunity? And then how should we think about if we use daraxonrasib in adjuvant setting, how does that change maybe how physicians will sequence the drug in the frontline setting and the second line as well?

Right. So roughly 25% of patients are radiologically identified in the first diagnosis as being resectable, meaning the surgeon looks at a CT scan and says, I think I can remove this. Of those 25%, about 2/3 of them proved to have truly resectable localized and resectable disease, which is a surgical pathologic diagnosis. So 15% versus the 25% who radiologically look like they might be. So that's the number. It's about 15% end up being have a formal pathologic diagnosis of resected disease. Those patients will have received cytotoxic chemotherapy either before surgery or after surgery or some doses before surgery and some doses after surgery. It varies from practitioner to practitioner and from country to country. But generally, almost everybody who received surgery will also receive cytotoxic chemotherapy. So it's not an insignificant population. There are 56,000 new pancreatic cancer diagnoses in the U.S. each year. So if we say 15% of those, so roughly, let's say, 7,500 patients each year in the U.S. alone, and you can globalize that number, really deserve to have the chance for a potential cure. Now of those patients who receive surgery and cytotoxic chemotherapy, maybe 20% of them will have long-term durable benefit from the surgery and chemotherapy. That means 80% don't. And adding an agent that biologically targets the pathway that's causing the disease seems like it gives a chance to actually increase that overall survival rate and potential cure rate. And at a minimum, it may extend people's lives. So we're excited to do it. We think that trial will enroll very readily, and it's compelling to do.

Got it. And then also for your G12D inhibitor, zoldonrasib, you also have very strong data in pancreatic cancer. So how should we think about the position of this asset in the kind of your -- in your clinical development strategy in terms of the pancreatic cancer franchise?

Yes. Thanks for mentioning zoldonrasib, sometimes called the zoldon at Revolution Medicines, zoldonrasib. And it is a G12D selective inhibitor. It's an interesting agent. It's orally bioavailable. It's once a day, and it is a covalent modifier of the aspartate-containing variant or the G12D variant. It's the only compound actually in history to go into the clinic to do that. It is -- carries with it a remarkable tolerability and safety profile as reported by investigators. Many patients can't distinguish it from taking no drug at all, which is quite amazing for a targeted agent. And it also carried with it significant antitumor activity in patients with pancreatic cancer and a G12D mutation. Back to our philosophy, we're very deeply committed to patients with pancreatic cancer and other RAS-driven diseases. And so we want to bring forward any compound that looks compelling and try to find its place in the armamentarium for treating pancreatic cancer patients. Zoldonrasib is clearly a compelling compound and deserves that. Whether it should be studied as monotherapy or in combination is something to be determined. We expect that it will be more of a combination agent than a monotherapy agent, particularly because of its high tolerability profile. We expect that it could be combined with cytotoxic chemotherapy of any form, but we also think it could be combined with deraxonrasib. And if deraxonrasib emerges as really the backbone of treatment for patients with pancreatic cancer, then it might make sense to combine with a mutant selective inhibitor. We've shown strong preclinical data supporting the thesis that the combination of a mutant selective inhibitor, zoldonrasib plus deraxonrasib actually delivers greater antitumor punch as measured by deeper responses, more frequent responses and more durable responses. We believe that combination can counter some of the major forms of resistance that can occur to a RAS inhibitor. So we're excited about all of those. We've announced that we expect in the first half of 2026 to initiate a zoldonrasib Phase III pancreatic cancer trial that would likely be in earlier disease, a first-line trial. And we're just developing the strategy now, and we'll lay out the details of it around the time that we initiate that trial, but that will be our fourth pancreatic cancer Phase III pivotal trial.

We spent a lot of time on pancreatic cancer, but I also want to make sure we also talk about non-small cell lung cancer development as well, and you do have a pivotal trial with daraxonrasib monotherapy in non-small cell lung cancer. So maybe talk about the time line for that trial? And then what's your overall vision and strategy in lung cancer?

Yes. That trial is known as the RASolve 301 trial. It is also a global Phase III randomized trial. This is a daraxonrasib versus standard of care in second and third-line non-small cell lung cancer containing a RAS mutation, which, as I mentioned before, is 30% of all non-small cell lung cancer patients. That trial is also enrolling well. I don't have any particular update on it, quantitative update, but it is meeting our targets for enrollment, and we'll continue to enroll those patients. And we're very excited about that, and that's our first foothold into non-small cell lung cancer, and there's more to come. We've indicated that we expect to initiate a first-line non-small cell lung cancer regimen in a global Phase III trial, and that would be a combination of daraxonrasib with pembrolizumab and chemotherapy. The details of that trial, we haven't laid out, but that's the basic design comparing that to the KEYNOTE-189 regimen alone and more to follow after that trial as well.

And for maybe the last 30 seconds, let's talk about your balance sheet, your cash position and your recent deal with Royalty Pharma, your AI collaborations.

Well, we're fortunate that we have a strong balance sheet. We're in a strong financial position. We just reported an update to that. Our cash balance was on the order of $1.9 billion. We had developed in June of this year and announced a really groundbreaking partnership with Royalty Pharma that put $2 billion at our disposal. We've drawn down $250 million of that, but we still have another $1.75 billion available, and we'll draw that down on a selective basis as needed to support our program. So we think we have the capital to pursue a very aggressive clinical trial strategy across RAS-driven indications.

Great. Really looking forward to the next updates. And thank you so much for your time, Mark, and thank you, everyone, for joining us in person and online. Enjoy the rest of the conference. Thank you.