RVMD

Day, and thank you for standing by. Welcome to the Revolution Medicines Q1 2026 earnings call. At this time, participants are in a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising you your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand it over to Ryan Asay, Senior VP of Corporate Affairs. Ryan, you have the floor.

Thank you, operator, and welcome everyone to the first quarter 2026 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Alan Sandler, our Chief Development Officer, and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D, Dr. Wei Lin, our Chief Medical Officer, and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call. We 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 forward-looking statements.

For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report 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 31st, 2026, and recent corporate updates. The press release and updated corporate presentation are available on the investor section of our website at revmed.com. 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 to discuss the tremendous progress we've made in 2026. This is a pivotal moment for our organization and for patients worldwide living with pancreatic cancer who are in need of new therapeutic options. It is anchored by the top-line readout for RASolute 302 last month, in which daraxonrasib monotherapy demonstrated an unprecedented improvement in overall survival compared with chemotherapy in patients with previously treated metastatic pancreatic cancer. The RASolute 302 results represent a transformative advance for patients. They also firmly validate our pioneering RAS(ON) inhibitor strategy and reinforce its potential to improve outcomes in RAS-driven cancers.

High investor conviction enabled an historic $2 billion dual tranche capital raise that will allow us to continue our important work broadly, advancing our current portfolio of four groundbreaking clinical-stage oral RAS(ON) inhibitors and bringing forward the next wave of innovation targeting RAS-addicted cancers, including our new class of catalytic RAS(ON) inhibitors. On today's call, following my remarks, I'll pass the call over to Dr. Alan Sandler, who will provide an overview on the recent clinical progress we've made across our portfolio, including the most recent data presented at the American Association for Cancer Research annual meeting. Jack Anders will summarize our first quarter financial results before we open the call to Q&A. Let me first spend a few moments talking about RASolute 302, the global phase III trial evaluating daraxonrasib monotherapy in patients with previously treated pancreatic cancer.

The top line readout for daraxonrasib marked a major milestone in this disease, significantly raising the bar in the development of new treatments for patients living with pancreatic cancer, the most RAS-addicted of all human cancers. In RASolute 302, daraxonrasib demonstrated unprecedented impact, meeting its primary and key secondary endpoints and showing statistically significant and clinically meaningful improvement in progression-free survival and overall survival compared to standard of care chemotherapy. In the overall intent to treat study population, which includes patients carrying tumors with or without an identified RAS mutation, daraxonrasib drove a 60% reduction in risk of death compared with chemotherapy and with a median overall survival exceeding one year. Daraxonrasib was generally well-tolerated and no new safety signals were observed. These are dramatic practice-changing results and our focus now is on moving with urgency to bring this potential new option to patients.

We intend to submit a new drug application to the U.S. Food and Drug Administration under the FDA Commissioner's National Priority Voucher Program and will also execute our plan to file with other global regulatory authorities. Last week, we reported that the FDA issued a safe to proceed letter allowing us to initiate an expanded access treatment protocol for daraxonrasib in patients with previously treated metastatic pancreatic cancer. This will allow us to move as quickly as possible to ensure safe and equitable access to daraxonrasib for eligible patients in the U.S. We were also pleased to announce recently that RASolute 302 will be featured in the plenary session of this year's American Society of Clinical Oncology, or ASCO, annual meeting in Chicago. We and the investigators look forward to sharing detailed results with the scientific community at that time.

I'll now pass the call over to Alan to walk through some recent clinical program updates. Alan.

Thanks, Mark. The extraordinary results from RASolute 302 validate our tri-complex inhibitor platform and give us increased confidence in daraxonrasib's potential in earlier treatment lines in pancreatic cancer. This confidence was reinforced at AACR, where we shared updated clinical data from the phase I/II studies for daraxonrasib monotherapy and in combination with chemotherapy in first-line metastatic pancreatic cancer. Both the monotherapy and combination cohorts demonstrated encouraging preliminary durability data. In the monotherapy study, while median progression-free survival and median overall survival were not mature as of the data cutoff, the Kaplan-Meier estimates at six months were 71% and 83% respectively. In the combination of daraxonrasib with gemcitabine and nab-paclitaxel, the Kaplan-Meier estimates at six months for progression-free survival and overall survival were 84% and 90% respectively.

Across both studies, daraxonrasib's safety and tolerability profile remained consistent with earlier findings in this patient population, with no new safety signals observed. These compelling results strongly support our decision to rapidly advance RASolute 303, our phase III study evaluating both daraxonrasib monotherapy and daraxonrasib in combination with chemotherapy in first-line metastatic disease. The trial is enrolling globally. In addition to our first and second-line daraxonrasib registrational studies in pancreatic cancer, patient enrollment is ongoing in RASolute 304, our registrational trial of daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease following conventional surgery and perioperative chemotherapy. We are also making progress in two registrational studies for zoldonrasib, our covalent RAS(ON) G12D selective inhibitor in first-line pancreatic cancer.

We have initiated RASolute 305, a randomized, double-blind, placebo-controlled registrational trial evaluating zoldonrasib in combination with investigator's choice of chemotherapy, either gemcitabine and nab-paclitaxel or modified FOLFIRINOX compared with placebo plus chemotherapy. We remain on track to initiate RASolute 309, our first registrational study to evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib with daraxonrasib in the second half of the year. Moving to non-small cell lung cancer, another focus of development for RAS(ON) inhibitors. With approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, unmet needs in non-small cell lung cancer remain a priority that we aim to address through several ongoing and planned registrational studies. Beginning with daraxonrasib, we continue to enroll patients globally in RASolve 301, our global randomized trial evaluating daraxonrasib monotherapy in previously treated patients.

Based on the strength of the phase I results for daraxonrasib monotherapy in non-small cell lung cancer, as well as additional confidence from the recent positive RASolute 302 results, we are expanding the RASolve 301 study to increase the statistical power of the overall survival component of the dual primary endpoint. Enrollment is going well, and we anticipate substantially completing enrollment in the expanded study this year. We also expect to disclose our plans regarding daraxonrasib combination therapy in first-line non-small cell lung cancer this year. Turning to G12D non-small cell lung cancer, at AACR, we presented updated clinical data for zoldonrasib monotherapy in a subset of patients who had previously been treated with immune checkpoint inhibitors and platinum chemotherapy. Zoldonrasib was generally well-tolerated and demonstrated a safety profile consistent with previously reported findings.

Zoldonrasib demonstrated encouraging clinical activity with a confirmed objective response rate of 52%, disease control rate of 93%, and a median progression-free survival of 11.1 months. Overall survival data were immature at the time of analysis. The estimated survival rate at 12 months was 73%, while the median had not yet been reached, which is encouraging data at this early look. We continue to believe deeply in the potential of zoldonrasib given its compelling safety and tolerability profile and encouraging clinical activity, which strongly support our plans to advance zoldonrasib across monotherapy and combination settings in lung cancer and other RAS G12D-driven cancers.

Building on the strength of our monotherapy data, we are preparing to initiate in the first half of this year RASolve 308, a global, double-blind, placebo-controlled registrational trial evaluating zoldonrasib in combination with the KEYNOTE-189 regimen, which is the standard of care in first-line treatment for metastatic non-small cell lung cancer compared to the KEYNOTE-189 regimen with placebo. For patients with G12C non-small cell lung cancer, elironrasib, a RAS(ON) mutant selective inhibitor, has demonstrated a differentiated and compelling clinical profile in both G12C inhibitor naive and G12C inhibitor experienced lung cancer patients. We remain on track to share an update on our elironrasib registrational strategy this year. Our third RAS-addicted cancer focus is colorectal cancer, which remains an area of high unmet need and interest for the company.

We have a range of combination studies underway designed to better understand this genetically complex and heterogeneous disease, including studies to evaluate RAS(ON) inhibitor doublet combinations and RAS(ON) inhibitors in combination with current standards of care and with other targeted drugs. We remain on track to share combination data this year as we work to prioritize registrational opportunities. I'll conclude with brief highlights on two of our early stage programs. We continue enrolling patients in the first-in-human trial of RMC-5127, our fourth RAS(ON) inhibitor. RMC-5127 is selective for RAS G12V, the second most common RAS variant in solid tumors. We expect to identify a recommended monotherapy phase II dose for this compound in the second half of 2026. Finally, AACR brought with it the opportunity to showcase our new class of innovative mutant targeted catalytic RAS(ON) inhibitors.

These inhibitors are designed to promote the conversion of mutant RAS in its active GTP bound RAS(ON) state back to the inactive GDP bound RAS(OFF) state, thereby mimicking the normal physiologic regulation of wild type RAS. These preclinical data demonstrated that at well-tolerated doses, RM-055 achieved robust and durable antitumor activity across KRAS G12 mutant xenograft models of pancreatic cancer, non-small cell lung cancer, and colorectal cancer. Notably, tumors that had escaped prior RAS inhibitor treatment were sensitive to RM-055, which drove deep and durable regression. Its compelling differentiated profile warrants clinical investigation of its potential to counter emergent drug resistance and to extend clinical benefit, and we remain on track to initiate a first-in-human clinical trial in the fourth quarter. With that, I'd like to pass the call back over to Mark. Mark?

Thanks, Alan. In addition to the substantial R&D progress we've made across our pipeline, we continue to be very gratified by the build out of our commercialization infrastructure and operational capabilities to support the company's global commercialization ambitions. We've established the operational wherewithal required to move with speed and agility, focused initially in the U.S. and extending into priority international regions. We are resourcing our efforts to ensure that we have the best strategies, tactics, operational capabilities, and people to bring daraxonrasib with urgency to patients pending regulatory approvals. We expect to be launch-ready under best case approval timing scenarios. We have experienced and talented executives leading our commercialization team across medical affairs, market access, marketing, and sales. These groups are deeply engaged in market preparedness and assessment, planning, physician and advocacy engagement, sharpening operational capabilities, and conducting other launch readiness activities.

We recently appointed several experienced leaders across the Asia Pacific and European regions, including Neil MacGregor as our General Manager for APAC, Tetsuo Endo as General Manager for Japan, and Martin Voelkl as General Manager for Germany. I'd now like to turn the call over to Jack Anders, our Chief Financial Officer, to summarize our first quarter financial results. Jack?

Thanks, Mark. We ended the first quarter of 2026 with $1.9 billion in cash and investments and further strengthened our financial position after the quarter with $2.1 billion in net proceeds from our concurrent upsized offerings of common stock and convertible debt in April. Before we dive into the income statement for the quarter, I'd like to highlight that our stock-based compensation expense for the quarter was higher than usual and explain the reason behind it. Stock-based compensation expense was $87.3 million for the quarter ended March 31st, 2026, compared to $25.1 million for the quarter ended March 31st, 2025. In the first quarter of 2026, the company updated its equity compensation program to introduce competitive retirement benefits for employees who meet specific minimum age and service requirements.

The modification of this program resulted in an incremental $44.6 million in stock-based compensation for the first quarter of 2026. This incremental expense was primarily due to the accelerated timing of recognition of stock-based compensation expense originally scheduled in future periods for outstanding eligible awards. As a result of this timing pull-in, we expect higher non-recurring lumpiness in stock-based compensation expense for the first half of 2026, with stock-based compensation expense decreasing and returning to a more normalized trajectory in the second half of the year. As a result of this change, the company is increasing its estimate of full year 2026 stock-based compensation expense by approximately $80 million, and now expects full year 2026 stock-based compensation expense to be between $260 million and $280 million.

Additionally, the company is also updating its projected GAAP operating expense guidance to reflect this expected increase in stock-based compensation expense, and now expects full year GAAP operating expenses to be between $1.7 billion and $1.8 billion. Moving to expenses for the quarter, R&D expenses for the first quarter of 2026 were $344.0 million, compared to $205.7 million for the first quarter of 2025. This increase was primarily due to higher clinical trial and manufacturing expenses for daraxonrasib and zoldonrasib due to acceleration of the pace and expansion of these programs. R&D expenses were also higher as a result of increased headcount costs and higher stock-based compensation expense, as described earlier.

G&A expenses for the first quarter of 2026 were $101.3 million, compared to $35.0 million for the first quarter of 2025. The increase in G&A expenses was primarily due to higher stock-based compensation expense, as described earlier, increased headcount costs, increased commercial preparation activities, and higher administrative costs. Net loss for the first quarter of 2026 was $453.8 million, compared to $213.4 million for the first quarter of 2025. The increase in net loss was due to higher operating expenses. That concludes the financial update. I'll now turn the call back over to Mark.

Thank you, Jack. The remarkable start to 2026 is the result of years of unwavering dedication, relentless perseverance, and hard work by our team and collaborators standing on the shoulders of others. With the unprecedented performance of daraxonrasib monotherapy in the RASolute 302 study, we believe we are in the position to change the standard of care for patients living with pancreatic cancer, subject to regulatory review and approval. The global response to the RASolute 302 data has been overwhelming. The news brings with it hope and possibility for patients, physicians, and the advocacy community that have all been waiting too long for new, more effective treatment options. We are now an important step closer to fulfilling our mission of discovering, developing, and delivering innovative targeted medicines to patients living with cancer.

We have an extraordinary opportunity, and we take very seriously the responsibility that goes with it. Before I close, I'd like to recognize our continuing partnerships with patients and caregivers, healthcare providers, and investors, as well as the remarkable dedication and efforts of RevMed employees. It requires the ongoing support of all of our partners and constituencies to do revolutionary work on behalf of patients. With that, I'll turn the call over to the operator for the question and answer portion of the call.

Thank you. At this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We do ask that each person limit their question to one question and one follow-up. Our first question comes from the line of Cory Kasimov with Evercore ISI. Cory, go ahead with your question.

Great. Good afternoon, guys. Thanks for taking the question, congrats on all the recent very exciting progress. Wanted to ask, you recently noted you could share data at a medical meeting that supports the rationale for RASolute 309, the phase III frontline PDAC trial looking at zoldonrasib plus daraxonrasib versus chemo. Would this include durability data or just response rate as we've seen with some of your initial disclosures? Maybe more importantly, how much additive efficacy would you be looking for here to say it's clinically meaningful to justify the combination over the, you know, the exciting monotherapy results we've seen with both of these agents? Thank you.

Thanks, Cory. Appreciate your comments and question. It's probably too early for us to lay out what that presentation would look like. We typically don't forecast it. You know, we'll show what we have. We think it will justify our plans, and we'll provide that in due course. The second question also probably, unfortunately, I can't be too helpful about what the, you know, what's the threshold for added value that justifies doing that? I mean, of course, we look at the totality of the evidence. We look at the historical benchmarks, and, ultimately, as you sort of implied in your question, durability is, you know, the most important parameter.

Got it. Thank you.

Our next question comes from Charles Zhu with LifeSci Capital. Charles, go ahead with your question.

Yes. Good afternoon, everyone. Thank you for taking my questions, and congrats on everything. I got a couple kind of at the opposite end of the spectrum. One, how many patients do you think you can accommodate on your expanded access program for the daraxonrasib program with 302? What are the potential implications as you start thinking about potentially converting-

Hey, Charles.

Can you hear me?

Charles, we're not able to pick up what you're saying. Stacy, I don't know if there's anything you can do on your side to improve the audio quality.

Charles, are you in a good position to speak with us? We'll get Charles back.

Why don't we move on to the next call and come back to Charles?

Yeah. We'll get Charles back queued up. Our next call comes from Michael Schmidt with Guggenheim Securities. Michael, go ahead with your question.

Yeah. Hey, guys. Thanks for taking my questions. You know, again, congrats on RASolute 302 data. Looking forward to the full data presentation at ASCO. Yeah, a question on the EAP program. I know this was just announced a few days ago, but Mark, I don't know if you could comment what you're seeing so far in terms of demand for the EAP program, and what do you think how many patients could potentially benefit from this prior to officially receiving FDA approval? Maybe just, if you could share your view of the size of the second-line pancreatic cancer opportunity. Based on your market research, how many patients in the U.S. do you think would be treatment eligible for the daraxonrasib based on the 302 study? Thanks so much.

Thanks, Michael. Nice to hear from you. You know, on the first question, of course, we're working hard to get to get in a position to be providing drugs to those who need it. The demand has been very clear from the moment that it was announced, and we don't expect that to slow down anytime soon. You know, we're putting all the resources that we can on it to help meet that need. I can't really give you a projection as to the number. I don't know how we could make that projection. We'll just have to play it out. I think there is clearly widespread knowledge of awareness of daraxonrasib and, you know, those calls started coming in within, you know, minutes after after the announcement.

The size of the second line opportunity, Wei might wanna talk about this. We can't characterize it for you in great depth, but, you know, we typically think about roughly 60,000 new cases in each year, and then maybe Wei can comment on both what's historical attrition, and then also whether or not daraxonrasib might affect that.

Yeah, happy to do that. These are obviously just estimates based on clinical practice. As Mark Goldsmith commented, about 60,000 Americans are newly diagnosed each year with pancreatic cancer. About 50%-60% of those patients are diagnosed with metastatic disease. Those patients are eligible to receive first-line therapy for metastatic disease. Typically, because of both the aggressive nature of disease as well as the toxicity of chemotherapy, about half of the patients receive first-line metastatic treatment, receive subsequent second-line treatment. That gives you a sense of the overall attrition as well as the size.

You know, just to add to that, you know, that could certainly change in the context of first-line treatment, but we don't have anything to address on that, on that point today.

Thank you.

Our next question comes from Faisal Khurshid with Jefferies. Faisal, go ahead with your question.

Hey, guys. Thank you so much for taking the question. Just wanted to ask on the RASolve 301 upsizing. Could you clarify what exactly led to the upsizing? What were you powered for before, and what are you powered for now? Does this change the timeline from enrollment completion to readout? Thank you.

Thanks a lot for your question. I'm gonna answer the second question. Alan Sandler is gonna talk about the first. We don't think it will change the timing of the readout given the high pace of enrollment and where we stand today. We don't expect to impact our projection that we'll complete or substantially complete enrollment this year. The more subtle question about the sizing of the trial, Alan can comment on.

Sure. Thanks. You know, an important point is we've realized the importance of overall survival. Given the results that we've seen in 302 and also the phase I monotherapy data, we have a very high conviction that on our ability to obtain overall survival benefit. As a result of that, we're gonna further prioritize overall survival in 301 by expanding the roll, the enrollment, as you've noted, going from 420 to 590 patients. That'll increase the statistical power of that component of what is a dual primary endpoint. Again, as Mark has mentioned, we, there's a great pace in terms of the patient enrollment, and we think that we will substantially complete the enrollment even with the expanded study this year.

Got it. Thank you.

Our next question comes from the line of Brian Cheng with JPMorgan. Brian, go ahead with your question.

Hey, guys. Thanks for taking our questions this afternoon. Mark, during the call, you said the best case timing scenario for darax launch across the globe. How should we think about the timing and the cadence then for the filing and launches specifically across APAC and European regions? Just on the NDA application towards the FDA, can you give us a little bit more color, a little bit more granularity in terms of the things that are left to complete? Thank you.

Yeah. Thanks, Brian. Can't really give you any specific timing with regard to the filings outside the United States, but just generally speaking, we are starting with the U.S. filing as the initial priority. There will be some sequential framework for filing in other countries, and we're already engaged with regulatory authorities outside of the United States in order to make sure that we can deliver what they need and in as timely a manner as possible. For the NDA, your question was what's left to deliver? Is that how you put it?

Yeah. What, what are the things that are left to complete before you complete the NDA application?

Well, we've been fully engaged with the FDA for a long time, as you know, of course, with the CNPV and the breakthrough designations, we've had a higher level of engagement than you might otherwise have. We are providing them information as it becomes available and mature enough to provide to them. You know, ultimately, the clinical package is the thing that will be provided. I can't give you specific timing on that. There's, you know, a full throttle effort to do it. We feel the urgency around it. Certainly, the question earlier about the EAP provides a pretty strong signal about how urgent that is, we'll continue to move this forward as fully as we possibly can.

Great. Thanks, Mark.

Our next question comes from Marc Frahm with TD Cowen. Marc, go ahead with your question.

Great. Thanks for taking my questions. Maybe following up a little bit on Cory's question earlier, just on the zoldonrasib plus daraxonrasib combo. Can you maybe speak to the 309 design, particularly in light of the 302 finding and, you know, the survival data, I mean, looking better than anything we've ever seen, even in first line? Just why is 309 comparing to chemo still the right design or should it really be switched over to consider daraxonrasib monotherapy as the comparator arm there, at a minimum? You know, one, to get the contribution of parts, but also just from a clinical execution perspective of, you know, where the ball is headed, seems to be headed in pancreatic cancer.

Yeah. Thanks, Marc. That's a good question. It, you know, it's a subtle one. You know, of course, today, standard care is chemotherapy. Until that's, you know, until there's a data set that moves the FDA, you know, to approve a different treatment, and a different treatment at the level that people consider the new standard of care, then chemotherapy is the standard of care. You know, I think you're sort of inviting me to comment that, of course, we think daraxonrasib has a real potential, in monotherapy, but also in combinations in first line. Among those combinations, chemotherapy is one that we've already provided some early stage data on and we're quite excited about. That combination is in the 303 trial. We're already going into combinations.

It's really just a question of when that bar moves. We have high confidence that the combination can deliver something that is differentiated from chemotherapy, but also even from monotherapy. I think the other thing to keep in mind is we do a lot of things where there's overlap in the patient populations that we might be able to serve in different ways. We don't shy away from that, as you know. We've discussed that before. Because every patient has his or her own specific needs, and giving doctors options, even if the outcomes on paper may look fairly similar across broad populations, there still may be reasons why one particular patient would benefit or would be perceived to benefit from one particular combination or monotherapy approach versus another.

Providing the most fulsome set that we can based on the science and then ultimately on the clinical data, increases the chance that we're the ones who are delivering the best possible options for patients. That's the high level of comment.

Stand by for our next question. Our next question comes from Jonathan Chang with Leerink Partners. Jonathan, go ahead with your question.

Hi, guys. Thanks for taking my questions, and congrats on the progress. Can you talk about your latest thinking on getting to a chemo-free option in frontline pancreatic cancer? What gives you confidence in being able to achieve this? What do you think is the best strategy for doing this?

Yeah. Thanks, Jonathan. Nice to talk with you. Well, we just talked about one of those strategies for a chemo-free frontline, which is monotherapy daraxonrasib. I think the data, single-arm data we've shown so far are compelling enough that it just very much justified incorporating that into the phase III first line trial, and we'll see how that performs. We have every expectation that it could deliver a chemo-free regimen. The second option is also one we just talked about, which is combining mutant-selective inhibitor with daraxonrasib. That would be a chemo-free strategy. That specific combination of zoldonrasib plus daraxonrasib, of course, is for the 40% of pancreatic cancer cases that are carrying a RAS G12D mutation.

We have other multi-selective inhibitors directed against additional mutations that are common in or can be found in RAS cancer. We could and would likely fill out that collection of regimens. It just happens that zoldonrasib plus daraxonrasib is on the vanguard of the work because of maturity of the compound and the data that we have so far. I think those are two very compelling chemo-free regimens. There are others that one can consider. There are immunologic agents that could be combined. There are other targeted agents that could be combined. We're already exploring, as you know, PRMT5 combination, PRMT5 inhibitor combination, et cetera. I'm sure there will be other things to come over time.

Understood. Thank you.

Our next question comes from Charles Zhu with LifeSci Capital. Charles, go ahead with your question.

Hello. Thanks for giving me another stab at this. Can you hear me now?

Yes.

Yes.

All righty. Perfect. I believe a bunch of clinical type questions were taken, so I'll ask one a little bit earlier. RM-055, nice to see your presentation at AACR, as well as some of the work you helped support over at Pier Paolo Pandolfi's lab that was just published yesterday. Can you comment a little bit perhaps on RM-055's ability to potentially address daraxonrasib resistance mechanisms that go beyond that of a KRAS amplification? Can you also talk a little bit about perhaps how you might be achieving what appears to be, at least pre-clinically, a wider therapeutic window for RAS mutants over RAS wild types over that which daraxonrasib can achieve?

Any color as to how you're accomplishing that mechanistically, and if you can also kind of see that in your pre-clinical models as you advance that into the clinic. Thank you.

Thanks, Charles. Those were loud and clear. Yeah, Steve Kelsey, I think will comment on both of those important topics.

Sure. Yeah, I think the RAS amplification can be perceived as a, you know, a standalone mechanistic basis for escape from daraxonrasib, but it also acts as a surrogate for increasing flux through the RAS pathway generally. In most of the experiments that we've done, RM-055 is a better inhibitor of flux through, increased flux through the RAS pathway generally, particularly when it's going down through a G12 mutation. I think there is a general principle of escape from daraxonrasib occurring through reactivation of RAS pathway signaling. It's not just amplification of the mutant allele that can do that, and I think there's every reason to believe that RM-055 may be effective beyond just pure RAS mutant amplification.

Your point about therapeutic index, it's all to do with the relative importance of hydrolysis of RAS(ON) back to RAS(OFF) between cancer and normal tissue. Normal tissue, most of the RAS in normal tissue was already in the OFF state anyway, but it's being catalyzed back. The active RAS is being catalyzed back to RAS(OFF) by very effectively by the naturally occurring GAPs. The whole point of RAS mutation cancer is that that just doesn't happen. The ability of the mutant RAS to withstand that catalytic hydrolysis back, that hydrolysis back to the RAS(OFF) state is very different, and it varies from mutation to mutation.

What we've done is very selectively targeted the inability of, particularly, as I said, G12 mutant RAS to be hydrolyzed back to RAS(OFF) by forcing it to be hydrolyzed back to RAS(OFF). This drug has almost negligible effect on normal tissue in that respect and a very significant increased a deactivation of mutant RAS in cancer cells.

Got it. Thanks for taking the questions. Congrats again on everything.

Thank you.

Our next question comes from the line of Michael Yee with UBS. Michael, go ahead with your question.

Great. Thanks, guys. Congrats on the progress. Two quick ones. On the colorectal cancer data coming up, can you help guide expectations on how to think about combination with EGFR given overlapping rash, and how to think about mitigation or how to interpret results given higher efficacy, but also trying to mitigate rash in that strategy? Also in the first-line PDAC study, which is enrolling, we definitely get huge feedback that it's gonna enroll super fast at a number of different sites. Is it safe to assume that there's probably an interim in that study as well eventually once you complete enrollment? Thanks.

Thanks, Michael. Nice to hear from you. Who wants to address the CRC? I mean, maybe I'll just make the comment that it is true that daraxonrasib itself has essentially overlap with the EGFR antagonists from the perspective of suppression RAS signaling that drives the skin side effects. That is a harder combination to contemplate. That really doesn't apply at all with the mutant selective inhibitors. That's why the G12C selective inhibitors that, you know, launched the field essentially, sotorasib and adagrasib and now others, can be combined pretty readily. It really fundamentally addresses the whole gap in the EGFR coverage that occurs in the RAS mutant tumors.

The whole reason why EGF receptor antagonism is contraindicated, typically in RAS mutant tumors, you really need the RAS inhibitor. That combination is in principle something that can be pursued. Stay tuned. We'll talk about it when we're able to do so. The question about the first line, I forgot the tail end of the actual question part of it. It was.

Does it have an interim analysis built into it?

Oh, does it have an interim analysis? Wei, you wanna comment on that?

Well, I guess, at this current state, we don't plan to disclose the analysis plan.

Okay. There, you've heard it from our Chief Medical Officer.

Thank you. Thank you. Thank you.

Our next question comes from Laura Prendergast with Stifel. Laura, go ahead with your question.

Hey, guys. Thanks for the update. I was curious, you know, what are some of the top variables still under consideration, for daraxonrasib in first-line lung cancer as far as strategy goes? On the back of RASolute 302, you know, showing such a, you know, unprecedented OS, you know, what kind of pricing power are you guys thinking, you know, this could unlock? Are there any benchmarks for pricing that you guys are most focused on?

Yeah. Hi, Laura. Nice to hear from you. Don't think we can really comment on the pricing. You know, of course, the OS impact is something everybody's interested in, starting with patients and their families and all the way up to insurers and payers in other geographies. You know, it will be relevant to their considerations, but that's about all we could say about pricing today. Your question on first line non-small cell lung cancer, which was what?

What are the variables we're thinking through?

Oh, I see. With regard to daraxonrasib in first-line. We've alluded to it. You know, we commented that there are a couple of things going on. Probably one of the most important is that we're now dosing patients with ivonescimab, which may become, you know, we're all waiting to see how that progresses, but it points towards, you know, potentially becoming the new standard of care for first-line non-small cell lung cancer, in which case, that's something we need to take into account, which we hadn't really taken into account before we had the real relationship with Summit. That's now, you know, very much active and we're dosing patients. That's probably the main variable.

I think the other thing just conceptually to comment on is, the mutant selective inhibitors are already pretty well established simply because of the G12C inhibitors that launched the field. That's sort of a paradigm that lung cancer doctors are now used to thinking that G12C is its own disease, which means G12D will be its own disease and G12V will be its own disease. Pretty quickly, you've covered, you know, most of the mutations in RAS, RAS lung cancer. We happen to have a G12D selective inhibitor which is performing, you know, particularly well. We happen to have a G12C selective inhibitor, which is quite differentiated and compelling. We have a G12V selective inhibitor that's in the clinic now, and we expect good things from that.

There are multiple ways to cover that, and it is in a field in which it's already broken down by a genotype. That's one possible strategy. Those are kind of several of the major considerations.

Understood. Thank you very much.

Our next question comes from Jay Olson with Oppenheimer. Jay, go ahead with your question.

Oh, hey. Congrats on all the progress. Thanks for providing this update. How would you like to set expectations for the upcoming ASCO plenary presentation in terms of where you'd like investors to focus their attention? Thank you.

I think my main expectation is it's going to be crowded. I'm not sure really how to help you on that. I mean, we'll be providing a, I think through the investigators a, you know, a full update on it and, you know, the update will be consistent with what we've said so far, but provide, you know, significantly more information that the experts in the field need to see and evaluate in that, you know, in that setting.

Great. Thank you.

Our next question comes from Kelsey Goodwin with Piper Sandler. Kelsey, go ahead with your question.

Hey, thanks so much for taking my question. Congrats on all the progress recently. I think two quick ones from me. First, I guess any additional color that you're providing on the sales force. Secondly, I think building on one of your prior answers in this question answer session, I guess as we start to think about that front line to second line attrition rate once daraxonrasib comes onto the market, I guess, do you have a sense what percent of that 50% of patients that don't proceed to second line are unfit for therapy altogether versus, you know, ineligible or unwilling to take another chemotherapy just as we, you know, start to model that out a bit more refined? Thanks so much.

Yeah, thanks. Thanks, Kelsey. Anthony, you wanna just comment on the sort of sales organization more broadly?

Thanks for the question, Kelsey. I think for the U.S. region, we're in the final stages of building out our field-based teams all across different functions in the field, Medical Affairs, market access and sales. We've had an MSL team and a thought leader liaison team in place for quite some time. We also have a market access account team that's been in place, that's been engaging with payers and organized customers, you know, really around the unmet need in pancreas cancer, around the pipeline and the early clinical data for daraxonrasib through pre-approval information exchanges. We're really pleased to say that we're in the final stages of onboarding our U.S. sales force that we're pleased with the team.

They have deep expertise in solid tumors across GI malignancies and in oral oncology, and they'll be fully trained and ready to go with HCP engagements, if we were to receive an FDA approval.

Thanks Anthony. On the first line to second line, it's a good question. It's an important question. It's a little bit hard to get a detailed and clear understanding of because in reviewing records and so on, it's not always clear. In fact, it's surprisingly how common it is that it's not clear why somebody hasn't gone on to second line. You don't always identify an obvious performance status issue or concurrent illness or disease status that would prevent somebody from moving on, and therefore they might have decided not to proceed because of intolerability, or they might have decided not to proceed because of perceived intolerability before they tried it, or because they wanna focus their life at this stage on family and not on chemo infusions. There's a wide variety of reasons.

You know, sadly, it's also true that patients who start chemotherapy in first line sometimes don't survive to second line. You know, it's a pretty devastating illness as everybody knows. There are a lot of different reasons. Some of those could be addressed by a regimen that is more convenient, that is better tolerated. A once a day pill that really is generally well tolerated and safety issues are manageable, could for sure impact somebody's decision. We don't know whether or not it will. We'll only know that if we get to the finish line with an approval and see how patients do in that context.

Perfect. Thank you so much.

Our next question comes from Kalpit Patel of Wolfe Research. Kalpit, go ahead with your question.

Hey, thanks for taking our questions. Congrats on the trial ahead, moving. For RASolute 303, how should we think about that study's enrollment ramp versus the second-line study that you just completed in terms of timing of enrollment completion? Can you remind us if crossover is allowed in that RASolute 303 study? Separately, any comments on potentially starting a registrational trial with daraxonrasib and a PRMT5 inhibitor? Thank you.

Thanks very much for your questions. The timing of completion, we can't comment on that now. We're just not at a stage where we can project a timeline with any confidence. Maybe the even more important point would be we know there's very, very high interest in this and, you know, sites that have activated are enrolling, but there are plenty of sites that still are yet to be online, and there are patients, you know, lined up at many of these facilities. We're aware of that. We expect there to be very high demand for this for a variety of reasons, not the least of which is the disclosure of the 302, you know, key findings which elicits people to, you know, do it. Crossover.

Crossover is not allowed in the trial design. As you know, of course, it's up to any individual patient. They can cross over on their own if there is an approved therapy to cross over to. In terms of actual crossover design, we can't really provide it when OS is the standard, and that's the sort of conundrum of a phase III trial for which overall survival is the endpoint. You know, we're currently kind of in the process of transitioning from equipoise to out of equipoise. Where we stand in that is sort of, it's a matter of judgment, and it's really a question for the regulatory agency. They have to make that determination, as long as OS is required, it's very difficult to achieve that with a crossover design.

Do you wanna add to those points? No.

The only additional comments I would make, again, because of the concern for overall survival being a primary endpoint is we've established a broad geographic footprint in order to mitigate the potential for impact of second-line therapy with daraxonrasib moving forward. Smaller U.S. footprint, larger ex U.S. moving forward.

Right. good comment. The last thing was with regard to PRMT5. We don't have any update to provide on that today. You know, we're enthusiastically engaged in a collaboration with several companies now who are evaluating PRMT5 inhibitors in combination with RAS inhibitors, and we're keenly interested in how that work goes.

Thank you.

Our final question comes from the line of Alec Stranahan with Bank of America. Alec, go ahead with your question.

Hey, guys. Thanks for taking my questions and for squeezing me in here at the end. I guess, two from me. First, would be interested to hear from your experience whether the initial ORR with daraxonrasib was a good metric for predicting PFS and OS benefit in larger studies. Like, does a higher numerical ORR translate to better survival, or is duration of response or time on therapy maybe more telling for this? Just trying to think through some headline numbers we're seeing from others in the space. Quickly, will you be allowing third-line plus patients into the EAP as well? Thank you.

Thanks, Alec. On the last question, yes, the eligible population includes previously treated, and it goes beyond the pure second-line that are in the that were in the 302 trial. Is ORR predictive of PFS or OS? Who wants to comment on that?

Well, we've done some analysis on that. It's broadly correlative with PFS. ORR is broadly correlates with PFS. It's not such a tight stoichiometric relationship that you can actually say that if the ORR is 5 percentage points higher, that the PFS is gonna be 5 percentage points higher. It is broadly correlate. There are better ways of predicting PFS and in which involve multiparametric analyses that include ORR, but are not restricted to ORR. We have not made those broadly available to other people because obviously it's a competitive advantage for us to know that and not share it with our competitors. Definitely ORR is a component of that framework for sure. I think as we're learning more, and you're right, you know.

I mean, we're learning a lot more now that we have decent drugs for pancreatic cancer. We're learning a lot more about the relationship between all of these outcomes. I mean, in other diseases like lung cancer, breast cancer, and colorectal cancer, it took years and years and years to figure out these relationships, and they're still not totally clear. Yeah. I think that you will see relationships emerging, whether they're causal or otherwise, but I wouldn't draw too many straight lines.

Yeah. That's a, I'll pile on on that. There's obviously some relationship, what you can do with that and how you should interpret ORR data and have vision for what that's gonna translate into, premature.

Yeah. The other thing is, of course, with RAS inhibitors, the numerical value of ORR at any point in time isn't very accurate anyway. You know, patients can take up to, and sometimes beyond six months to fulfill the RECIST definition of response. At any given point in time, there may still be people who might become responders who have not yet become responders. The RECIST definition of response isn't a particularly robust endpoint in its own right. You know, there's a lot of wiggle room and uncertainty around all of these analyses. It's very tempting to believe that the overall response rate determined by RECIST is a pure and absolute and accurate measurement. I can tell you it absolutely is not.

If you look at those CT scans and try to compute the unidimensional measurements of the target lesions, then you'll realize just how fraught with uncertainty the whole thing is.

Alec, I'm glad you asked.

Very good. Thank you, guys.

Sorry, Alec. Really hard one.

This does conclude the question and answer session. I'd now like to turn it back to Mark Goldsmith for closing remarks.

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

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.