Revolution Medicines, Inc.

Good day, and thank you for standing by. Welcome to Revolution Medicine's fourth quarter 2025 earnings conference call. After the speaker's presentation, there will be a question and answer session. To ask a question during your session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 11 again. 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 Acy, Senior Vice President of Corporate Affairs. Ryan, please go ahead.

Thank you, and welcome everyone to our fourth quarter and full year 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, our Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of Research and Development, Dr. Alan Sandler, our Chief Development Officer, 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. Before we begin, I'd like to remind everyone 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 that is filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter and full year ended December 31, 2025, and recent corporate updates. The press release is available on the Investors 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. Good afternoon, and thank you for joining us. We will keep our prepared remarks brief today, highlighting the substantial progress and growing momentum for our pioneering Rason inhibitor pipeline and outlining several important priorities for the year ahead. Jack Anders will summarize our financial results along with financial guidance for the year ahead. At Revolution Medicines, we remain steadfast in our commitment to revolutionizing treatment globally for patients living with RAS-addicted cancers through the discovery, development, and delivery of innovative, targeted medicines directed against these common mutational drivers of human cancers. As pioneers in the RAS targeting field, with a singular focus on RAS-addicted cancers and a great deal of validating data behind us, We are well positioned to continue building on important scientific drug discovery and clinical breakthroughs that have the potential to change standards of care for patients. Our efforts throughout 2025 strengthened our leadership position as we advanced our robust pipeline that includes four novel investigational drugs that target the major oncogenic RAS drivers. Duraxone RASib, our most advanced program, a groundbreaking RAS on multi-selective inhibitor, Alir on RACIB, a differentiated, highly active, and well-tolerated Rason G12C selective inhibitor, Zold on RACIB, an innovative, highly active, and well-tolerated Rason G12D selective inhibitor, and our newest clinical compound, RMC5127, a promising Rason G12D selective inhibitor. We have eight ongoing or planned phase three registrational trials and extensive clinical experience to date with more than 2,500 patients having received one or more of our RAS-on inhibitors in the aggregate. This clinical work is built upon the foundation of a strong discovery and preclinical platform that continues pushing the boundaries. Our virtuous cycle of innovation fuels how we discover new ways of targeting RAS through our highly productive Tricomplex platform, develop novel investigational drugs through robust and parallel clinical development plans, and systematically expand our commercialization and operational capabilities to deliver potential new therapies to patients globally. I'll provide an update on our clinical activities in pancreatic cancer, our most advanced clinical program. With more than 90% of pancreatic cancers being RAS-driven, there's a profound need for RAS-targeted therapies, which we aim to address with multiple registrational trials underway or that we plan to initiate in 2026. Dyraxon RASIB, our pioneering RAS on multi-selective inhibitor, has shown an unprecedented clinical profile across RAS mutations and lines of therapy, either alone or in combination with standards of care. Our broad conviction around Dyraxon RASIB was further strengthened by the U.S. FDA designation of Dyraxon RASIB as a breakthrough therapy and its award of one of the agency's first commissioner's national priority vouchers, based on its potential to address significant unmet needs in pancreatic cancer. We're currently evaluating Draxon RASIB in three randomized registrational studies in pancreatic cancer across lines of therapy. Resolute 302, a randomized registrational trial evaluating Draxon RASIB monotherapy in second-line metastatic disease. As a reminder, Resolute 302 employs a nested trial design the largest population of patients with tumors carrying a Ras G12 mutation in the core, and the expanded population that includes patients with tumors carrying other Ras mutations and tumors without a detected Ras mutation. The trial employs hierarchical testing to maximize the probability of success in the core population and potentially enable a broad label not requiring biomarker testing. With global enrollment now complete, we expect a readout to occur in the first half of 2026. In earlier lines of therapy, two randomized registrational studies were recently initiated. Resolute 303 is evaluating both Deraxon RACIB monotherapy and Deraxon RACIB in combination with chemotherapy in first-line metastatic disease. Evaluating both monotherapy and combination approaches may enable treatment optionality for physicians and patients. Rasolut 304 is evaluating duraxone-rasib monotherapy in the adjuvant setting in patients with resectable disease after receiving conventional surgery and perioperative chemotherapy. The data we've collected to date support our strong conviction that these studies have the potential to establish new global standards of care across lines of treatment for patients living with pancreatic cancer. Zoldanracib, our covalent G12D selective inhibitor, is another first-of-its-kind compound that has shown a highly differentiated safety and tolerability profile. We recently disclosed encouraging initial data from patients with metastatic pancreatic cancer receiving first-line treatment with the combination of Zoldanracib and Fulfironox. The initial safety and tolerability profile for the combination of both treatments was largely consistent with a well-known profile of modified fulfirinox alone, and a high zoldonracid dose intensity was maintained. As of the data cutoff date, 63% of patients achieved a partial response, either confirmed or pending confirmation. The disease control rate was 95%, and the vast majority of patients remained on treatment. With these data reinforcing confidence in this compelling G12D selective inhibitor, we plan to advance two first-line registrational combination studies this year. Today, we're pleased to announce that RASLUTE-305 has been initiated. RASLUTE-305 is a randomized, double-blind, placebo-controlled trial that is evaluating Zoldan RASB in combination with investigators' choice of either gemcitabine, NAB-paclitaxel, or modified Fulfironox chemotherapy compared to investigators' choice of chemotherapy with placebo. RASL309 will evaluate the RAS on inhibitor doublet combination of Zoldon RASib plus Durex on RASib, and we plan to initiate this trial in the second half of 2026. We plan to share clinical data from the initial trial of the Zoldon RASib plus gemcitabine-NAB-paclitaxel combination and the Zoldon RASib plus Durex on RASib RAS on inhibitor doublet combination in PDAC at one or more medical meetings this year. A second area of focus in which we've shown continued clinical advancement is non-small cell lung cancer. With approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, this tumor type remains a key priority. To date, we've shown encouraging initial safety tolerability and anti-tumor activity in patients with RAS mutant lung cancers across our three lead compounds, that supports their potential to establish new standards of care. And we are building a set of registrational trials accordingly. Resolv301, our global randomized trial evaluating Draxon RACIB monotherapy in previously treated patients continues enrolling patients across sites both in the U.S. and globally. We anticipate substantially completing enrollment this year. We also expect to disclose our plans for advancing Draxon RACIB combination therapy and first-line non-small-cell lung cancer this year. With Zoldon RASIB and Aliron RASIB, we've reported highly encouraging safety tolerability and anti-tumor activity data from previously treated patients with lung tumors harboring RASG12D or G12C mutations, respectively. The Zoldon RASIB monotherapy expansion cohort is fully enrolled, and earlier this year, Zoldon RASIB was awarded breakthrough therapy designations. making it our third RAS-on inhibitor to have received this distinction. Building on these milestones, we are preparing to initiate Resolve 308, a first randomized registrational trial of Zolon RASib in combination with standard of care as a first-line treatment for patients with metastatic RAS G12D non-small cell lung cancers. For Aliron RACIB, we continue to evaluate this compelling G12C-selective inhibitor that has demonstrated a differentiated clinical profile in both G12C inhibitor-naive and G12C inhibitor-experienced lung cancer patients. We've reported encouraging results with monotherapy or in combinations with either pembrolizumab or as part of a RACON inhibitor doublet with Duraxone RACIB. And as we consider multiple approaches, We plan to share an update on a registrational strategy for Aliron RACIB this year. The third area of focus, colorectal cancer, remains of high interest and engagement for the company. Approximately 50% of patients with colorectal cancer harbor a RAS mutation. Given the genetically complex and heterogeneous nature of the disease, combinatorial approaches are key to maximizing clinical impact. We have a range of studies underway, including evaluating RAS on inhibitor doublets and evaluating RAS on inhibitors with current standards of care and with other novel approaches. We plan to provide visibility into combination data in colorectal cancer this year as we work toward prioritizing registrational opportunities. Our development efforts include several clinical collaborations, studying our RAS on inhibitors with new targeted therapies in clinical development. Our collaboration with Tango Therapeutics is studying our Rasson inhibitors in combination with Vopimetastat, Tango's MTA-cooperative PRMT5 inhibitor in patients with tumors carrying both a RAS mutation and MTAP deletion. We also recently entered into a clinical collaboration with Bristol-Myers Squibb to evaluate Teraxon Rassib in combination with Navlimetastat, its MTA-cooperative PRMT5 inhibitor, in patients with pancreatic cancer whose tumors carry both RAS mutation and M-TAP deletion. This collaboration extends our commitment to evaluating novel targeted agents, such as PRMT5 inhibitors, that may be appropriate to combine with RAS-on inhibitors in some settings. Our ongoing collaboration with Summit Therapeutics is evaluating our RAS-on inhibitor with Summit's PD-1 VEGF bispecific antibody, Ivernesimab, across multiple solid tumor settings. The first patient in this trial was recently dosed. We recently brought our fourth Rason inhibitor, the Rason G12V selective inhibitor RMC5127 into the clinic and announced that the first patient had been dosed in the first in human trial. We expect to identify a recommended monotherapy phase two dose for this compound in the second half of 2026. As leaders in developing treatment strategies for patients with RAS-addicted cancers, we recognize the importance of continuing to invest in new approaches that advance the science and have the potential to further transform treatment paradigms. Our discovery team continues pioneering novel approaches, including an innovative new class of RAS-on inhibitors from our laboratory designed to overcome RAS-driven drug resistance and thereby extend the clinical benefit of RAS-on inhibitors. As we disclosed in January, in preclinical pancreatic cancer and non-small cell lung cancer models that had developed resistance to duraxone racibs, treatment with a representative compound from this new class, RM055, drove deep and durable regressions. This year, we plan to share more information about this new class of compounds at a scientific meeting and later in the year to begin clinical development of a first compound from this class as our fifth investigational clinical-stage RAS on inhibitor. As late-stage programs, notably Deraxon RACID, advance toward possible commercialization, we are committed to building a world-class, end-to-end global oncology enterprise to deliver compelling targeted therapies to patients with RAS-addicted cancers. We have established a strong operational foundation to move with speed and agility to ensure a successful first commercial launch, initially focused in the U.S. market. To that end, we have made key strategic hires to form a strong leadership team of professionals who have established track records and launched some of the most impactful oncology products in recent years. In addition to recently onboarding regional field sales leadership to support the U.S. launch, recruitment for our first field sales team is now underway. I'd now like to turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance. Jack?

Thank you, Mark. We ended the fourth quarter of 2025 with $2.03 billion in cash and investments. In 2025, we entered into our innovative and flexible strategic partnership with Royalty Pharma, which provided us access to up to $2 billion in committed capital under the terms of the agreement. We received the first Royalty monetization tranche of $250 million in June 2025, and there remains an additional $1.75 billion in future committed capital under this arrangement. Turn into expenses. R&D expenses for the fourth quarter of 2025 were $294.9 million compared to $188.1 million for the fourth quarter of 2024. The increase And R&D expenses was primarily due to increases in clinical trial and manufacturing expenses related to our multiple ongoing clinical development programs and an increase in personnel-related expenses and stock-based compensation expense associated with additional headcount. G&A expenses for the fourth quarter of 2025 were $66.7 million, compared to $28.2 million for the fourth quarter of 2024. Increase in G&A expenses was primarily due to increases in commercial preparation activities and personnel-related expenses and stock-based compensation expense associated with additional headcount. Net loss for the fourth quarter of 2025 was $364.9 million compared to 194.6 million for the fourth quarter of 2024. The increase in net loss was primarily due to higher operating expenses, as described earlier. Net loss for the fourth quarter of 2025 also included specific non-cash charges of 33.7 million in stock-based compensation expense, 12.6 million in non-cash warrant expense related to a mark-to-market change and the fair value of warrants we inherited as part of our EQRX acquisition, and $11.9 million in non-cash interest expense related to the accounting treatment for our royalty pharma arrangement. Full-year 2025 financial results are available in our corresponding press release and also included in our Form 10-K that was filed with the SEC this afternoon. To turn into financial guidance, we would like to note that we are switching the forward-looking financial guidance we provide from gap net loss to gap operating expenses for fiscal year 2026. The switch to gap operating expenses is intended to provide expectations on our anticipated level of spend for 2026 in a more straightforward and easier to follow manner. As gap net loss includes certain non-cash items within non-operating income and expense, such as the change in fair value of the warrant liability and non-cash interest expense associated with our royalty pharma arrangement. With that said, we expect full-year 2026 GAAP operating expenses to be between $1.6 and $1.7 billion, which includes estimated non-cash stock-based compensation expense of between $180 and $200 million. The increase in expected gap operating expenses for 2026 is a result of the progression and expansion of our clinical development programs. In particular, the multiple ongoing and planned registrational studies we have outlined as priorities. We also expect higher expenses in 2026 as a result of increased commercial preparation activities as we continue to build and expand our organizational capabilities in preparation for becoming a global commercial stage company. That concludes the financial portion. I will now turn the call back over to Mark.

Thank you, Jack. 2025 was a pivotal year for RevMed, and 2026 is poised to be one of substantial impact as we seek to create the industry-leading global targeted medicines franchise for patients with RAS-addicted cancers. We believe that each asset in our pipeline has the potential to transform the treatment landscape for these difficult to treat cancers. With key milestones across our clinical programs, advancing new programs to the clinic, continued investment in innovation, and preparing for our first commercial launch, we are well set up for the future, building on our foundational achievements to date. Of course, none of the work we do would be possible without the partnership and ongoing support of healthcare providers, patients and caregivers, and investors, and the remarkable dedication and efforts of RevMed employees. With that, I'll turn the call over to the operator for the Q&A portion of today's call.

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. Please limit your questions to only one follow-up question when prompted. Please stand by while we compile the Q&A roster. Our first question comes from Jonathan Chang of Lyric Partners. Your line is open.

Hi, this is Albert Agustinus on for Jonathan Chang. Thanks for taking our question. I was just wondering, could you please share your thoughts or clarify in your plans to advance combination in first-line non-small cell lung cancer this year. Are you still guiding towards the initiation of a registrational trial in this setting? Thank you.

Thanks, Albert, for your question.

So, I think you're asking about our plans for durexone RACID in first-line lung cancer. We still have a high commitment to continue developing durexone RACID in lung cancer, particularly in first-line.

higher resolution answer to that.

The reality is that there are a number of options available to us. We continue to both dose optimize duraxomer acid in combination with the combination partners that you might expect us to use for that indication testing to get the requisite proof of concept required to invest in a large base-through trial. So as soon as we have that information and a plan to go with it, we'll be able to share it with you. And I think we've committed to providing more information on that during the course of this year.

Yeah, and if I could just add, I think the other element to this, of course, is that we just started dosing patients with libanesimab. in combination with our Rasson inhibitors that obviously has fairly impact on how we think about lung cancer.

Understood. Thank you.

Thank you. One moment for our next question. Our next question comes from Brian Chang of JP Morgan.

Your line is now open.

Hey, guys. Thanks for taking our questions this afternoon. As we get closer to the top line for the second line PDAC trial, what is your latest thought on the efficacy measure that we could get at the time of the top line? And just curious if you can provide a bit more color on the rates of events towards this upcoming top line. Thank you.

Hi, Brian. Thanks for your questions.

You know, of course, we've entered the period in which we indicated we'd be providing a disclosure, so I don't think we'll be able to give you higher resolution today. It doesn't seem like the right time to do that. It is an OS event-driven readout, and the study's powered for OS, but it's, of course, also overpowered then for PFS. So we'll have an interim read on that information. I don't think we'll be able to provide any expectations other than that we are directly comparing standard of care and that will be the set of benchmarks that will be used in our analyses.

Got it, thank you.

Thank you. One moment for your next question.

Our next question comes from Michael Schmidt of Guggenheim. Your line is now open.

Hey, good afternoon. Thanks for taking my questions, and congrats on all the progress. Mark, I heard one on your ongoing and planned studies in first-line pancreatic cancer. So obviously, there's a lot of excitement among physicians and patients. in the pancreatic cancer community are on durexinracid. We've heard from docs more recently that, you know, if approved, they think that over 90% of their second-line patients could go on durexinracid within months of approval. And so, when you think about that, to what degree do you think durexinracid use in your first-line studies post-progression in the control arm could potentially impact OS outcomes in RASLUT 303 and 305, and how important is it to demonstrate OS in these studies in the first place? Thank you.

Okay, thanks, Michael. I think I understand the question. To what extent does the availability of an approved duraxone RASID with a second-line label potentially provide the chemo arm in the in the second line study in the 302 study there is some potential risk for that of course the label would not necessarily indicate ability to cross over unless somebody was declared that they were now formally a second line patient we wouldn't be able to speak to what somebody might do off label but there is some there is some risk associated with that we have the ability to address that both through timing. We're moving forward with that first-line trial, and it will be some period of time before the FDA would review and potentially approve the product. So I think during that period, we can probably establish some significant momentum and buffer against that concern. And the other contribution to solving that is geography. significantly in those settings, it's not likely that the product would be approved yet during the early course of the study.

Makes sense. Thank you.

Thank you.

Our next question comes from Charles Zhu of LifeSci Capital. Your line is open.

Hey, good afternoon, everyone. Congrats on all the progress and thanks for taking the questions. I have a couple regarding some of your ongoing partnered collaborations. First, can you talk about your decision to also combine your pipeline assays with Bristol's PRMT5 inhibitor and how this kind of fits in context with your ongoing collaboration with Tango? And second, your collaboration with Ivan Nesimab. At what point might you make go-no-go decisions on later stage clinical development? with your pipeline assets, and how do you weigh not only the emerging combination data that you're generating, but also the broader landscape amongst the various Harmony trials shaping up?

Thank you. Thanks, Charles. I appreciate those questions. Really two different topics.

One is PRMT5 inhibitors and why assess or support assessment of RAS1 inhibitors in combination with more than one PRMT5 inhibitor. To some extent, we'd already established that precedent because we have an ongoing collaboration with both Amgen and Tango, and the PRMT5 inhibitors appear to be emerging as a potentially important new targeted class of therapies for patients with MTAP gene deletion. So it makes sense for us to make our compounds, which are differentiated and compelling, and make them available to to the work that's ongoing with Tango or Amgen.

It's rather more of an inclusive approach and to allow for compounds to be considered in other contexts as well.

With regard to the second question, which is Ivo Nesimab and how will we make decisions about when to advance into a late stage trial? It will depend on the context. You know, potentially this class of inhibitors could offer significant advantage over the first-generation PD-1 inhibitors. There is a growing body of evidence to support that. We don't have the definitive data yet, and we are staying very much on the front lines of a combination of strategies involving Ivo with our Rasson inhibitors.

I think we'll be in a great position to make the decision with some data in hand. Understood. Thanks for taking the questions.

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

Thanks for taking my question. Congrats on all the progress. Maybe just first off on more of a bit of a housekeeping thing. Can you just confirm whether any event thresholds have been reached in 302 to trigger interim analyses yet, or if just none of those have been hit yet? And then thinking more broadly about pancreatic cancer, now you have several first-line trials either ongoing or getting started in the next handful of months. Just what is the kind of long-term vision you have for what the treatment paradigm in pancreatic cancer looks like in four or five years? How do Durex and RASib, Zoldan and RASib, chemo all get sequenced for maybe the typical patient?

Thanks for your question, Mark. I think I'll comment on the first one, and then maybe Alan Sandler can comment on your question about sort of future landscape and future expectations for treatment paradigms. My comment is I don't really have any answer to your question. When the data are unblinded, that causes us to do an analysis, which then leads to a disclosure.

And that's about all I can say today.

On your question about how does pancreatic cancer look a few years from now, Ellen?

Thanks for the question. Well, I think we've set up very nicely with multiple studies to kind of have a major say as to what pancreatic cancer will look like in the next three to five years. You know, with our early studies looking at second-line therapy with duraxone RACIP, moving into the first line setting also with Teraxon RASB, looking at it both with respect to as a monotherapy, but also potentially in combination with chemotherapy. And then we're doing that with a more specific agent such as Zoldan RASB for D, and looking at that as well in combination with chemotherapy versus chemotherapy in the frontline setting, but also the novel ability to combine it with Teraxon RASB also in that first line setting. This will provide patients with the optionality in first-line setting to actually potentially have a chemotherapy-free opportunity, as well as building upon the results that have been seen with chemotherapy alone. In addition, and potentially even more importantly, we have the opportunity to impact patients who have potentially curable pancreatic cancer by conducting 304, which is our adjuvant study for those patients who have had resected cancer in perioperative therapy. So we really are covering the gamut of patients with pancreatic cancer from second line therapy all the way to resectable and potentially curable pancreatic cancer. And I think that covers probably three to five and maybe even a year or two beyond that as well. And then in addition, of course, as Mark mentioned earlier, there are other agents in our pipeline that we'll be looking at as well that will also potentially have an impact.

Okay, thank you.

Thank you.

Our next question comes from Alex Stranahan of Bank of America. Your line is open.

Hey, guys. Thanks for taking our questions. With the Ivanesumab study now dosing patients, I guess, could you maybe speak a bit about the study design and which tumor types and lines of therapy you expect might enrich in the study as it enrolls? And longer term, how is this combo maybe emblematic of how you're hedging your RAS therapies alongside potential shifts in standards of care? Thank you. Thanks, Alex.

I think Dr. Lin, our chief medical officer, can comment on what's our approach to Ivo in the initial phase one context.

Thanks for the question. So the trial, as has been pointed out, has been initiated, and that's the APEX study. It involved all three clinical stage Raxon inhibitors. That's Raxon RASFib, Sodon RASFib, as well as Veyron RASFib that covers ORAS, the GCO-D, as well as the GCO-C population. There's a standard dose escalation involving Ionizumab in combination with Raxon, in combination with Sodon, and in combination with Veyron RASFib. And the dose isolation is standard O solid tumors, and it will help to define the safety and preliminary activity across some of the major solid tumors that's going to be seen. And then once the dose has been defined and safety has been cleared, there is dedicated expansion cohort across the three major disease of interest, both summit as well as revenue management.

that include pancreatic cancer, non-small cell lung cancer, and colorectal cancer.

And do you want to repeat your second question, which had to do with, I guess, hedging how treatment landscape may evolve in the context of Ivo?

Yes. Just broadly, how you're thinking about combos as standard of care evolves across these treatment settings.

Yeah. Well, I think we're not holding anything up. We're certainly developing things in combination with PEMBRO to the extent that that makes sense to do. But we also have to recognize that that field is evolving. And so we're right on the leading edge of it in collaboration with Summit to make sure that we're the first to evaluate RAS inhibitors, and particularly class-leading RAS on We'll learn a lot. With regard to non-small cell lung cancer, where PEMBRO really is a dominant standard of care in most parts of the world, it will take more to knock that off and for there to be a real change. And that will be up to IVOD to prove itself, which is currently work that's underway. In the GI tumors, there's much less there and again to be the first RAS inhibitors for the RAS speed versions of those of those tumors in combination with Ivo is an exciting thing to do so we're playing playing all of it all the time sort of like our overall strategy everything everywhere all at once and and that's pretty much what we have to do in a rapidly evolving environment that makes sense thanks so much for the color

Thank you.

Our next question comes from Ashika Gunnarwardeen from Truist. Your line is open.

Hey, guys. Nice to take my question. I want to kind of go back to Albert's question at the beginning, specifically on Durexan and frontline non-small to small. I guess in previous calls, we talked about, and you pointed out how PEMBRO plus chemo is a backbone therapy and how it makes a lot of sense to consider that in combination with duroxaniracid. But when you talked about other options today, I wanted to just get a little clarity here. When you talk about other options, do you mean other PD-1s in combination with chemo, other mechanisms, like maybe involving PD-1 and CTLA-4, or are you thinking, are you considering chemo-free options here for the ideal regimen you want to take, Durexan, into frontline non-small cell lung?

I think that was really in reference to first-line lung Durexan-RASib and whether it should be combined with with PEMBRO and chemo, or whether potentially Ivo emerges during that period of time. I think that was the context for that narrow answer, is that we're now evaluating Ivo, and so we'll have some of that information. But in the meantime, as Steve had articulated, we are continuing the dose optimization and efficacy analysis of Duraxone plus PEMBRO plus chemo, the Kino-189 context. So those are running in parallel.

to make the best decisions.

Got it. Thank you. It's going to take a quick one in.

Any thoughts on whether you will use your commission's priority review voucher for second line PDAC once you have the Resolute 302 data in hand?

Thanks, guys.

Thank you. What's the question? CNPB will be used for certifying PDAC.

Oh, I see. Yeah, I think that's been made clear that it wouldn't really make sense hold back, the CNPB was awarded on the basis of largely second line and third line data that we have shown publicly and shared with the FDA.

And so, I can't really see a scenario in which we wouldn't be operating under the CNPB in that second line 302 data readout context.

Thank you. One moment for our next question.

Our next question comes from Laura Prendergast at Stiefel. Your line is open. Hey, guys. Thanks for taking the question.

In a recent public appearance, Mark, you brought up the concept of treating beyond progression in PDAC, you know, from the angle of patients progressing under XMR in large part due to amplification of the RAS target. It seems to be a pretty unique consideration in oncology, you know, where perhaps removing the drug upon progression of PDAC is not in the best interest of the patient. I think that raises a few important questions at our end. First, are investigators on the phase three studies, first and second MLA-PDOT, being encouraged to treat insulin progression?

Is it allowed through safety protocols?

Since I could only hear every other word of what you were saying, I'm going to have to sort of infer. The question was about treatment beyond progression. We have made the comment that we've heard a number of anecdotes from investigators who have chosen to continue treating patients based on clinical criteria, even in the face of some sort of radiographic progression. And in that context, they've observed a number of patients who continue to do quite well on duraxone or acid for even long periods of time. with a RAS inhibitor, and it's the driver after you stop treating with a RAS inhibitor. And so, in reality, it probably doesn't make much sense to discontinue if a patient's continuing to benefit, and that set of observations that we've heard syncs up nicely with that underlying biology. But we don't have enough quantitative data to really say anything definitively. We're really giving you anecdotal comments here and theoretical comments, but now, We'd like to collect some more data to determine if that really does establish an additional benefit over and above the benefit they've already received at that point in time. That's my general comments, but I don't know what the actual question was. Can you clarify what you were specifically asking beyond that?

Yeah, so specifically as it relates to study protocols, was there any restrictions on how much, on whether or not this is a possibility on the first line or second line phase three? and then how you guys think this could impact overall survival of those studies.

Yeah, okay, I do understand the question now. So did we formalize this in the 302 study versus other studies? It's not in the 302 study because that study was already too far underway to make that modification that would be difficult to do in the middle of a study. And so progression beyond, treatment beyond progression is not permitted, was not permitted, is not permitted in the 302 study. We've encouraged investigators to evaluate that possibility and where it makes sense to continue treatment beyond progression, particularly in the earlier line studies. And so we'll be able to generate a lot more information in those contexts.

Got it. Thank you. Thank you.

Our next question comes from Jay Olson of Oppenheimer. Your line is open.

Oh, hey, guys. Congrats on all the progress. Thanks for taking our question. Since you're making a lot of headway in PDAC and non-small cell lung cancer, can you talk about your vision and strategy in colorectal cancer? And how are you prioritizing the CRC opportunity for RevMed? Is CRC an area that you would prefer to focus on with partnerships, for example, in combination with Ivanesumab? Or is CRC something that you plan to pursue independently and from a BD perspective, would you consider in-licensing some molecules that have synergy with your RAS portfolio so you wouldn't need to rely on partnerships in CRC? Thank you.

Yeah, Jay, thanks for your question. Maybe Steve and Kelsey can just comment in general on our approach to CRC, and then if there's anything left on BD at the end, I can come back and comment on it. Yes.

Colorectal cancer has never been deprioritized. We, right from the very first, right from the start of the Durex on RAS and Zolvin RAS of this escalation studies, we included patients with colorectal cancer. I think what we found, which was hardly surprising because a number of other people have also found this both before and since, is that colorectal cancer is an incredibly complex and heterogeneous disease with multiple subclones, each of those clones often containing multiple genetic abnormalities. And as a result, what happens is that two things happen, really. One is the overall response rates are lower than they are traditionally in the other RAS-driven diseases, which makes rapid decision-making about future clinical development more complicated because now you have to wait for somewhat longer-term readouts like PFS. And secondly, it becomes an obligate combination play. There really are no opportunities for developing a single agent in advanced colorectal cancer. In the late-stage colorectal cancer, after chemotherapy's failed, it's such a combinations and in earlier lines of therapy you really need to combine with combination chemotherapy which is standard of care so it becomes more difficult and more time-consuming to reach a point where there's a clear path forwards into pivotal trials and I think that's what we have found and it's got nothing to do with prioritization it's got it's really down to the biology of the disease and how that translates into early stage clinical trials. With regards to methodology, our philosophy as a company is that we have made the decision to be a standalone global organization and we are not looking to change that purely based on a disease or a history type. there may be opportunities for doing studies in collaboration with partners if the right partner, if we believe that's the right combination and we have the right partner, we may choose to do it as part of a clinical collaboration or maybe even as some other type of business arrangement. But right now, that's not the preferred or even the base case plan. Our plan is to figure out which combinations involving a Rasson inhibitor can make the biggest impact and cover up the cancer and prosecute those to registration? I think your answer covered it pretty darn well.

You know, maybe the one last little piece is would we bring in additional compounds into our pipeline? That's always possible. We have a very robust process by which we evaluate other people's assets. We receive a lot of inbound. proposals and occasionally we reach out to somebody else to learn more. So that's all just practical considerations.

The fundamental points I think Steve made are the fundamental points.

Thank you.

Our next question comes from Leo Timishev from RBC. Your line is open.

Thanks for taking my question. I wanted to ask a little bit on RMO55 and that class of molecules. I guess, does this address secondary mutations, or does it really only work directly on RAS mutations themselves? And I guess, said another way, do you think you'll ultimately need to be selecting patients that might be amenable to this? And then, you know, just based on some of the preclinical work you've shown, it looks like it drives very deep responses even relative to Durex on RAS. So, are you seeing this ultimately be positioned as a, you know, next line option, or can this be something that ultimately replaces and is a better Durex on RAS?

Thanks. Yeah, thanks, Leo. Appreciate the question. All interesting ideas. I think that will become a little bit clearer when our scientific team has a chance to present more formally and in a more fulsome way at an upcoming scientific meeting. The one thing I'll say biologically is that point mutations have not emerged as the major form of resistance for duraxone RASP. What has emerged is reactivation of the RASP pathway through other means, typically amplification of the original mutant allele through increased signaling, for example, through RTKs, to increase flux through the pathway, and so on. And so, Dyraxon RACIP seems to do, generally, a very good job of suppressing new oncogenic mutations that might have otherwise emerged in the setting of a mutant selective inhibitor. So, that really isn't the primary problem that we're trying to address, or that the team had as its mission in developing this new class of inhibitors. But more to come.

Stay tuned. Thanks for the question.

Thank you.

Our next question comes from Ami Fadiyah from Nebium and Company. Your line is open.

Hi, this is Poonah on for Ami. Thank you for taking our question. I just want to understand how soon can you get to commercialization of data in case the first interim is positive? What are some of the aspects within the commercialization preparation that you still need to work through? Thank you.

Thank you for those questions. So I think you're asking about what have we done to prepare and what does the timeline look like? I think Anthony can step into that.

Yeah, thanks for the question. I think we're really pleased with how our launch readiness plans are advancing. And we continue to add highly experienced and talented members of the team. And we're really achieving broad organizational readiness led by the US, but also in Europe and in Japan. So we're really pleased with the launch readiness across the board. As Mark alluded to in his prepared remarks, that launch readiness in terms of the US, the first launch is actually proceeding quite well with leadership teams in place across commercialization and across functions field-based leaders across meta fairs market access marketing and sales and as mark mentioned as well we've we've now initiated uh the posting of our our further uh extension of our field-based teams uh you know our sales team so we're really really pleased with how uh with how the launch readiness overall is coming together. And certainly, as we get closer to filing and launch, we'll provide some more color there.

Thank you. Thank you.

Our next question comes from Kalpit Patel of Woof Research. Your line is open.

Hey, thanks for taking the question. I guess how should we think about the disclosure of the pivotal update here in second-line pancreatic if for any reason you missed the interim PFS analysis and that does not cross the pre-specified boundary? Would you expect to provide an update at that point or would you just wait for the OS-driven readout thereafter?

Well, thanks for your question. I don't think we can give you much of an answer to that question right now. We'll see what the data show and decide what we consider as appropriate disclosure at that time. Just a reminder, it's OS event driven. It's powered for OS, which means it's more powered for PFS. So the possibility that it doesn't cross PFS is It's less likely than not crossing OS at that interim analysis. So if there's a split result, it could be PFS is crossing OS, has not reached a statistical significance yet. That's conceivable. I'm not emphasizing that particularly, but it is one of the possible scenarios.

And we'll just have to see what that looks like at that point in time and make an appropriate disclosure decision.

Thank you. Thank you.

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

Hey, guys. Thanks for the questions. Can you speak to the staggering of enrollment for RASLUTE 302, 305, and 309 and the 303 protocol components to ensure a representative sample of mutations in 303 and avoid an enrichment of non-G12D patients? and perhaps germane to that as well. Can you speak to your expectation for the G12D versus the G12V and G12R patients? And the GNP arm given G12D tends to be a bit more aggressive and chemoresistant.

Thanks. Okay. I got the general idea. There were a lot of specifics in that. Maybe just the staggering of enrollment. Just make sure we understood your question. Were you linking the staggering of enrollment to the mutation representation, or was that more of a broad question about getting access to patients and enrolling patients?

Didn't quite follow that.

Yeah, linking. So, obviously, 303 is all comers there versus 305 and 309 being G12D. So, the staggering as it relates to kind of shuttling the patients, you know, avoiding shuttling the G12D patients to the 305 and 309 studies.

Do you want to comment on that?

Sure. I think some of this will be managed by the site selection. All three are global trials. We're certainly mindful that we want to have a fair and equitable representation of all RAS mutants or actually an all-comer population in the 303 study and the G12D mutant population in 305 as well as 309. And the control arm do vary among these three trials. So 305 specifically does offer both GMP as well as Folfirinox versus 309 and 303 offers GMP as a control. And as you know, there are local regional practices as well as institutional practices when it comes to preference for GMP and Folfirinox. So we have a variety of sites, region, country to select from. The PDAC patients are certainly very common. As you know, there's about nearly 60,000 Americans newly diagnosed with PDAC every year. Half of those are probably first-line metastatic patients. The U.S. alone would account for about 30,000 in a year, and globally, certainly many more. I don't think there'll be a lack of patients they'll be selecting from. It's really trying to identify sites based on their local practice and investigator interest in any of these trials, and then offering these trials as options to their patients. And we're still being mindful about the site footprint overlap around these three studies to ensure that the competition across these three studies are not going to be at individual site level.

Maybe back to mutations and their representation, 85% of PDAC cases have a G12 mutation. I think it's going to be hard to bias that dramatically just from a few ongoing trials. And so there should be fairly similar representation across any of the multirast inhibitor trials. And then in a G12D trial, it's going to be G12D mutations. It's going to be very specific for that. And then within any given trial, there should be balance between the control groups and treatment groups because there will be randomization after patients designated for a particular chemo type. If it's a chemo-bearing trial, then they would be randomized to treatment arm versus chemo. So there should be balance throughout these.

I'm not sure that there's any inherent bias that would lead towards anything unusual.

Thank you.

Understood, thanks.

Yeah, and just on the expectation for the, in the 303 study for G12D performance relative to G12V and G12R, given the, you know, respective expectations for each of those mutations being treated with GMP. Thanks.

Well, you're asking a question as to, the question as posed presupposed that they are very well established differences amongst these mutations and how patients perform in a given treatment. I don't think that's so well established. In fact, if you look at multiple studies, you can find very conflicting results. It's just not particularly well established. So again, though, whatever it is, whatever the underlying biology is, will be randomized and balanced in a given

versus experimental.

Understood. Thanks.

Thank you. Our next question comes from Faisal Khurzad of Jefferies. Your line is now open.

Hey, guys. Thanks for taking the question. I just want to ask, now that you've had the commissioner priority review voucher for a little bit, can you speak to what benefits you are either seeing now or expect to receive from that above and beyond what you'd otherwise get from programs like Breakthrough Designation and the Realtime Oncology Review? Thank you.

Yeah, thanks for your question. We don't have much to offer on this particular point. We don't generally disclose a great deal about our interactions with the FDA other than to say we do have a constructive interaction with the review team at the FDA with the division that's handling this. It's the same group that's been handling it all along. They just now have a CMPB to manage, and we found them to be very communicative, and we have a good constructive dialogue underway. The main advantage that's been described to go with this would be a faster review process. That's really what it's all about. That's really a question for the FDA and not for us. What we'll do is we'll provide the data and the sequence that they're requesting it, and as quickly as we can, and then their clock, as they see it, starts ticking once they accept a submission, which means after everything's in, they've reviewed it and decide that it's an adequate submission, then they can accept it, and then they've given a suggested timeframe for how long, how quickly they would review it, but that's not in our hands, so we don't really have any comment to make on that.

Great, thank you.

Thank you. I am showing no further questions at this time. I would now like to turn it back to the Chairman and CEO, Mark Goldsmith, for closing remarks.

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

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