Good day, and thank you for standing by. Welcome to the Revolution Medicines Q1 2025 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to our first quarter 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer; Dr. Steve Kelsey, our President of Research and Development; and Dr. Wei Lin, our Chief Medical Officer; and Jack Anders, our Chief Financial Officer. I would like to inform you that certain statements we make during this call will be forward-looking. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties and please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31, 2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. Along with an updated investor presentation, which we will be referencing during today’s call. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. It's good to be with you this afternoon. Today, I'll highlight some of the progress we've made this quarter against the strategic priorities we outlined earlier this year. I'll then pass the call over to Dr. Steve Kelsey, who will walk through a strategic framework for our developing plans in non-small cell lung cancer. Dr. Wei Lin will then highlight updated data from several of our ongoing non-small cell lung cancer cohorts that provide support for our plans in lung cancer. Jack Anders will then provide a summary of our first quarter financial results before I share closing remarks and open the call to Q&A. At Revolution Medicines, we remain committed to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines. We continue to make important strides in pursuit of this mission as we execute, advance and extend our understanding of our novel RAS(ON)inhibitors. We believe and have increasingly been able to demonstrate that our compounds have the potential to become important therapeutic options for patients living with RAS-addicted cancers. Our first three clinical stage RAS(ON) inhibitors with highly differentiated and promising clinical profiles include daraxonrasib, a groundbreaking RAS(ON) multi-selective inhibitor, elironrasib, a distinguished G12C selective covalent inhibitor and zoldonrasib, a highly innovative G12D selective covalent inhibitor. We continue to make substantial progress advancing these programs with a vision to maximize the clinical impact across tumor types and lines of therapy through a mix of single agent and combination strategies. Pancreatic cancer is an important priority and our strategy involves executing on the ongoing Phase three RASolute 302 trial of daraxonrasib in patients with previously treated disease, while moving aggressively into earlier lines of therapy. We're working quickly to prepare for the initiation of two additional Phase 3 studies with daraxonrasib in pancreatic cancer in the second half of 2025. One of these trials will be in patients with first-line metastatic disease and is expected to compare a reference arm of patients treated with chemotherapy to two investigational arms, one with patients treated with daraxonrasib monotherapy and one with patients treated with daraxonrasib plus chemotherapy. The other early line trial will be as adjuvant treatment for patients with resectable pancreatic cancer, who have undergone surgery and perioperative therapy, typically including chemotherapy. In addition to this robust plan for daraxonrasib to play an important role in the treatment of pancreatic cancer across lines of therapy, we have similar ambitions for broad development in RAS mutant non-small cell lung cancer. The principal focus of today's call is to provide further color and support for our non-small cell lung cancer strategy, and I'd like to invite Dr. Steve Kelsey to walk you through our current conceptual framework. Steve?

Thanks, Mark. Improving treatment options for patients with RAS mutant lung cancer is an important priority for Revolution medicines. The majority of patients with non-small cell lung cancer are either diagnosed with or later develop metastatic disease. Treatment objectives for these patients include symptom improvement by reducing tumor burden, delaying disease progression, prolonging survival and improving quality of life. Thirty percent of patients with non-small cell lung cancer harbor a RAS mutation. There are still no full regulatory approvals for RAS inhibitors in any RAS mutant lung cancer. Nevertheless, due to the commercial availability of KRAS G12C(OFF) inhibitors by accelerated and conditional approval mechanisms, RAS mutant non-small cell lung cancer has effectively evolved into two diseases and treatment paradigms. G12C mutant disease, which represents around 12% of non-small cell lung cancer and other RAS mutant non-small cell lung cancer, which we are referring to as non-G12C RAS mutant non-small cell lung cancer. The second group counts for around 18% of non-small cell lung cancer. We expect segmentation of the RAS mutant non-small cell lung cancer space to continue into mutational groups as other mutant selective inhibitors advance through clinical development and receive regulatory approvals. Our aim at Revolution Medicines is to establish our portfolio of RAS(ON) inhibitors as the leading therapies for patients with RAS mutant non-small cell lung cancer across all RAS mutations and lines of therapy. We strive to develop first and or best-in-class RAS(ON) inhibitors and combinations. Our strategy for metastatic disease depends on a number of variables. First, which RAS mutation the tumor harbors and whether a mutant selective RAS(ON) inhibitor has achieved proof of concept. Second, the line of therapy for metastatic disease as the expectations and standards of care are different between initial therapy and salvage therapy. Daraxonrasib has shown encouraging anti-tumor activity in…

Thank you, Steve. I'll start by providing monotherapy updates across our portfolio. Beginning with daraxonrasib, our most advanced RAS(ON) inhibitor. This multi selective inhibitor has demonstrated compelling results across multiple tumors, including lung cancer, and is currently being evaluated in a Phase 3 registrational study for patients with previously treated non-small cell lung cancer. We're currently activating study sites for RASolve 301. The study randomized approximately four twenty patients to either daraxonrasib monotherapy or docetaxel. These patients must have received either one or two prior lines of therapy, including immunotherapy and platinum-based chemotherapy given either concurrently or sequentially. RASolve 301 incorporates a nested design with a primary analysis being performed in the core population of non-small cell lung cancer patients with RAS G12X mutations, excluding G12C. Extended population will incorporate all patients with RAS mutant non-small cell lung cancer, including those with tumors harboring G12C, G13 or Q61 mutations. The study has dual primary endpoints of progression free survival and overall survival. Moving to G12D non-small cell lung cancer. We've previously shown promising activity by daraxonrasib in patients with these tumors and the ongoing RASolve 301 recreational study includes such patients. Last month at AACR, initial clinical results were presented for zoldonrasib, our RAS(ON) G12D-Selective Covalent Inhibitor from a non-small cell lung cancer cohort. I'll walk you through these data. Zoldonrasib was well tolerated with manageable and predominantly low-grade treatment related adverse events as shown on the safety table. As of the December 02, 2024, data cutoff, at the 1200 mg once daily dose, two Grade 3 adverse events were reported among ninety patients with only two dose interruptions and no dose reductions. Zoldonrasib achieved a favorable mean dose intensity of 98%. Zoldonrasib monotherapy at the 1200 mg daily dose demonstrated encouraging antitumor activity. The waterfall plot shows the best…

Thanks, Wei. We ended the first quarter of 2025 with $2.1 billion in cash and investments, which we project can fund planned operations into the second half of 2027 based on our current operating plan. R&D expenses for the first quarter of 2025 were $205.7 million compared to $118 million for the first quarter of 2024. The increase in R&D expenses was primarily due to increases in clinical trial related expenses and manufacturing expenses for our three clinical stage programs, with daraxonrasib being the largest driver of the increase given the program is now in two Phase 3 trials. Personnel related expenses and stock-based compensation expense also increased in 2025 due to additional headcount. G&A expenses for the first quarter of 2025 were $35 million compared to $22.8 million for the first quarter of 2024. The increase in G&A expenses was primarily due to increases in personnel related expenses and stock-based compensation associated with additional headcount and commercial preparation activities. Net loss for the first quarter of 2025 was $213.4 million compared to $116 million for the first quarter of 2024. The increase in net loss was due to higher operating expenses. We are reiterating our 2025 financial guidance and continue to expect projected full year 2025 GAAP net loss to be between $840 million and $900 million which includes estimated non-cash stock-based compensation expense of between $115 million and $130 million. That concludes the financial update. I'll now turn the call back over to Mark.

Thank you, Jack. We are making meaningful progress as we successfully execute on our 2025 strategic priorities in pursuit of our goal to revolutionize treatment for patients with RAS-addicted cancers. A key focus this year is executing on the daraxonrasib registrational studies in both previously treated pancreatic and non-small cell lung cancers. I'm pleased to share that RASolute 302, our ongoing global Phase 3 trial in patients with second-line metastatic pancreatic cancer, continues its strong pace of enrollment in the U. S. following regulatory clearances in the E.U. and Japan, we've also begun enrolling patients in those geographies. We are confident that we'll be able to substantially complete enrollment this year to enable an expected data readout in 2026. We are also currently activating study sites for RASolute 301, our Phase 3 trial in patients with previously treated RAS mutant non-small cell lung cancer. We're making good progress toward advancing daraxonrasib into earlier line randomized pivotal trials with planning underway to initiate registrational trials for daraxonrasib in first-line and adjuvant pancreatic cancer in the second half of this year. Today, we've shared important data that create exciting opportunities for us in both previously treated and first-line metastatic non-small cell lung cancer and eventually earlier lines of treatment, including treatment approaches that include our mutant selective inhibitors. We continue to expand our clinical programs and follow study patients to enable the initiation of one or more pivotal combination trials in 2026. Progressing our earlier stage pipeline, including advancing next generation innovations, continues to be an important priority. At AACR recently, our RMC-5127, our G12V mutant-selective RAS(ON) inhibitor was presented in the new drugs on the horizon session. We continue to advance the program and expect to reach a clinical stage later this year to enable the initiation of a Phase 1…

Thank you. [Operator Instructions] Our first question comes from the line of Michael Schmidt of Guggenheim. Your line is now open.

Hi, thanks for taking my questions and congrats on all the progress. A lot of new information here to digest today. But I had a question on your first-line non-small cell lung cancer strategy. Obviously, there are interesting new data disclosed today for some of the various doublets. And based on your slide, it seems like for the KRAS G12C, first-line patient population, you're sort of focusing in on a triplet of elironrasib, daraxonrasib and pembrolizumab. Is probably the only combination where we haven't seen data yet today. But just looking at some of the other doublets, perhaps could you just comment on your confidence and tolerability of that triplet just based on some of the rash rates that we're seeing in some of the doublets and some of those reductions there?

Hi, Michael. Thanks for your question. Maybe Wei can speak to that.

We're optimistic given the profile we've seen so far. Obviously, we're still in the dose optimization and we have not yet defined the final dose for the triplet combination. I think we have characterized the monotherapy fairly well and we're not seeing any new safety signaling emerging. And regarding safety signaling that are known characterized such as rash, regarding daraxonrasib as well as the QTc, both are within what we have expected to observe with the monotherapy. So I think when we have longer follow-up and define the dose, we'll be sharing those prior to initiating our Phase 3 trial.

Thank you. Our next question comes from Marc Frahm of TD Cowen. Your line is now open.

Hi, thanks for taking my questions and congrats on all of the data sets today. Maybe just looking across the various combination data sets you presented, I'm struck by, I mean, it looks like the vast majority of the responders are still ongoing as of the last data cutoff. Again, PFS is clearly immature, but maybe can you give us a sense of just kind of the average follow-up in those cohorts to maybe give a sense of where durability and PFS may be headed? And then kind of looking longer term, what type of data set do you think you need to gather before you can kind of formally declare Phase 3 intent for these various combinations? Do you just need to get a little bit more data to get more comfortable on safety and select the final dose? Or is it you need real robust PFS estimates? Just kind of what's needed there?

Hey, Marc. Thanks for your question. I think the first question really is something that refers back to the swimmer plots that we provided in December. And I think those are available. So I'd recommend just taking a look at those in terms of follow-up time for those. We don't have an update today on that because we haven't done a fresh data cut, but the December data had those duration of treatment parameters listed. Your main question I think is about what's really gating now to the triplet. Steve, you want to comment on that?

Yes. I mean, let's be clear that there's a differentiation here between the G12C program and the non-G12C program. The non-G12C program is pretty much ungated. It's more of a sort of operational execution type question. I think we've shown very conclusively that adding daraxonrasib to the KEYNOTE-189 schedule is tolerated and the efficacy is pretty impressive. So we don't think we need any more data to press ahead with that. We just have to grind through the operational and regulatory milestones that you have to go through in order to get a study off the ground. As Wei alluded to in his prepared remarks, the G12C program is currently gated by optimizing the dose of that RAS(ON) doublet, the combination of daraxonrasib and elironrasib. Because it's a novel, novel combination and it's going into patients who have never received treatment for their non-small cell lung cancer. We really have to get the dose right -- to get the dose right to the satisfaction of the company, but also to the satisfaction of the regulators and the payers and the prescribers. So a little bit more refinement is needed there. We're pretty close. We have a range within which we're operating. And I don't think it will take too long, but that's essentially what's gating the G12C first-line non-small cell lung cancer program.

And a subpart of that was, is PFS required? Are we waiting for PFS? And I think that's a simple answer that. PFS is really not driving that decision. We understand PFS based on the second-line data, and now we have confidence that the response rates are very competitive. So I think we're good to go from that perspective.

Yes. We should say we should add that both from the published literature and historical data and from our own very pretty intense in-house analysis, Response rate is a reasonable correlate of PFS in non-small cell lung cancer. That has not been the case for pancreatic cancer, but for lung cancer it is. So we're more confident about the link between our response rates that we've just disclosed in lung in the lung cancer patients and the predicted PFS that we will achieve. And of course, PFS in lung cancer more compelling as a regulatory endpoint unlike in pancreatic cancer where we have the overall survival. So lung cancer has got a lot more going for it.

Thank you.

Thank you. Our next question comes from Eric Joseph of J.P. Morgan. Your line is now open.

Thanks for taking the questions and let me also just concur. Lots of data updates here and a lot to digest. Maybe Steve, I could get you to expand a little bit on your last comment, the types of datasets, publications perhaps that grant you confidence that response rate higher response rates will be a predictor for better PFS outcomes, sort of outside of your own pipeline work. I'm also curious to know whether you are continuing to enroll the frontline lung cancer cohorts to sort of build upon the dataset that you are observing so far? And then we finally on the safety side, I know this is more than one question, but, on the safety side, this nonclinical, this subclinical QT signal that you're seeing with fair wide combinations, you're confident that it won't become something greater with the triplet regimen? Thank you.

I think the first part was a question -- thank you, Eric. I think the first part was a question about the literature reflecting predictive utility of response rate for durability. I think we can provide some references offline. But by the way, it's something we've heard from investors for the last several years. Why don't we use response rates more? So I think it's pretty generally well known and our observations are very consistent with that. Do you have anything you want to add to that? What was the second part?

Do you want to comment on that?

Yes. We have not seen that to be the case. Certainly, we've reported the QTc signal, it's fair. It's actually on par with even lower than what was monitored. Obviously, for longer follow-up and larger patient sample, we do not expect there is going to be a enhancement of QT. So I think QT is well within line of what osimertinib has reported in their label. So I don't think it will be.

And consistent with the larger earlier on and longer for elironrasib dataset that we showed at the beginning here, which I think makes that point pretty clear.

The other question was on whether you're continuing to enroll these chronic cohorts.

Well, there's dose optimization, yes, ongoing, so pretty much answers that.

Okay. Thanks for taking the questions. Congrats on the updates.

Thank you.

Thank you. Our next question comes from Jonathan Chang of Leerink Partners. Your line is now open.

Hi, guys. Thanks for taking my question. How are you thinking about the duration of clinical benefit of daraxonrasib versus the mutant-selective inhibitors like zoldonrasib and elironrasib? What are the reasons for why one could be more durable than the other? And how could this and other factors impact how you're thinking about future development strategies? Thank you.

Thanks, Jonathan. Maybe I'll comment on that and then if Steve Wai wants to add anything to it. I don't think we have any direct head-to-head comparison because the daraxonrasib study was done in tumors that carry different mutations than the elironrasib study. So we really can't compare those. So we can't say which is superior to the other and they're not matched for other prognostic factors as well. So I don't think we have any information on it. If you're wondering what we might predict, I don't know. We'll see. And ultimately, we're combining these anyway as both Wei and Steve have talked about. And so one ought to get the benefit of whatever the pros are on each side of that. Is there anything more specific that you're trying to get out there?

I was just thinking about how in in in situations where you might be considering, advancing the multi-RAS or a mutant-selective one or maybe the combination of both, how you might consider things like duration of clinical benefit and how long patients may stay on treatment, in addition to other considerations?

It's the number one consideration. Because that's the key driver of the sort of patient experience, assuming that we obviously have a combination that patients can tolerate for the time that they're on the treatment without having a miserable life. It's the number one consideration. The mechanisms of escape from the mutant-selective inhibitors are very different from the mechanisms of escape from daraxonrasib. We have only disclosed mechanism of escape data for daraxonrasib in pancreatic cancer, but it's very different pattern of escape from what's being disclosed for mutant-selective inhibitors in non-small cell lung cancer. And that's why we're so enthusiastic about the combination, because all of those putative mechanisms of escape are covered by the combination. The novel RAS mutations that emerge on the mutant selective inhibitors are inhibited by daraxonrasib and the putative amplification of mutant KRAS that we might see in lung cancer, which we have seen in pancreatic cancer, is suppressed by hitting the mutant harder with the combination of the two RAS on inhibitors together. So we do expect the PFS to be longer with the combo than with either agent alone. And as we described, the increase in response rate is a good harbinger of that. We just have to wait for that data to mature in order for it to be worthwhile disclosing publicly because immature PFS data isn't helpful to anybody.

Yes. And Steve's comments are entirely consistent with what we have reported in the preclinical context. And I think Wei showed two figures, representative of a much larger dataset that we presented over several scientific meetings that the combination does tend to deliver significantly greater benefit and including the figure on the right side of that slide, I'm not sure what it is in your deck, but that right figure shows the combination of the doublet plus anti PD-1 basically provided for no progression in any of the animals in that experiment across 100 days. So I think the totality of the evidence is supportive of what Steve suggested.

Got it. Thanks for taking the question.

Thank you.

Thank you. Our next question comes from Kelly Shi of Jefferies. Your line is now open.

Hi, this is Clara on for Kelly. Thanks for taking our question. Congrats on the data. So for non-small cell lung cancer with all the combination updates and it seems like you have really multiple paths to pursue the opportunity in lung and you also have total pancreatic development as well as maybe other early initiatives such as G12V. So maybe from a resource allocation perspective, what are the key criteria driving priorities between all those developments. And also for lung cancer specifically, how should we think about the cadence of initiating pivotal combination trials? And you mentioned you might initiate combination trials in 2026. Thank you.

Okay. Thank you, Clara. Let me start with the second comment about timing. I mean, we have provided some timing and I think that's all we can provide today. We do have, of course, daraxonrasib in non-small cell lung cancer already underway in the 301 study. But then in terms of first-line and combination studies, we'd expect to begin rolling those out in 2026. In terms of resource allocation, I don't think there's a simple single word or sentence answer to help clarify that for you. It's obviously a pretty complex and rich set of opportunities. It's sort of an embarrassment of riches that each clinical study we've done so far opens up pretty exciting new pivotal trials that we could consider doing. So, it certainly does create some need for prioritization. We start with the clinical data, the biological rationale behind the data. We look at the competitive landscape. As Steve pointed out, ultimately what's most important is to provide durable clinical benefit. So that's a key characteristic that gets ranked in all of this. So many, many factors. And at this point, we're able to proceed with a large chunk of the priorities that we have defined. We're basically moving everything forward right now that is ready to be moved forward in 2025, and we'll continue to do that into 2026, constantly looking at justification for the investments, but also trying to achieve the goal that we've alluded to several times here, which is to deliver significant changes on behalf of patients across RAS mutations, tumor types and lines of therapy, and we think we're best positioned in the industry to do that.

Thank you. Our next question is from Ellie Merle of UBS. Your line is now open.

Hey, guys. Thanks for taking the question and congrats on all the progress. Just curious your latest thinking on a potential commercial strategy ex U.S. And your general philosophy around potential partnering. And then just in terms of the designs for the pivotal combination, trial or trials. Could you give us maybe any more color on when you might expect to meet with the FDA to discuss the designs and when we might be able to learn more about the specifics of the designs from our end? Thanks.

Hi, Ellie. Thanks for your question. On the second point, unfortunately, no, we don't typically sort of lay out the time line for our future interactions or ongoing interactions with the FDA. Our pattern that we try to establish is once we definiteize a plan or close to a definitive plan, we often provide some sort of update including the data to support whatever commitment we're making. But beyond that, I can't give you any further higher resolution answer to it. With regard to the ex-U.S. strategy, that's obviously very much on our minds as I think it is on our investors. Since I first raised almost two years ago now the possibility that we might engage with others to help us commercialize outside the U.S., while we would certainly focus on retaining the U.S. market. We have had strong interest from multiple global pharma companies. We've had concrete and productive dialogue with them. And without a doubt, we could enter an attractive partnership and that's really creates a great deal of optionality for us. We've also felt no need to rush into such a partnership and we've continued to use time to our advantage. We've continued tracking the portfolio, tracking the assets, progress trajectory. We've also tracked organizational progress and trajectory and all of those have continued to exceed our expectations. So now we're in the position to assess the pros and cons of all the options that are available to us. And we have to make a strategic judgment, which we're just not ready to make today, which is what's the best approach for serving patients not only in the U.S., but also internationally and that also serves our business. And we are continuing to look at that, but now through the lens of where we are in 2025 with a very different organization in terms of depth and breadth, programs -- maturity programs and also with the addition now of Anthony, who joins the team and can bring a very broad commercial perspective to it as well. So we will complete that analysis at some point and continue to provide updates as appropriate.

Great. Thanks.

Thank you. This now concludes the question-and-answer session. I would now like to turn it back to Mark Goldsmith for closing remarks.

Thank you, operator. Thanks to everyone for participating today and for your continued support of Revolution Medicines.

[Operator Closing Remarks]