Revolution Medicines, Inc.

conference call. At this time, all 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 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. We ask that you please limit to one question and one follow-up. 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 U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended September 30th, 2025 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 Medicine's 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 continue 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 Durexanracib in pancreatic cancer. I'd like to note that Durexanracib 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, Durexanracib was awarded breakthrough therapy status, And recently, it received both orphan drug designation and an FDA 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. Direction RAS inhibits are 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 Direction RAS and monotherapy cohort of patients with second-line metastatic pancreatic cancer. These results reinforced our understanding of the strong clinical anti-tumor 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 out-of-care cytotoxic chemotherapy regimens that were reported in randomized control trials to provide a median over survival of six to seven months in second line and approximately 11 months in the first line setting. Resolute 302, our phase three 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 directional RASP in first-line metastatic pancreatic cancer, both as monotherapy and in combination with standard care chemotherapy. As shown in slide 11, directional RASP 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 continued to follow these patients to assess the durability of clinical benefit. The acceptable safety profile of duroxanuracid 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 duroxanuracid plus gemcitabine napaklitaxel, or GMP, 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 directional acid with or without GMP 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 RASBLU 303, a randomized three-arm phase 3 trial in patients with first-line metastatic PDOT, as shown on slide 13. This retricional trial will compare droxoracid monotherapy or droxoracid plus GMP, followed by droxoracid monotherapy, to a comparator arm of GMP alone. The design of this three-arm study provides two distinct opportunities to demonstrate potential survival benefit for patients. treatment with directional massif as monotherapy in first line, followed eventually by chemotherapy in second line, or alternatively, treating concurrently with both directional massif and chemotherapy in first line. Both strategies have scientific and clinical merit and deserve to be evaluated. We remain on track to initiate Resolute 303 this year. I'd like to provide an overview of the current standard 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 care for perioperative treatment is cytotoxic chemotherapy, either modified fulfironox or gemcitabine, capecitabine. The publicly reported disease-free survival rate on these chemotherapy regimens ranges from 13.9 months to 21.6 months, while three-year disease-free survival ranges from approximately 20 to 40 percent. We believe there remains significant room for improvement that may be served with RAS target therapy. The strength of the directional massive monotherapy data so far in both first and second line MEDSAT disease provides a compelling rationale for advancing directional massive into the adjuvant setting. And slide 15 shows our phase three trial design for resolute 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 care, either Fofurinox or gemcitabine, capecitabine, administered before and or after surgery. Patients will be randomized to either observation or drug-free 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 Zodon RASF, our covalent Rasong G12D selective inhibitor in pancreatic cancer. Zodon RASF has demonstrated compelling clinical profile with encouraging anti-tumor activity and a particularly favorable safety probability profile. With this differentiated profile, we believe Zodon RASFib has high potential to contribute as a key component of accommodation therapy in first-line PDAC with current standard care chemotherapy and or with direction RASFib 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 Zodon RASF with Thraxon RASF can maximally inhibit RASG12D and improve both depth and durability of response. We expect to initiate our first Zodon RASF combination registrational trial in first-line metastatic PDAC in the first half of 2026. We look forward to share the trial details and additional supporting data around that time frame. And now we turn 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 duraxone RACID, the RESOLVE 301 registrational trial studying duraxone RACID 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 direxon RASib 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 Durexone RASIB with Pembrolizumab with or without chemotherapy was well tolerated and demonstrated encouraging early anti-tumor activity. In the G12C non-small cell lung cancer space, we continue to make progress with Aliron RASIB, our RasOn 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, Elyra and Rassib 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 alluron-rastive monotherapy and combination studies while exploring a number of options for continued development of this differentiated Rason G12C selective inhibitor. Regarding Zoldanracib and lung cancer, we are evaluating a phase one monotherapy expansion cohort of patients with previously treated non-small cell lung cancer, as well as exploring combination regimens, including Zoldanracib with pembrolizumab and Zoldanracib with Durexanracib. In addition to plans mentioned earlier to initiate a registrational trial for a Zoldon-RASIB 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 Zoldon-RASIB or Leron-RASIB. We also continue to advance RMC5127, an oral tricomplex Rason G12V selective inhibitor. As a reminder, approximately 48,000 patients are diagnosed with a KRAS G12V mutant cancer in the US each year, including non-small cell lung cancer and gastrointestinal cancers, such as pancreatic and colorectal. RMC5127 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 Rasson 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 ovoprimetastat, a PRMT5 inhibitor under our agreement with Tango Therapeutics, and ibonestamab, a bispecific PD-1 VEGF inhibitor under our 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 duraxone or acid 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 gap net loss to be between $1.03 billion and $1.09 billion. which includes estimated non-cash stock-based compensation expense of 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 a 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, advisors, 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.

Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Once again, we ask you please limit to one question and one follow-up question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Jonathan Chang of Lyric Partners. Your line is now open.

Hi, guys. Thanks for taking my question. How are you thinking about the impact of receiving the Commissioner's National Priority Voucher on Drax and RACIB timelines 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 timelines by some significant amount, potentially making the review timeline 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 timeline might be delivered under the CNPB process.

Understood. Thanks for taking my question.

Thank you. Our next question comes from a line of Charles Zhu of LifeSci Capital. Your line is now open.

Hello. Good afternoon. It's a nice evening, and thank you for taking our questions, and congrats on the progress. I've got a couple regarding RAS Leak 304, the adjuvant or axon RACID trial process. This might be a little naive, but can you help us understand and perhaps educate us on the decision to randomize against observation in a post-perioperative chemotherapy setting? And is there, I guess, clinical value in maybe at some point evaluating whether or not one could displace chemotherapy in this particular disease setting as well? Can you also help us understand and talk about the requirement for at least four months of a perioperative chemotherapy as an eligibility criteria prior to, you know, randomizing against the two arms. Thank you.

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

Great. Yeah, thanks. It sounds like it's a three-part question, and hopefully I'll remember all three parts. So the aspect of the – I'll start with the four months of therapy. That's considered to be the standard for of care that's been established previously. And so we wanted to add to that. So we're requiring that patients receive standard of care therapy. And for that, that's at least four months of therapy. So that's number one. Then the idea is to randomize patients to no further treatment or two years of additional adjuvant therapy with Duraxime. And the idea then is to build upon the success that has been seen. It's modest, but success that has been seen with chemotherapy in this setting. And so this, I think, offers the best approach to patients with resectable pancreatic cancer. Your last question, I think, was to potentially replace chemotherapy. And I think, you know, based on what we see from the adjuvant study, we'll reassess a plan accordingly. But I think we've... We're very excited about this particular opportunity already and are looking forward to initiating the trial.

Excellent. Thank you very much for taking the questions, and congrats on all the progress. Thank you.

Thank you. Our next question comes from the line of Michael Schmidt of Guggenheim, and the line is now open.

Hey, thanks for taking my questions, and congrats on all the progress. Couple questions on PDAC. So, as we think about RAS Load 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 wrapping up commercial infrastructure? Thanks so much.

Thanks, Michael. Appreciate the questions. Maybe Dr. Lin can first comment on the phase three,

phase three randomized studies have been reported historically. I think our patient populations are actually fairly similar in looking at all the baseline characteristics that are prognostic or predictive of response to either chemotherapy or our own therapy. There's a almost all the metrics are either comparable or in in the phase one setting that's fairly representative of what we expect to enroll on the phase three. And furthermore, the Resolute 302 study, while it's a global study, the predominant enrollment will occur in the U.S. with representative enrollment in Europe and in Japan. And therefore, another reason why we feel that the population on the phase one will translate to the phase three. And then finally, look at historically. replicate to a large measure because the patient population as well as the performance of the treatment historically are represented.

Thanks. And then the question regarding commercial readiness, maybe I'll answer, comment on part of it, and then Anthony Mancini can comment on the other part. With regard to manufacturing, we have a very strong organization and supply chain. that's really been prepared over the last number of years. We're already scaling at the proper level to be able to support whatever level of uptake there might be should we be able to launch a product. So I think we're in a very strong position there and don't anticipate anything that could pose a significant problem for us. With regard to commercialization readiness beyond that, maybe Anthony can comment.

Yeah, thanks Mark and thanks Michael for the question. We're really pleased with how our launch readiness plans are advancing. 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.

Thank you.

Our next question comes from the line of Andrea Newkirk of Goldman Sachs. Your line is now open.

Hi, Tim. Thank you for taking my question. This is Morgan. I'm for Andrea. Based on the initial frontline metastatic PDAC data, how do you think about the efficacy of combination treatment relative to monotherapy? Rather, greater time on treatment could increase the delta on ORR and DCR. And then with regard to updated direct-on-racid monotherapy and combination data in the first half of next year in frontline metastatic PDAC, how should we be thinking about durability? Thank you so much.

Thanks for the question, Morgan. What would you like to comment on those?

The first question being the difference, what level of difference is there between monotherapy versus combination, and will that clarify over time?

Yeah, so the monotherapy versus combination in France Only two lines of effect therapy exist for patients, a GEM-based and a 5PV-based. And by using directional monotherapy, we produced a third line of therapy. And could that introduction of third line therapy with very promising data in the set line setting translate to prolongation or survival? And then the other chemo combination arm really tests very distinct hypothesis. of survival that can also translate to long-level 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 spinal therapy. And just to add a And they're both very credible and meritorious scientific prophecies.

The second question, I think, had to do with what sort of update can be expected next year with regard to the durability of the effects that we have already reported. We do intend to provide an update in the first half of 2020.

Okay, thank you.

Thank you. Our next question comes from the line of Brian Chang of JPMorgan. Your line is now open.

Hey, guys. Thanks for taking our questions this afternoon. 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 PDOC. And then we have a follow-up. Thank you.

Yeah, 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 available today.

Okay, and then just quickly on Sodon's combo phase three 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 comparative piece. How should we think about which active comparative arm you should put in to make sure that physicians understand how they look at sodon combo in the future?

Yeah, 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. You know, 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're able to lay that out much more explicitly.

Great. Thank you.

Thank you. Our next question comes from the line of Mark Fromm of TD Cowan. Your line is now open.

Thanks for taking my questions, and congrats on all the progress. Maybe to start on that Zoldan-Raseb 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 Durex and Raseb 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, Mark. I'm not sure about that last comment. I'm not sure that we ever gave any inclination with regard to Zolonracid 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. Deraxonracid alone we're setting in first line as monotherapy. We're going to learn a lot from that study. And Zolonracid is an ideal combination agent because of its 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, 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, you know, if the interim results in some sort of stoppage of the trial.

Unfortunately, Mark, I think you're 0 for 2 on those questions.

Anything to comment on either of those at this time? Okay, fair enough.

Thank you. Our next question comes from the line of Leonid Timoshev of RBC. The line is now open.

Thanks for taking my question. I just wanted to ask on the commercial opportunity, given that you recently hired presidents of EU strategy, just how you're thinking about the landscape in the European Union with respect to where patients lie in terms of commercial opportunity, the concentration there, you know, awareness, diagnostic opportunities, just anything you can speak to to how you think the European strategy might take shape. Thanks.

Thank you. Appreciate the question. It's a gigantic question, so I'm immediately going to ask Anthony to address it.

No, look, there's been a lot of thought put into, you know, how we're thinking about bringing the Raxon RAS into patients. Clearly, different from many companies' opportunities with a first launch and a first indication. We think the second line pancreatic cancer indication is a meaningful one. So you can look at the epi in the key European markets, starting with Germany and the EU4 and beyond, and there are many patients to treat. We think that we'll bring a compelling value proposition in Europe, and we think it's going to be a meaningful opportunity in Europe in the U.S. and Japan, and so we're pursuing that. I think there's nothing more to comment on except that those are our priority markets, and we intend to put our best foot forward.

All right. Thank you.

Our next question comes from the line of Clara Dong of Jefferies. Your line is now open.

Hi, good afternoon. Thanks for taking our questions. This is Jenna for Clara. Could you talk about if there were any rationale behind starting the adjuvant study before the first-line study? Thank you.

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.

Okay. Thank you so much.

Thank you. Our next question comes from the line of Estika Gunawardine of Truva Securities. Your line is now open.

Hi, guys. Thanks for taking my question. So you've described what resistance mechanisms emerge with Deroxon in PDAC. And you should have a considerable amount of data with Deroxon in non-small cell lung cancer, too, under the 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 PEMBRO and chemo for the combination versus just a chemo-sparing PEMBRO combo. I'm going to have a follow-up.

Thanks for your question.

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 that we have on emerging mechanisms of resistance to Duraxone RAS in the non-small cell lung cancer is probably not sufficiently mature for public disclosure at this stage. There are a number of confounding issues around that. The first is, as you know, we declared our recommended phase two dose for non-small cell lung cancer after we had declared the recommended phase two dose in pancreatic cancer. So The information that we have would only really be important at the recommended phase two dose. The second is the number of people that actually have progressed and been documented to progress. And the third issue there are the number of patients with progression that actually have detectable circulating CT DNA in order to make an assessment of whether there's anything to see. The other thing is that traditionally in non-small cell lung cancer, there appear to be, from the literature that's available, a lot of resistance mechanisms that are possibly not even genomic. And so it's going to take a little bit more time to figure that out. And I think that all bets are off really mapping mechanisms of resistance in pancreatic cancer to mechanisms of resistance in non-small cell lung cancer, we already know that the biological resistance mechanisms in colorectal cancer, for instance, to G2C inhibitors are different from the biological resistance mechanisms to G2C inhibitors in non-small cell lung cancer. They are qualitatively similar in overlap, but they're not identical, and I don't think that we can infer anything at this stage. With regards to how that information informs how we move forward with combinations, it really has no bearing on it. The selection of Pembrolizumab as a partner for any of our Rasson inhibitors is driven really by two things. One is the almost ubiquitous inclusion of Pembrolizumab or an equivalent checkpoint inhibitor into the standard of care for non-small cell lung cancer. And the second is the the increasingly compelling body of evidence that suppressing RAS does actually make pembrolizumab more effective because it profoundly changes the immune microenvironment and allow the immune system much more access to the tumor for a whole load of reasons that we have published and a number of other groups have published. When we have the data, we will disclose it, and it may influence how we move forwards, and it may not. But they're really two separate issues, I think.

Thank you for that, Carla. 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?

Thanks, guys. Yeah, hi.

I'll take that. No, the first we'll talk about the purpose of it was, again, the four months of standard of care. The question about your borderline and, you know, the readily resectable, what we've done is we've allowed those patients to undergo the standard treatment that they would locally and whether they're surgically resectable or not. And then the only way they're able to enter on study is if they are pathologically completely resected, either with totally clear or narrow margins, the R0 or R1 that was shown on the slide. And then those patients are then randomized to the treatment as such. In a sense, it eliminates those patients who are not able to be resected, but it also allows those patients with the borderline resectable an opportunity to receive adjuvant therapy if their perioperative therapy and surgery was successful. So it broadens the number of patients who have access to this therapy in the study.

I could also add one point about the question of why four months. You know, 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 regimens.

All right. Thank you.

Our next question comes from the line of Alex Tranahan of Bank of America. Your line is now open.

Hey, guys. Thanks for taking our questions and congrats on the update. Two from us. First on Zoldon RASIB, curious how you're thinking about the opportunity for Zoldon on top of Chemo versus Drax on RASIB plus Chemo and Raslu 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 zolonracib, duracib, and the frontline PDAC. Thank you.

Okay. Maybach can just comment on the second one, and then maybe Wei can comment, can address your first question. So with regard to racon inhibitor doublets, we still have high conviction about it. We just showed some data on zolonracib plus duraxonracib in preclinical models just last month. at the triple meeting, and we feel like it's a compelling option. Just stay tuned as we roll out the various studies that will be coming in the future. I think we have high interest in that. The first question I think had to do with Zoldan versus Daraxan, each in a first-line population, and are we selecting patients differently between those? obviously one is all RAS mutations and the other is just KRAS G12D mutations so there's that difference between them but are there any other differences?

Clinically the eligibility otherwise are no different and I think in the phase one setting when we're doing the combination with the chemotherapy the eligibility are really mainly designed to make adequate

All right, great. Thank you. Thank you.

Our next question comes from the line of Joe Catanzaro of Mizuho. Your line is now open.

Hey, great. Thanks so much for taking my question. 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.

Thanks for your question. Thanks for joining us.

Steve, do you want to comment on CRC?

Yeah, I'm happy to do that. I'm not going to comment on timing because we haven't really guided to data disclosure with regards to colorectal cancer. But I think we have previously made it pretty clear that due to the biological complexity of Ras mutant colorectal cancer, we believe that combination therapy is absolutely essential in order to maximize clinical benefit and the studies that are designed to figure out which combinations are most efficacious in that context are currently ongoing. And so as soon as we've figured it out, then we can, we can follow the path forward. You know, we also don't forget that we have the, there are several, there are several dimensions to this issue. I mean, you mentioned one of them, which is line of therapy, whether or not we try and go into the first line metastatic setting or whether we just tackle patients in the third and fourth line who are essentially being salvaged after chemotherapy has failed. There are several different biologically rational combinations, including combinations within our own portfolio of Rasson doublets. And so we just need the opportunity to figure that out. It's a very complex process. Colorectal cancer is a very complex disease. It's not entirely clear that RAS, mutant RAS, is the only driver, the only oncogenic driver, even in situations where it's actually mutated. So we're just going to sort it out.

Okay, that's helpful. Thanks so much.

Thank you.

Our next question comes from the line of Sean McCutcheon of Raymond James. Your line is now open.

Hi, good afternoon, team. This is Yang Ong for Sean. We have two quick ones. The first one regarding the first line NLCSD with Dyruson RACIP. What kind of threshold for efficacy bar are you looking at anticipating that you have the update for the front line and also commenting on the Dyruson? dyracinracid and iracid combination in the first line ASLC. Thank you.

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

No, sorry. Yeah, that's on non-small cell lung cancer front line dyracinracid What's the threshold efficacy bar you're looking at?

Ah, okay. So in lung cancer, since we indicated that we'll proceed with a trial and we'll provide information later. Yeah, 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 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 to be able to offer you today on that.

And your second question?

Yes, the second question is related to the combination potential with your PEN-RAS and G12C iliron racib in first-line NLCLC.

Ah, okay. That's back to the racon inhibitor doublet, and in this case, it's the doublet of iliron plus direxon racib, and that, too, is a very interesting combination. I think I'd just reiterate that we are We believe that the combination of a mutant selective inhibitor with the transmultant inhibitor provides potentially the benefits of both of those compounds as complementary and delivering the greatest impact. And we've now shown two clinical data sets that support that, one in colorectal cancer and one in lung cancer. That's a very complex matrix of considerations and don't have anything to be able to guide you to specifically today about that.

Okay. Thank you.

Thank you. Our next question comes from the line of Laura Prendergast of Stifel. Your line is now open.

Hey, guys. Congrats on the quarter. I'm just curious if it's possible that any type of accelerated approval pathway could be there for first-line PDAC, whether that's an early cut for the Phase III study or something, or anything else. Also, how are you factoring Durexon RASID being approved in second line into how you're thinking about the statistics for OS in the first-line study?

Okay, Laura, thanks for your questions. Maybe I'll comment on the AA question, and then maybe Wayne can comment on the . No comment. That's basically, you know, that's always a question for the FDA. That's not so much of a question for us. And, you know, I think there's no doubt that the initial data that we showed were quite encouraging, and I'm sure they're viewed that way by many people. what the FDA, how they view it in a formal sense and what they want to do with it would be the subject of future dialogue and so on. Really nothing that we can say about that. I would say just generally speaking, we've had a pretty strong habit of focusing on full approval strategies, which I think has served us well with regard to PDAC for sure so far. We're not at the end game yet, but it seems to have made sense. And we'll continue to prioritize that. There may be some situations in which an accelerated approval can make sense to get something to patients as early as possible and where we think it makes sense. And the FDA, more importantly, thinks it makes sense. Then we could always welcome that opportunity.

Yeah. 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. So from that regard, it doesn't really impact the fact that we deliver on overall survival. We still intend to deliver overall survival in frontline, even after delivering overall survival in the second line. It only impacts our operational, and at footprint, I think we'll certainly assign the sites more on the ex-U.S. to minimize the impact of crossover due to the availability of draft for acid for second-in-patient in the U.S.

Got it. Thank you very much.

Thank you. Our next question comes from the line of Ami Fadia of Needham. Your line is now open.

Hi, good afternoon. Thanks for taking my question. And apologies if this has been asked already. I've been getting some calls here. So my question is regarding the acquired alterations post-DARA monotherapy that was proposed. presented at the triple meeting, how do you see that potentially impacting the durability of response in first line? And, you know, where you're studying in combination with chemo, would you consider exploring combinations with, you know, other mechanisms at this stage? Thank you.

Thanks, Ami. in order to increase . Sure, we're already considering it. We're already actively exploring some of those and are open to and may well expand that. There's obviously many potential targets that could influence the outcome if you were to inhibit them. And we look at these opportunities all the time. We have significant operations studying those, and we have a lot of inbound requests

to combine things, and we try to prioritize them based on their scientific – the scientific data behind them, and for sure we'll continue to do that. Thank you. Thank you.

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 Medicine.

This does conclude the program. You may now disconnect.