Revolution Medicines, Inc. Q3 FY2025 Earnings Call

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q3 2025 Earnings Conference Call. 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 to our third quarter 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; Dr. Wei Lin, our Chief Medical Officer; and Jack Anders, our Chief Financial Officer; Dr. Steve Kelsey, our President of Research and Development; Dr. Alan Sandler, our Chief Development Officer; and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call. I'd 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, 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 September 30, 2025, and recent corporate updates. The press release and updated corporate presentation are available on the Investors 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, and good afternoon. At Revolution Medicines, we are tireless in our commitment to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. With robust operational capabilities, financial strength, and three compelling clinical-stage RAS(ON) inhibitors, we are building the leading global RAS-targeted medicines franchise that we believe has the potential to transform treatment for patients living with pancreatic, lung, and colorectal cancers. In the quarter, we continued to make substantial progress as we scale the organization and advance our pipeline to fulfill our global development and commercialization ambitions. Today, we'll begin by highlighting recent progress across our pipeline, beginning with daraxonrasib in pancreatic cancer. I'd like to note that daraxonrasib has received three special designations from the FDA, recognizing its potential role in treating patients with pancreatic cancer, an aggressive disease that is nearly always caused by a RAS mutation. Previously, daraxonrasib was awarded breakthrough therapy status and recently, it received both Orphan Drug Designation and a Commissioner’s National Priority Voucher for accelerating review of a new drug application. These highlight the significant unmet medical needs in pancreatic cancer and the potential of this investigational drug to transform treatment for patients living with this devastating disease. I'd like to invite Dr. Wei Lin to walk through our most recent clinical updates in pancreatic cancer. Wei?

Thanks, Mark. Daraxonrasib is our RAS(ON) multi-selective inhibitor with a promising clinical profile in multiple indications, including pancreatic cancer. In September, we presented long-term follow-up data from the Phase I daraxonrasib monotherapy cohort of patients with second-line metastatic pancreatic cancer. These results reinforce our understanding of the strong clinical antitumor activity and durability. The acceptable safety and tolerability profile remained consistent with earlier findings, with no new safety signals observed. Slide 10 shows that with longer follow-up, durability outcomes remained encouraging. The estimated median progression-free survival for patients with both the RAS G12X and all RAS mutant groups exceeded eight months. The estimated median overall survival was 13.1 months and 15.6 months for patients in the G12X and RAS mutant groups, respectively, with a lower bound of 95% confidence interval at approximately 11 months. These results are particularly compelling, especially in the context of standard of care cytotoxic chemotherapy regimens that were reported in randomized controlled trials to provide a median overall survival of six to seven months in the second line and approximately 11 months in the first-line setting. RASolute 302, our Phase III registrational trial in patients with second-line metastatic PDAC is winding down enrollment globally as we near completion of enrollment across all U.S. and international sites. We remain on track for an expected data readout in 2026. In September, we also shared encouraging initial results for daraxonrasib in first-line metastatic pancreatic cancer, both as monotherapy and in combination with standard of care chemotherapy. As shown in Slide 11, daraxonrasib monotherapy induced tumor regressions in most patients with an objective response rate of 47% and disease control rate of 89%. The majority of patients remained on study treatment as of the data cutoff. While the data were not sufficiently mature to estimate the median progression-free survival or overall survival, we continue to follow these patients to assess the durability of clinical benefit. The acceptable safety profile of daraxonrasib monotherapy in the first-line metastatic setting was generally consistent with what has been reported in patients with second-line metastatic disease. On Slide 12, the combination of daraxonrasib plus gemcitabine nab-paclitaxel or GnP chemotherapy also delivered significant antitumor activity represented by deep and sustained tumor regressions with an objective response rate of 55% and disease control rate of 90%. Most patients remained on treatment as of the data cutoff. Again, longer follow-up is required to estimate median progression-free survival and overall survival. As with monotherapy, the combination regimen showed an acceptable safety profile. The rates of treatment-related adverse events were additive of the individual agents. No new safety signals were observed. We expect to share updated data from patients treated with daraxonrasib with or without GnP in first-line PDAC, including preliminary durability in the first half of 2026. Building on the encouraging early phase data in the first-line and second-line settings, we are advancing RASolute 303, a randomized three-arm Phase III trial in patients with first-line metastatic PDAC as shown on Slide 13. This registrational trial will compare daraxonrasib monotherapy or daraxonrasib plus GnP followed by daraxonrasib monotherapy to a comparator arm of GnP alone. The design of this three-arm study provides two distinct opportunities to demonstrate potential survival benefit for patients. Treatment with daraxonrasib as monotherapy in first line, followed eventually by chemotherapy in second line or alternatively treating concurrently with both daraxonrasib and chemotherapy in first line. Both strategies have scientific and clinical merit and deserve to be evaluated. We remain on track to initiate RASolute 303 this year. I'd like to provide an overview of the current standard of care in the setting of resectable PDAC. While surgery along with perioperative cytotoxic chemotherapy offers patients the possibility of a cure, the relapse rate is high at approximately 80%. The current standard of care for perioperative treatment is cytotoxic chemotherapy, either modified FOLFIRINOX or gemcitabine and capecitabine. The publicly reported disease-free survival rate on these chemotherapy regimens ranges from 13.9 months to 21.6 months. Our three-year disease-free survival ranges from approximately 20% to 40%. We believe there remains significant room for improvement that may be served with RAS-targeted therapy. The strength of the daraxonrasib monotherapy data so far in both first- and second-line metastatic disease provides a compelling rationale for advancing daraxonrasib into the adjuvant setting. And Slide 15 shows our Phase III trial design for RASolute 304 in perioperative therapy. We plan to evaluate approximately 500 patients after surgical resection and four months or more of perioperative therapy with the local standard of care, either FOLFIRINOX or gemcitabine, capecitabine administered before and/or after surgery. Patients will be randomized to either observation or daraxonrasib monotherapy 300 milligrams daily for two years. The primary endpoint will be disease-free survival with secondary endpoints of overall survival and safety. We have initiated this trial and site activation is currently underway. I'll also touch briefly on zoldonrasib, our covalent RAS(ON) G12D-selective inhibitor in pancreatic cancer. Zoldonrasib has demonstrated compelling clinical profiles with encouraging antitumor activity and a particularly favorable safety tolerability profile. With this differentiated profile, we believe zoldonrasib has high potential to contribute as a key component of a combination therapy in first-line PDAC with current standard of care chemotherapy and/or with daraxonrasib as a RAS(ON) inhibitor doublet. The potential for this doublet was featured at last month's triple meeting, where new preclinical data demonstrated that the combination of zoldonrasib with daraxonrasib can maximally inhibit RAS G12D and improve both the depth and durability of response. We expect to initiate our first zoldonrasib combination registrational trial in first-line metastatic PDAC in the first half of 2026. We look forward to share the detailed insights and additional supporting data around that time frame. I'll now return the call to our CEO, Mark.

Thank you, Wei. Following closely behind pancreatic cancer, our non-small cell lung cancer clinical program remains an area of strategic priority, and we are progressing well in our efforts. Focusing first on daraxonrasib, the RASolve 301 registrational trial studying daraxonrasib versus docetaxel in previously treated patients with RAS-mutant non-small cell lung cancer continues to enroll patients across sites in the U.S. and is now also enrolling in Europe and Japan. We also continue advancing plans to initiate a registrational trial in the first-line metastatic setting in 2026 evaluating daraxonrasib in combination with pembrolizumab and chemotherapy, and we expect to disclose study details around the time of initiation. As a reminder, this plan was based on the encouraging initial data we presented in May showing the combination of daraxonrasib with pembrolizumab with or without chemotherapy was well tolerated and demonstrated encouraging early antitumor activity. In the G12C non-small cell lung cancer space, we continue to make progress with elironrasib, our RAS(ON) G12C inhibitor. Last month, at the Triple Meeting, we presented encouraging monotherapy data in heavily pretreated patients with G12C non-small cell lung cancer who had received a median of three prior lines of therapy, including treatment with a G12C(OFF) inhibitor. As shown on Slide 22, elironrasib demonstrated a confirmed objective response rate of 42%, a disease control rate of 79%, and a median duration of response of 11.2 months. On Slide 23, the median progression-free survival was 6.2 months in these heavily pretreated patients. While the median overall survival had not yet been reached, 62% of patients were alive at 12 months. We are encouraged by the strength of these data in late-line KRAS G12C(OFF) inhibitor experienced patients and continue to expand enrollment in this and other elironrasib monotherapy and combination studies while exploring a number of options for continued development of this differentiated RAS(ON) G12C selective inhibitor. Regarding zoldonrasib in lung cancer, we are evaluating a Phase I monotherapy expansion cohort of patients with previously treated non-small cell lung cancer as well as exploring combination regimens, including zoldonrasib with pembrolizumab and zoldonrasib with daraxonrasib. In addition to plans mentioned earlier to initiate a registrational trial for a zoldonrasib combination in patients with first-line metastatic pancreatic cancer in the first half of 2026, we expect to initiate one or more additional pivotal combination trials in 2026 that incorporate either zoldonrasib or elironrasib. We also continue to advance RMC-5127, an oral tri-complex RAS(ON) G12V-selective inhibitor. As a reminder, approximately 48,000 patients are diagnosed with the KRAS G12V mutant cancer in the U.S. each year, including non-small cell lung cancer and gastrointestinal cancers, such as pancreatic and colorectal. RMC-5127 has been shown to induce deep and durable regressions in preclinical models, and it has been advancing toward clinical development. We are on track to initiate the planned first-in-human trial in Q1 2026. Based on the progress we've made across our three clinical stage assets, we are confident in the potential of our RAS(ON) inhibitor portfolio to change the standards of care across pancreatic, lung, and colorectal cancers. We also have several discovery and clinical collaborations designed to expand the range of treatment strategies we can bring to bear for patients with RAS-addicted cancers. These collaborations enable us to explore diverse combinations of our RAS(ON) inhibitors with inhibitors of novel disease targets, including vopimetostat, a PRMT5 inhibitor under our agreement with Tango Therapeutics and ivonescimab, a bispecific PD-1/VEGF inhibitor, under an agreement with Summit Therapeutics. With our rich promising clinical and preclinical pipeline, we continue making investments to scale our organization to meet the extraordinary range of opportunities it affords. In support of this work, we've made new key appointments across late-stage functions. In our R&D organization, we announced that Dr. Alan Sandler joined RevMed as our new Chief Development Officer. As an accomplished leader in oncology with a strong track record in cancer drug development, Alan brings valuable insights and expertise to our organization. We likewise expanded and strengthened our global and regional commercialization capabilities with additional appointments across our commercialization functions, including two key regional leaders. Alicia Gardner was appointed Senior Vice President and General Manager of the U.S. region, and Gerwin Winter recently joined RevMed as Senior Vice President and General Manager of the European region. I'd now like to turn the call over to Jack Anders to summarize our third quarter financial results.

Thanks, Mark. We ended the third quarter of 2025 with $1.93 billion in cash and investments. This balance includes the receipt of the first royalty monetization tranche of $250 million in June 2025 from our partnership with Royalty Pharma, and there remains an additional $1.75 billion in future committed capital under this arrangement. Turning to expenses. R&D expenses for the third quarter of 2025 were $262.5 million compared to $151.8 million for the third 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 ongoing Phase III trials. Personnel-related expenses and stock-based compensation expense also increased in 2025 due to additional headcount. G&A expenses for the third quarter of 2025 were $52.8 million compared to $24.0 million for the third quarter of 2024. The increase in G&A expenses was primarily due to increases in personnel-related expenses and stock-based compensation expense associated with additional headcount, increased commercial preparation activities, and increased legal expenses. Net loss for the third quarter of 2025 was $305.2 million compared to $156.3 million for the third quarter of 2024. The increase in net loss was primarily driven by higher operating expenses. We are reiterating our 2025 financial guidance and expect projected full year 2025 GAAP net loss to be between $1.03 billion and $1.09 billion, which includes estimated noncash stock-based compensation expense between $115 million and $130 million. That concludes the financial update. I will now turn the call back over to Mark.

Thank you, Jack. We are highly encouraged by continuing momentum as we seek to build the leading global targeted medicines franchise for patients living with RAS-addicted cancers. We believe our strong financial position, expansive development plans for our compelling pipeline assets, and global commercialization ambitions will allow us to establish new global standards of care. We've made great progress across our pancreatic and lung cancer clinical programs and continue to generate encouraging data that informs our plans in colorectal cancer. Underpinning the passion and drive at RevMed is our collective commitment to patients. November is recognized globally as both Pancreatic Cancer Awareness Month and Lung Cancer Awareness Month, which align with two highly visible cornerstones of the clinical development efforts by our organization. We have expanded our partnerships with the advocacy community to better understand the dynamics that affect the patient's experience with RAS-driven cancers. Insights from these engagements will continue supporting our development of patient-friendly clinical protocols, access solutions, and educational initiatives. We hope you will join us in supporting the high-impact work by advocacy organizations as they seek to improve outcomes for patients through educational resources, support, and research. Before closing, I'd like to acknowledge the continued support of our patients and caregivers, clinical investigators, scientific and business collaborators, advisers, shareholders, and importantly, the remarkable team of revolutionaries who drive exciting steps forward on behalf of patients. This concludes our prepared remarks, and I'll now turn the call over to the operator for the Q&A session.

Our first question comes from Jonathan Chang of Leerink Partners.

How are you thinking about the impact of receiving the Commissioner's National Priority Voucher on daraxonrasib time lines and your plans?

Jonathan, thanks for your question. Well, obviously, we're very proud to have received one of the first nine vouchers. Actually, it's the only oncology product that's featured in that particular set. The stated goal of that voucher program, the pilot program is to accelerate the review time lines by some significant amount and potentially making the review time line as short as one to two months, and we'll do everything we can to support that. But we've been aggressively preparing for the data readout and then an expected submission of an NDA and to be ready at the earliest possible time for launching a product. I don't think at this point in time, we anticipate that we would have any difficulty meeting whatever time line might be delivered under the CMDB process.

Our next question comes from the line of Charles Zhu of LifeSci Capital.

Congrats on the progress. I have a couple of questions about RASolute 304, the daraxonrasib trial. This might be a bit naive, but could you help us understand the decision to randomize against observation in the post-perioperative chemotherapy setting? Is there clinical value in evaluating whether chemotherapy could be displaced in this particular disease setting as well? Also, could you explain the requirement for at least four months of perioperative chemotherapy as an eligibility criterion before randomizing between the two arms?

Thanks a lot, Charles, for your question. I think Dr. Sandler would be happy to comment on the rest of the RASolute 304 trial.

Thank you for your question. I believe it was a three-part inquiry, and I'll try to address all aspects. To start, the four months of therapy we require aligns with the established standard of care. We want to ensure that patients undergo at least this duration of therapy. Next, we plan to randomize patients either to no further treatment or to two years of additional adjuvant therapy with daraxonrasib, aiming to build on the modest successes observed with chemotherapy in this context. I believe this represents the best approach for patients with resectable pancreatic cancer. As for your last question regarding the potential to replace chemotherapy, we will reassess our strategy based on the adjuvant study results. We are genuinely excited about this opportunity and look forward to launching the trial.

Congrats on all the progress.

Our next question comes from the line of Michael Schmidt of Guggenheim.

And congrats on all the progress. A couple of questions on PDAC. So as we think about RASolute 302, how would you expect results from the Phase II study to translate to the large global Phase III study? Are there any anticipated differences, for example, in patient characteristics when you go from a smaller Phase II to a large global study? And secondly, I guess, in anticipation of positive data next year, how are you tracking towards commercial readiness in terms of CMC manufacturing capacity and then ramping up commercial infrastructure?

Thanks, Michael. Appreciate the questions. Maybe Dr. Lin can first comment on the Phase III versus Phase I/II question.

Yes, I'm glad to address that. Thank you for the question. It's definitely an important topic that we carefully considered before starting Phase III. We conducted a thorough comparison of the patients in the Phase I cohort with those in the historically reported Phase III randomized studies. Our patient populations appear quite similar when examining the baseline characteristics that may indicate responses to chemotherapy or our treatment. Most metrics are comparable, and in some instances, the historical Phase IIIs even showed slightly poorer characteristics. This suggests that the Phase I population is representative of what we expect for the Phase III study. Additionally, while the RASolute 302 study is global, the majority of enrollment will take place in the U.S., along with significant representation from Europe and Japan. This further reinforces our confidence that the Phase I population will be similar to that in Phase III. Historically, we have consistently seen Phase III trials delivering similar results with chemotherapy over the past decade or two. We anticipate that the control arm will perform similarly to historical data. All these factors provide us with considerable confidence in our ability to replicate findings due to the comparability of both the patient population and the historical treatment performance.

Regarding commercial readiness, I'll comment on part of it and then Anthony Mancini can address the other part. In terms of manufacturing, we have a robust organization and supply chain that has been developed over the past several years. We are already scaling appropriately to support any level of demand if we are able to launch a product. Therefore, I believe we are in a strong position and do not foresee any significant challenges. For further details on commercialization readiness, I'll let Anthony share his insights.

Yes. Thanks, Mark, and thanks, Michael, for the question. We're really pleased with how our launch readiness plans are advancing. We've as was outlined earlier, we now have experienced and talented executives leading our commercialization team, including now building into the region, so across multiple functions, including medical affairs, market access, marketing, and sales. And we're deeply engaged in market-shaping activities and planning and KOL and advocacy organization engagement and building broader organizational capabilities around launch readiness. We continue to add highly experienced and talented team members as we advance our organizational launch readiness, including U.S. field-based teams, and we're making great progress there. And we're confident in our ability to continue to attract the right talent with the right experience and capabilities, which is a key success factor for a successful launch, and we're confident that we can do that.

Our next question comes from the line of Andrea Newkirk of Goldman Sachs.

This is Morgan on for Andrea. Based on the initial frontline metastatic PDAC data, how do you think about the efficacy of combination treatment relative to monotherapy, whether greater time on treatment could increase the delta on ORR and DCR? And then with regard to updated daraxonrasib monotherapy and combination data in the first half of next year in frontline metastatic PDAC, how should we be thinking about durability?

Thanks for the question, Morgan. Would you like to comment on those? The first question is about the level of difference between monotherapy and combination treatment. Will that become clearer over time?

Yes. So the monotherapy versus combination in frontline, I think as we discussed previously, really test two very distinct hypotheses. I think one is really the sequential treatment by introducing additional line of therapy because currently standard of care, only two lines of therapy exist for patients, a gem-based and a 5FU based. And by using daraxonrasib monotherapy, we introduced the third line of therapy. And could that introduction of third-line therapy with very promising data in the second-line setting translate to prolongation of overall survival. And then the other chemo combination arm really tests a very distinct hypothesis, which is a potential synergy by combining the two. Those patients still get two lines of therapy, but then the first-line therapy is actually a combination regimen of standard of care chemotherapy potentially extending the progression survival and can also translate to longer overall survival. So I think these hopefully will translate into surviving benefit as well as different options for patients who can tolerate a more potent regimen versus who are seeking better quality of life and that provides by monotherapy.

And just to add that there's really no way to answer the question about how those two regimens compare except to test them both. Both are very credible based on a strong scientific hypothesis. The second question was about what sort of update can be expected next year regarding the durability of the effects we have already reported. We intend to provide an update in the first half of 2026.

Our next question comes from the line of Brian Cheng of JPMorgan.

Just first on your Voucher. What additional pieces of information have you learned on the use of it since you received it mid-October? Specifically, do we know which line of setting the Voucher is for since the language on the press release seems to be more broadly applicable to PDAC? And then we have a follow-up.

Yes. Thanks for your question, Brian. We don't really have any additional information to share with you today. We are certainly in ongoing dialogue with the FDA and learning more about how this voucher system will work and what impact it might have on how we approach preparing an NDA, but no other comments are available today.

Okay. And then just quickly on zoldon's combo Phase III in frontline PDAC. Now that you have 303 on track to start later this year, I'm just curious if you can talk a little bit about just some consideration that you currently have when it comes to the selection of the doublet versus triplet. And I think also the active comparator piece. How should we think about which active comparator arm you should put in to make sure that physicians understand how they look at zoldon combo in the future?

Yes, that's a great question, and it perfectly tees up when we present some information about that, we'll be able to address all of those questions. But I assure you we will comment on all of that. Maybe the big picture right now is just that we are taking multiple approaches to treating this devastating disease. And we're in the second or third inning of this battle, and we're going to keep investing in it until we've really moved the needle as much as we possibly can. So we're excited to bring that approach forward, and we'll give you more color about it when we are able to lay that out much more explicitly.

Our next question comes from the line of Marc Frahm from TD Cowen.

On all the progress. Maybe just start on that zoldonrasib first-line trial. Just the idea of only pursuing combinations, I guess, should we read into that the monotherapy maybe doesn't seem as durable as daraxonrasib as a monotherapy since you were interested in pushing forward the monotherapy in first line in that setting? And then I'll likely have a follow-up.

Thanks, Marc. I'm not sure about that last comment. I'm not sure that we ever gave any inclination with regard to zoldonrasib in first line and what sort of strategies we might pursue. So I don't think we need to explain something that I don't think we ever committed to. Daraxonrasib alone, we're studying in first line as monotherapy. We're going to learn a lot from that study. And zoldonrasib is an ideal combination agent because of its pretty remarkable safety and tolerability profile. So it is a real opportunity to see how far we can push things. And in terms of further differentiating options for patients, we will certainly continue to be committed to that. So I don't think you should infer anything from that decision and that strategy other than we're looking for the best possible ways to deliver impact for patients that would complement the other options that are coming out of our portfolio.

Okay. That's helpful. And then on 302, now that you're getting pretty close to the end of enrollment, you can maybe speak to kind of how the event rate has been trending maybe relative to kind of how you guys were projecting it when you designed the trial? And then as the interim start to get taken, just what's the latest thoughts on disclosure strategy? Will you inform investors whenever an interim is taken, whatever the result of that was or likely only speak if the interim results in some sort of stoppage of the trial?

Unfortunately, Marc, I think you're over for two of those questions, anything to comment on either of those at this time.

Our next question comes from the line of Leonid Timashev of RBC.

Just wanted to ask on sort of the commercial opportunity. I mean, given that you recently hired President of EU strategy, just how you're thinking about the landscape in the European Union with respect to where patients lie in terms of the commercial opportunity, the concentration there, awareness and diagnostic opportunities. Just anything you can speak to how you think the European strategy might take shape.

Thank you. Appreciate the question. It's a gigantic question. So I'm immediately going to ask Anthony to address that.

There has been considerable thought about how we plan to deliver daraxonrasib to patients. This opportunity differs from many companies launching a treatment for the first time in its initial indication. We believe that the second-line pancreatic cancer indication is significant. You can observe the key European markets, starting with Germany and the EU4, where there are many patients who need treatment. We believe we will offer a compelling value proposition in Europe, and it represents a meaningful opportunity both in Europe and in the U.S. and Japan. We are actively pursuing this. Our priority markets are clear, and we aim to make a strong effort in those areas.

Our next question comes from the line of Clara Dong of Jefferies.

This is Jenna on for Clara. Could you talk about if there were any rationale behind starting the adjuvant study before the first-line study?

Jenna, thanks for your question. That's pretty straightforward. There's nothing profound underneath it. It's a simpler study. Obviously, it's a single treatment arm, and we're just able to get that up and running a little bit earlier, but I don't think it will materially differ in terms of the overall conduct of it. Of course, that is going to be a longer study in terms of the readout given the timelines that we talked about. So it doesn't make much difference, and it just happened that we were able to proceed with it.

Our next question comes from the line of Asthika Goonewardene of Truist Securities.

So you described what resistance mechanisms emerge with daraxonrasib in PDAC. And you should have a considerable amount of data with daraxonrasib in non-small cell lung cancer, too under hood. So I'm just wondering, do you expect non-small cell lung cancer to also follow a similar path of resistance as PDAC? Or are there any new resistance mechanisms that are emerging that you can tell us about? I'm wondering how this guided your choice of selecting pembrolizumab and chemo for the combination versus just a chemo-sparing pembrolizumab combo? And then I have a follow-up.

Thanks for your question. That's sort of a subtle comment at the end of that question. Maybe Dr. Kelsey can discuss resistance, what we know about PDAC expectations across other tumor types and how has that affected our thinking for trials?

The data we have regarding new resistance mechanisms to daraxonrasib in non-small cell lung cancer is likely not ready for public release at this time due to several complicating factors. First, we established our recommended Phase II dose for non-small cell lung cancer after doing so for pancreatic cancer, meaning the relevant information is tied to the Phase II dose recommendations. Secondly, we need more data on the actual number of patients who have documented progression. Thirdly, we need to consider how many of these patients have detectable circulating tumor DNA to evaluate any findings. Additionally, literature suggests that non-small cell lung cancer has various resistance mechanisms that may not even be genomic. Therefore, understanding these will take more time. The mechanisms of resistance seen in pancreatic cancer may not necessarily translate to non-small cell lung cancer. For example, biological resistance mechanisms in colorectal cancer to G12C inhibitors differ from those in non-small cell lung cancer, even though there might be some overlap. At this point, it is too early to draw conclusions. Regarding how this information will impact our approach to combinations, it won’t have an immediate effect. The decision to select pembrolizumab as a partner for our RAS(ON) inhibitors is based on two key factors: the widespread use of pembrolizumab or similar checkpoint inhibitors in the standard treatment of non-small cell lung cancer, and the strong evidence suggesting that suppressing RAS enhances the effectiveness of pembrolizumab by significantly altering the tumor's immune microenvironment, facilitating better immune access to the tumor as supported by our research and that of others. Once we gather the necessary data, we will share it, and while it may influence our future actions, it may also not have any bearing. These are two distinct topics.

And then if I can just tag on to Charles' previous question. By requiring in the 304 study, by requiring patients to have four months of chemotherapy, does this help select out patients who are deemed to be borderline resectable?

Yes, I'll take that. First, the purpose was the four months of standard care. The question regarding borderline and readily resectable patients is that we allow those patients to undergo the standard treatment they would receive locally, regardless of whether they are surgically resectable. The only way they can enter the study is if they are pathologically completely resected, with either totally clear or narrow margins, classified as R0 or R1 as shown on the slide. Those patients are then randomized to the treatment. This approach eliminates patients who cannot be resected while providing those with borderline resectable conditions the chance to receive adjuvant therapy if their perioperative therapy and surgery are successful. It thereby increases the number of patients who can access this therapy and participate in the study.

I'd also add one point about the question of why four months. There is a variety of different approaches that people take in treating that disease. They all center around using chemotherapy before, after, or both before and after and by requiring a standardized duration of treatment, we can make the patient population more uniform and easier to compare the two groups to each other and avoid imbalances in their treatment regimen.

Our next question comes from the line of Alec Stranahan of Bank of America.

And congrats on the update. Two from us. First on zoldonrasib. Curious how you're thinking about the opportunity for zoldon on top of chemo versus daraxonrasib plus chemo and RASolute 303. Do you plan to enroll similar patients in both studies or maybe try to subset the frontline opportunity? And secondly, how important is the RAS doublet in terms of your ideal commercial strategy longer term, specifically thinking about zoldonrasib to daraxonrasib in the frontline PDAC?

I can comment on the second question and then Wei can address your first question. Regarding the RAS(ON) inhibitor doublets, we remain confident in this approach. We recently presented data on zoldonrasib combined with daraxonrasib in preclinical models at the Triple Meeting last month, and we believe it is a strong option. Please stay tuned for the upcoming studies we will be launching, as we are very interested in this. The first question was about zoldon versus daraxon in a first-line population and whether we are selecting patients differently between the two. One involves all RAS mutations while the other focuses solely on KRAS G12D mutations, so there is that distinction, but are there any additional differences, Wei?

Clinically, the eligibility otherwise are no different. And I think in the Phase I setting, when we're doing the combination with chemotherapy, the eligibility is really mainly designed to make adequate organ function allow to deliver chemotherapy. So they're actually also very, very similar.

Our next question comes from the line of Joe Catanzaro of Mizuho.

Just maybe one quick one from me. As it relates to CRC, just wondering if there are any sort of key data points you are looking towards before maybe committing to earlier line, later-stage trials and whether we should expect any of those data points in 2026?

Thanks for your question. Thanks for joining us. Steve, do you want to comment on CRC?

Yes, I can do that. I won't comment on timing since we haven't provided guidance on data disclosure related to colorectal cancer. However, we have previously indicated that because of the biological complexity of RAS mutant colorectal cancer, we believe that combination therapy is essential for maximizing clinical benefit. The studies aimed at determining the most effective combinations in this context are currently in progress. Once we have that information, we can establish a plan going forward. It's important to remember that there are several facets to this issue. You mentioned one, which is the line of therapy—whether we should aim for the first-line metastatic setting or focus on patients in the third and fourth lines who are being treated after previous chemotherapies have failed. There are various biologically sound combinations to explore, including those within our own RAS(ON) doublets portfolio. We need the opportunity to work through these complexities, as colorectal cancer is a very intricate disease. It's not entirely clear that RAS is the sole oncogenic driver, even in cases where it is mutated. We will sort it out.

Our next question comes from the line of Sean McCutcheon of Raymond James.

This is Yang on for Sean. We have two quick ones. The first one regarding the first-line NSCLC with daraxonrasib. What kind of a threshold for efficacy by you looking at anticipating that you have the update for the frontline and also commenting on the daraxonrasib and elironrasib combination in the first-line NSCLC?

Thanks for your questions. Let me make sure I understand. The first question had to do with an update on first-line PDAC with daraxonrasib...

No, no. Sorry. Yes, that's all non-small cell lung cancer, frontline daraxonrasib, what's the threshold efficacy bar you're looking at?

Okay. So in lung cancer, since we indicated that we'll proceed with a trial, and we'll provide information later. Yes, I mean, obviously, we look at standards of care and what we see in a single-arm trial versus standards of care, even though they're not immediately comparable since it's not randomized data, but we'll look at standard of care and see if we can improve upon that. We typically wouldn't provide guidance as to what we consider an acceptable improvement. That's something that's a complicated topic, and that's between us and the statistical analysis plan and the FDA and so on. So no pre-guidance that we'll be able to offer you today on that. And your second question?

Yes. The second question is related to the combination potential with your pan-RAS and G12C elironrasib in first-line NSCLC.

Okay. That's back to the RAS(ON) inhibitor doublet, specifically the combination of elironrasib and daraxonrasib. This combination is quite intriguing. I want to emphasize that we believe using a mutant selective inhibitor alongside the RAS multi-inhibitor can harness the advantages of both compounds, working together to create a significant impact. We have now demonstrated this with two clinical data sets, one focused on colorectal cancer and the other on lung cancer, both showing similar trends. Regarding how we prioritize this compared to other options, it's a complex situation, and I don’t have specific guidance to provide you with today.

Our next question comes from the line of Laura Prendergast of Stifel.

Congratulations on the quarter. I was wondering if there could be any kind of accelerated approval pathway for first-line PDAC, such as an early cut from the Phase III study or anything else. Additionally, how are you incorporating the approval of daraxonrasib in second line when considering the overall survival statistics for the first-line study?

Okay, Laura, thank you for your questions. I'll address the question about accelerated approval and then Wei can discuss daraxonrasib. Regarding accelerated approval, that’s primarily a matter for the FDA and not something we can comment on. The initial data we've presented are quite positive, and I'm sure many view them that way. However, how the FDA interprets this data and their next steps will require further discussions. Generally speaking, we have consistently focused on full approval strategies, which has been beneficial for us with PDAC so far. We're not at the final destination yet, but this approach seems to be effective, and we will continue to prioritize it. There might be cases where an accelerated approval is appropriate to deliver treatments to patients sooner, and if both we and the FDA find it sensible, we would be open to that possibility.

Yes. Regarding the design and statistics of the frontline given our second-line efforts and data, I think probably there are several layers to maybe that question. So on the first layer is, we're still designing a fully powered randomized trial to enable registration based on overall survival. And from that regard, it doesn't really impact the fact that we deliver on overall survival. We still intend to deliver overall survival in front line, even after overall survival in second line. I think the second line data that we have reviewed so far, I think, give us further confidence about the monotherapy benefit and therefore, give us confidence about the arm with monotherapy as well as the combination. Therefore, we're actually fully evaluating and fully powering both arms independent testing them. So that does affect in that sense. That's the second layer. The third layer is, I think you may be hinting at a question we addressed previously, which is with the second approval in the U.S., there may be an impact on crossover and whether that will impact our design. It doesn't really impact our design per se. It only impacts our operational footprint. I think we'll certainly assign the sites more on ex-U.S. to minimize the impact of crossover due to the availability of daraxonrasib for second patients in the U.S.

Our next question comes from the line of Ami Fadia of Needham.

And apologies if this has been asked already. I've been juggling some calls here. So my question is regarding the acquired alterations post-dara monotherapy that was presented at the Triple Meeting. How do you see that potentially impacting the durability of response in first line? And where you're studying in combination with chemo, would you consider exploring combinations with other mechanisms at this stage?

Thanks, Ami. I'm trying to get to the gist of that question. Would we consider combining daraxonrasib with other compounds that target other potential drivers that are resistance mechanisms? In order to increase...

That's right.

Sure. We're already considering and actively exploring various options and may expand those efforts. There are numerous potential targets that could affect the outcome if inhibited. We continuously assess these opportunities, have significant operations dedicated to this study, and receive many requests for combinations. We prioritize them based on the scientific evidence available, and we will definitely continue this approach.

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

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

This does conclude the program. You may now disconnect.