Revolution Medicines, Inc. Q1 FY2026 Earnings Call

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q1 2026 Earnings Call. Please be advised that today's conference is being recorded. I would now like to hand it over to Ryan Asay, Senior Vice President 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 reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31, 2026, 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. 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 topline 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. 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 then 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 topline readout for daraxonrasib marked a major milestone in this disease, significantly raising the bar for 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 the risk of death compared with chemotherapy 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 Review Program, and we'll 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 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 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 investigators' 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 for RAS(ON) development, approximately 30% of non-small cell lung cancers harbor 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% and the median had not yet been reached, which is encouraging 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 to the inactive GDP-bound RAS-OFF state, thereby mimicking the normal physiologic regulation of wild-type RAS. 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 regressions. 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.

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, positioning 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 McGregor 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 31, 2026, compared to $25.1 million for the quarter ended March 31, 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 nonrecurring 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 the 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 a 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, health care providers and investors as well as the remarkable dedication and efforts of Rev Med 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.

Our first question comes from the line of Cory Kasimov with Evercore ISI.

Congrats on all the recent very exciting progress. I 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 chemotherapy. Would that include durability data or just response rate as we've seen with some of your initial disclosures? And more importantly, how much additive efficacy would you be looking for here to say it's clinically meaningful to justify the combination over the exciting monotherapy results we've seen with both of these agents?

Thanks, Cory. I 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. We'll show what we have. We think it will justify our plans, and we'll provide that in due course. As for the second question about the threshold for added value that justifies the combination, we look at the totality of the evidence and historical benchmarks. Ultimately, durability is the most important parameter.

Our next question comes from Charles Zhu with LifeSci Capital.

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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 queued up. Our next call comes from Michael Schmidt with Guggenheim Securities.

Again, congrats on RASolute 302 data, looking forward to the full data presentation at ASCO. A question on the EAP program: I know this was just announced a few days ago, but Mark, could you comment on what you're seeing so far in terms of demand for the EAP program? And how many patients could particularly benefit from this prior to official FDA approval? Also, could you 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 daraxonrasib based on the 302 study?

Thanks, Michael. We're working hard to be in a position to provide drug to those who need it. Demand has been very clear from the moment it was announced, and we don't expect that to slow down anytime soon. We're putting all available resources into meeting that need. I can't give you a precise projection as to the number; we'll have to play it out. There is clearly widespread awareness of daraxonrasib and inquiries started coming in within minutes after the announcement. Regarding the size of the second-line opportunity, Wei might want to comment on the clinical estimates; we typically think about roughly 60,000 new cases each year, and then Wei can comment on historical attrition and whether daraxonrasib might affect that.

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

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

Our next question comes from Faisal Khurshid with Jefferies.

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?

Thanks for the question. I'll answer the timing question and Alan will address the sizing. We don't think the upsizing will change the timing of the readout given the high pace of enrollment and where we stand today. We don't expect it to impact our projection that we'll substantially complete enrollment this year. Alan?

An important point is we've realized the importance of overall survival, and given the results that we've seen in 302 and the Phase I monotherapy data, we have high conviction in our ability to obtain an overall survival benefit. As a result, we're prioritizing overall survival in 301 by expanding enrollment from 420 to 590 patients. That will increase the statistical power of that component of the dual primary endpoint. As Mark mentioned, enrollment is progressing at a great pace, and we believe we will substantially complete enrollment in the expanded study this year.

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

Mark, you said best-case timing scenario for daraxon at launch across the globe. How should we think about the timing and cadence for filings and launches specifically across APAC and European regions? And for the NDA application to the FDA, can you give more color on what's left to complete?

Thanks, Brian. I can't give specific timing for filings outside the United States. We're starting with the U.S. filing as the initial priority. There will be a sequential framework for filing in other countries, and we're already engaged with regulatory authorities outside the U.S. to ensure we can deliver what they need as timely as possible. Regarding what remains for the NDA: we've been fully engaged with the FDA for a long time. With the Commissioner's National Priority Review designation and our interactions, we've had a high level of engagement. We are providing the FDA information as it becomes mature enough to share. Ultimately, the clinical package will be provided. We can't give a specific timing, but we are proceeding at full throttle and feel the urgency around this, as signaled by the EAP activity.

Our next question comes from Marc Frahm with TD Cowen.

Following up on Cory's earlier question about the zoldonrasib plus daraxonrasib combo: can you speak to the RASolute 309 design, particularly in light of the 302 findings and the survival data? Given the strong monotherapy results, is comparing to chemo the right design, or should the comparator be daraxonrasib monotherapy at a minimum to get contribution of parts and better reflect where the field is headed in pancreatic cancer?

Good question. Currently, chemotherapy is the standard of care, and until a different treatment is approved and becomes accepted as the new standard, chemotherapy remains the appropriate comparator. We believe daraxonrasib has real potential both as monotherapy and in combinations in first line. Among combinations, chemotherapy is one we've provided early-stage data on and are excited about; that combination is being evaluated in the 303 trial. We recognize that multiple overlapping approaches may serve different patients, and providing a broad set of options based on science and clinical data increases the chance we deliver the best options for patients.

Our next question comes from Jonathan Chang with Leerink Partners.

Congrats on the progress. Can you talk about your latest thinking on achieving a chemo-free option in frontline pancreatic cancer? What gives you confidence in achieving this, and what do you think is the best strategy?

Thanks, Jonathan. One strategy is monotherapy daraxonrasib; the single-arm data we've shown justify incorporating that into a Phase III first-line trial, and we expect it could deliver a chemo-free regimen. Another option is combining a mutant-selective inhibitor with daraxonrasib, which would also be chemo-free. The zoldonrasib plus daraxonrasib combination targets the roughly 40% of pancreatic cancers with a RAS G12D mutation. We have other mutant-selective inhibitors directed at other common mutations and could fill out a portfolio of chemo-free regimens. There are also possibilities combining RAS inhibitors with immunologic agents or other targeted agents such as PRMT5 inhibitors; we are exploring some of those combinations.

Our next question comes from Charles Zhou with LifeSci Capital.

RM-055: nice to see your presentation at AACR as well as the work you helped support over at a collaborating lab that was just published yesterday. Can you comment on RM-055's ability to potentially address daraxonrasib's resistance mechanisms that go beyond KRAS amplification? Also, can you discuss how you might be achieving what appears to be, at least preclinically, a wider therapeutic window for mutant RAS over RAS wild type compared with direct daraxonrasib? Any color on the underlying mechanism and how that appears in preclinical models as you advance into the clinic?

Thanks, Charles. Steve Kelsey will comment on both those topics.

Sure. RAS amplification can act as a stand-alone mechanism of escape from daraxonrasib, but it also serves as a surrogate for increased flux through the RAS pathway generally. In many of our experiments, RM-055 is a better inhibitor when there is increased flux through the RAS pathway, particularly with G12 mutations. So there is a general principle that escape from daraxonrasib can occur through reactivation of RAS pathway signaling, not just allele amplification, and RM-055 may be effective beyond pure amplification. Regarding therapeutic index, it relates to the relative importance of hydrolysis of RAS(ON) back to RAS-OFF between cancer and normal tissue. In normal tissue, most RAS is already in the off state and is efficiently hydrolyzed by physiological GTPase-activating proteins. Mutant RAS in cancer resists that catalytic hydrolysis. RM-055 is designed to selectively promote hydrolysis of mutant G12 RAS back to the off state. It has negligible effect on normal tissue RAS and drives significant deactivation of mutant RAS in cancer cells. That is reflected in our preclinical models, where RM-055 showed robust, durable antitumor activity and activity in tumors that escaped prior RAS inhibitor treatment.

Next question comes from the line of Michael Yee with UBS.

Congrats on the progress. Two questions: on colorectal cancer data coming up, how should we think about combinations with EGFR given overlapping rash? How should we think about mitigation or interpretation of results given higher efficacy but greater skin toxicity? And in the first-line pancreatic study that is enrolling quickly, is it safe to assume there will be an interim analysis once enrollment is complete?

Thanks, Michael. On CRC, daraxonrasib itself overlaps mechanistically with EGFR antagonists because both suppress RAS signaling that drives skin toxicity, so that combination can be harder to pursue. That overlap doesn't apply to mutant-selective inhibitors, which makes combinations with EGFR antagonists more straightforward in principle. We'll discuss combination plans when data support them. Regarding an interim analysis in the first-line trial, Wei commented that we do not intend to disclose the analysis plan at this time.

At this current state, we don't intend to disclose the analysis plan.

Our next question comes from Laura Prendergast with Stifel.

What are some of the top variables still under consideration for daraxonrasib in first-line lung cancer strategy? And on the back of RASolute 302 showing such an unprecedented OS, what kind of pricing power are you thinking this could unlock? Are there any pricing benchmarks you're focused on?

Laura, I can't comment on pricing today. OS impact will be relevant to payer considerations, but we have no further comment on pricing. Regarding first-line non-small cell lung cancer, one key variable is the evolving standard of care. We are dosing patients with ivonescimab, which may become a new standard, and that affects our strategy. The mutant-selective inhibitor paradigm is established in lung cancer, so genotype-directed approaches will continue to be an important consideration. We have G12D-selective, G12C-selective, and G12V-selective inhibitors in development and will consider multiple ways to address the disease depending on data maturity and standard-of-care changes.

Our next question comes from Jay Olson with Oppenheimer.

How would you set expectations for the upcoming ASCO plenary presentation in terms of where you'd like investors to focus their attention?

I expect the plenary to be highly attended and competitive. Investigators will provide a full update consistent with what we've already communicated but with significantly more information that the experts in the field need to see and evaluate.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Any additional color on the sales force? And building on earlier answers about front-line to second-line attrition once daraxonrasib is on the market, do you have a sense what percent of the patients who don't proceed to second-line therapy are unfit for therapy versus ineligible or unwilling to take another chemotherapy, as we model attrition?

For the U.S. region, we're in the final stages of building out our field-based teams across medical affairs, market access and sales. A medical science liaison team and thought-leader liaison team have been in place, and a market access account team has been engaging payers and organized customers around unmet need in pancreatic cancer and early clinical data through pre-approval information exchanges. We're in the final stages of onboarding our U.S. sales force. They have deep expertise in solid tumors across GI malignancies and in oral oncology, and they'll be fully trained and ready for HCP engagement if we receive FDA approval.

Regarding attrition, it's hard to precisely categorize why patients don't proceed to second line from retrospective record review. Reasons include poor performance status, comorbid illness, intolerability to first-line therapy, patients choosing not to pursue more chemotherapy to focus on quality of life, or patients who do not survive to receive second-line therapy. A more convenient and better-tolerated regimen, such as a once-daily oral agent, could address some reasons for not receiving second-line therapy, but we'll only know the effect once we have broader clinical experience and potential approvals.

Our next question comes from Kalpit Patel of Wolfe Research.

For RASolute 303, how should we think about that study's enrollment ramp versus the second-line study you completed in terms of timing of enrollment completion? Also, can you remind us if crossover is allowed in RASolute 303? And any comments on potentially starting a registrational trial with daraxonrasib and a PRMT5 inhibitor?

We can't provide a precise timing for completion, but there's very high interest and many sites still to be activated with patients lined up. Regarding crossover: the trial design does not include study-mandated crossover. Individual patients can seek approved therapies as they become available, but crossover as part of the randomized design is not included. With regard to PRMT5, we have no update to provide on a registrational trial today, but we are engaged with several companies evaluating PRMT5 inhibitors in combination with RAS inhibitors and are keenly interested in those results.

To add, because overall survival is a primary endpoint, we've established a broad geographic footprint to mitigate potential impacts related to second-line therapy access. That includes a relatively smaller U.S. footprint and larger ex-U.S. footprint to manage potential downstream treatment variations.

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

First, from your experience, is initial ORR with daraxonrasib a good metric for predicting PFS and OS benefit in larger studies? Does higher numerical ORR translate to better survival, or is duration of response or time on therapy more telling? Second, will you allow third-line-plus patients into the EAP as well?

On the EAP: yes, the eligible population includes previously treated patients and extends beyond pure second line as in the 302 trial. For ORR versus PFS/OS, Steve can comment.

ORR is broadly correlated with PFS, but it's not a tight stoichiometric relationship where a small change in ORR translates directly to the same change in PFS. There are better predictive approaches that involve multiparametric analyses incorporating ORR and additional factors. We haven't made those analyses broadly available because they are competitive. Also, with RAS inhibitors, responses can take time: patients may take up to and sometimes beyond six months to meet the RECIST definition of response. At any given timepoint, some patients who will ultimately meet RECIST response criteria have not yet done so. RECIST provides a useful framework, but there is inherent uncertainty and measurement variability in determining response from radiographic measurements.

Yes. There's some relationship between ORR and longer-term outcomes, but interpreting ORR in isolation can be misleading. We'll continue to learn more as we accrue data and patients remain on therapy.

This concludes the question-and-answer session. I will now turn the call 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 concludes the program. You may now disconnect.