Good day, and thank you for standing by. Welcome to the Revolution Medicines Q4 2024 Earnings Conference Call. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay. Please go ahead.

Thank you, and welcome, everyone, to our fourth quarter 2024 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; and Dr. Wei Lin, our Chief Medical Officer, will join us for the Q&A portion of today's call. Certain statements we make during this call will be forward-looking. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended December 31, 2024, 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 Medicines' Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. Good afternoon, and thank you for joining us. Today, I'll cover highlights of progress with our pioneering RAS(ON) inhibitor pipeline and outline important priorities for 2025 as well as markers of progress we expect going forward as we pursue these priorities. Jack Anders will then summarize our financial results and provide a forward-looking financial view. Our mission at Revolution Medicines, one that we have pursued for much of our 10-year history, is to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. This mission is anchored in three pillars: discovery, development, and delivery. First, our innovative clinical stage RAS(ON) inhibitors have shown our discovery capabilities to be among the most productive in the industry. Extensive original research in RAS biology and advances in our technology platform have given us critical know-how and a deep pipeline of proprietary assets we expect will enable us to continue raising the bar for what’s possible in treating patients with RAS-addicted cancers. Second, our first-rate development capabilities have advanced multiple assets through first-in-human studies and progressed our lead program into late-stage development. We will continue strengthening these capabilities as we move into additional registrational studies across our portfolio and across a number of tumor settings and lines of therapy. Third, we are preparing to deliver our novel therapies to patients by building strong commercialization capabilities in support of a successful launch, subject to regulatory approval for daraxonrasib. Supporting our mission is an ambitious strategic roadmap for maximizing the impact our RAS(ON) inhibitor portfolio can have for patients living with RAS-addicted cancers. Our commitment to the level of ambition is reinforced by our track record of productivity and successful execution. We have been pioneers in the RAS space. Scientific innovation within RevMed has resulted in the first three clinical stage RAS(ON) inhibitors: RAS(ON) multi-selective inhibitor, a RAS(ON) G12C-selective inhibitor, and a RAS(ON) G12D-selective inhibitor, each with a unique and promising clinical profile. Last month, we introduced the international non-proprietary or generic names for these three compounds, each of which is centered on the shared phrase onrsaib that alludes to the novel RAS(ON) mechanism of action for this new class of compounds: daraxonrasib or RMC-6236, our groundbreaking multi-selective RAS(ON) inhibitor; elironrasib or RMC-6291, our distinguished G12C-selective covalent inhibitor; and zoldonrasib or RMC-9805, our innovative G12D-selective covalent inhibitor. In 2024, we built on our record of execution. We made substantial progress in advancing this portfolio of RAS-focused investigational drugs. We reported compelling monotherapy clinical data with our first wave of RAS(ON) inhibitors, particularly daraxonrasib in pancreatic ductal adenocarcinoma or PDAC and in non-small cell lung cancer, and zoldonrasib in PDAC. We also reported initial evidence of two promising combination strategies. The first is initial clinical proof-of-concept for the first-of-its-kind RAS inhibitor doublet with the combination of elironrasib with daraxonrasib. These data are highly encouraging and increase our confidence in the innovative RAS doublet concept more broadly. We've completed dose escalation on a second RAS(ON) inhibitor doublet, zoldonrasib combined with daraxonrasib. We will study both RAS(ON) inhibitor doublets further as potentially compelling options for patients, particularly as we move into earlier lines of treatment. The second is early safety and tolerability data for both daraxonrasib in combination with pembrolizumab and elironrasib in combination with pembrolizumab, observations that are highly encouraging and potentially enable a path to develop therapies for first-line metastatic non-small cell lung cancer. In addition, we entered discovery and clinical collaborations designed to expand the range of treatment strategies we can bring to bear for patients with RAS-addicted cancers. Such collaborations enable us to explore a range of combinations with inhibitors of novel targets, exemplified by a PRMT5 inhibitor under our agreement with Tango, and novel approaches such as bispecific antibodies under our agreement with Aethon Therapeutics. We also formed collaborations with leading industry and academia translational research partners, such as the breakthrough cancer organization that presents a valuable opportunity to uncover new patient-centric scientific insights to further inform our ongoing commitment to transformative science. Last year, we also made progress in building the organizational capabilities needed for us to drive the next stage of our strategic plan. In particular, we deepened our late-stage clinical development presence by launching our first Phase III registrational trial, reaching commercial-scale manufacturing of daraxonrasib, and strengthening our organizational capabilities in preparation for a potential first regulatory approval. We formed select partnerships to help us fulfill our tireless commitment to patients as we prepare to deliver our novel therapies to patients broadly. For example, to ensure that we keep patient needs at the forefront as we advance these medicines, we now have a relationship with the Pancreatic Cancer Action Network, or PanCan, a distinguished organization devoted to improving the lives of people living with pancreatic cancer. We ended 2024 in an exceptionally strong financial position, allowing us to continue our ambitious patient-centric strategy. 2025 will be an important year for RevMed as we advance our strategy aiming to maximize the impact we can have for patients with RAS-addicted cancers. I'd like to outline the highest current priorities that we anticipate could drive significant company transformation and value creation and to identify some of the markers of progress to follow. Our first priority is to execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic pancreatic cancer and non-small cell lung cancer. For the global Phase III RASolute 302 randomized controlled trial currently underway in patients with second-line metastatic PDAC, enrollment is an important measure of progress. So far, we have seen very strong interest among patients and investigators with highly encouraging enrollment at the initial U.S. investigational centers, and we are actively opening new U.S. sites in line with our plan. With regulatory clearances in the EU and Japan in hand, we are also activating ex-U.S. sites to support the global strategy. We currently anticipate substantially completing enrollment in the trial this year to enable an expected data readout in 2026. For non-small cell lung cancer, I'm pleased to confirm that activation of investigational sites is now ongoing in the Phase III RASolve 301 randomized controlled trial comparing daraxonrasib to docetaxel in patients with previously treated metastatic RAS tumors. Our second priority is to advance daraxonrasib into earlier line randomized pivotal trials in patients with PDAC. We expect to initiate a trial in first-line metastatic disease comparing a reference arm of patients treated by chemotherapy to two investigational arms: one with patients treated with daraxonrasib monotherapy and one with patients treated with daraxonrasib plus chemotherapy. Based on single-agent data and preliminary chemotherapy combination data, we are optimistic that both treatment arms containing daraxonrasib have the potential to become important therapeutic options for patients living with metastatic pancreatic cancer. We plan to finalize the trial design later this year when we have sufficient safety and tolerability data from the currently ongoing daraxonrasib plus chemotherapy safety cohorts. Of course, we'll need to align with the relevant regulatory authorities, including the U.S. FDA before we can initiate the global randomized Phase III trial in patients with first-line metastatic PDAC. As a further step in our ambition to serve patients with earlier stage disease, I'm very happy to share that we are actively designing a registrational trial with daraxonrasib as an adjuvant treatment for patients with resectable pancreatic cancer who have undergone surgery and perioperative therapy, often including chemotherapy. This population constitutes approximately 15% of newly diagnosed pancreatic cancer cases in the U.S. each year. We expect to move quickly on developing this program in parallel with our work to finalize the pivotal trial in first-line metastatic disease mentioned earlier. We anticipate that both of these pivotal trials will be initiated in the second half of this year. Our third priority is to generate sufficient data to inform development priorities for the mutant selective inhibitors, elironrasib and zoldonrasib and prepare to initiate one or more pivotal trials either as monotherapy or in a drug combination; and a number of options are under consideration. For example, we continued development of zoldonrasib, our innovative RAS(ON) G12D selective inhibitor for which the first-in-human clinical data, including a favorable tolerability profile and encouraging antitumor activity in RAS G12D PDAC, were reported at the triple meeting last quarter. A key mark of progress against this priority is generating additional clinical data that helps to qualify and prioritize these options, and we expect to share additional clinical safety and antitumor activity on this exciting compound in the second quarter of 2025. Another example is our ongoing efforts to identify and advance rational combination strategies with our RAS(ON) inhibitors. We are data-driven in prioritizing among multiple combination options for advancing into earlier lines of therapy. As noted earlier, we have already provided initial encouraging safety and tolerability data for both daraxonrasib and elironrasib in combination with pembrolizumab, thereby enabling potential combination paths to pivotal studies in first-line metastatic non-small cell lung cancer where pembrolizumab is the global standard of care. We also provided initial encouraging data on the combination of elironrasib with daraxonrasib in KRAS G12C colorectal cancer that provide initial validation of this innovative approach. We are actively enrolling and evaluating this RAS(ON) inhibitor doublet in combination with pembrolizumab as a triplet regimen in KRAS G12C non-small cell lung cancer as a potential chemotherapy-sparing first-line treatment. A trial evaluating a doublet of zoldonrasib with daraxonrasib is currently in an expansion phase across a range of solid tumors at the anticipated single-agent recommended Phase II dose for each agent. We plan to evaluate emerging data from multiple ongoing studies to help us prioritize among the range of potential monotherapy and combination clinical development plan options. Based on this work, we expect to initiate one or more pivotal combination trials in 2026 that incorporate either elironrasib or zoldonrasib, likely based on a RAS(ON) inhibitor doublet, and anticipate sharing clinical data supporting these plans in the second or third quarter of this year. Our fourth priority is to progress our earlier-stage pipeline, including advancing next-generation innovations from our highly productive discovery organization. In particular, we currently expect to advance RMC-5127, our RAS(ON) G12D selective inhibitor to a clinic-ready stage this year. This will enable initiation of a first-in-human dose escalation Phase I clinical trial in 2026 and a subsequent evaluation of a RAS(ON) inhibitor doublet with daraxonrasib. Based on a highly productive virtuous cycle between the preclinical and clinical sciences enabled uniquely by our platform and pipeline, we are excited about other promising next-generation preclinical programs that will continue to be areas of investment for us to sustain our innovation pipeline beyond the current development stage assets. Finally, we are growing our commercial and operational capabilities and increasing pre-commercial activities in support of a potential launch. We have experienced and talented executives leading our commercial and medical affairs teams, and these groups have already begun expanding our visibility in key settings, including clinical conferences to reach leading oncology practitioners. It is clear that our presence and growing leadership role are being felt. We continue to expand key aspects of our organization to support a commercial launch by adding top talent, including our U.S. field teams. We expect to continue to partner with translational and clinical experts and leading patient advocacy organizations to complement our internal capabilities. We are resourcing our efforts to ensure that we have the best strategies, tactics, operational capabilities, and people to bring daraxonrasib with urgency to patients with previously treated metastatic PDAC through a successful launch, pending regulatory approvals. We see the U.S. as a core foundation and an important driver of potential long-term shareholder value. We are committed to retaining control of U.S. commercial rights as a main element of our current strategy. We also continue exploring strategies for serving patients outside the U.S., potentially including partnership opportunities to help us determine the best approach to ensure global access. We're excited about the continuing momentum and remarkable opportunity we have in front of us and look forward to reporting on markers of progress as we advance programs throughout the year. I'll now turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance.

Thanks, Mark. We ended the fourth quarter of 2024 with $2.3 billion in cash and investments, which includes $823 million in net proceeds from our upsized equity offering last December. We project that our cash and investment balance can fund planned operations into the second half of 2027 based on our current operating plan. This operating plan has been updated to reflect anticipated increased spend resulting from our growing confidence in the advancement of our clinical development programs. Turning to expenses. R&D expenses for the fourth quarter of 2024 were $188.1 million compared to $148.5 million for the fourth quarter of 2023. Please note, the prior year quarter included $13.1 million in wind-down costs associated with the EQRx acquisition. The increase in R&D expenses was primarily due to increases in clinical trial-related expenses and personnel-related expenses associated with additional headcount. G&A expenses for the fourth quarter of 2024 were $28.2 million compared to $32.2 million for the fourth quarter of 2023. The decrease in G&A expenses was due to $13.8 million in EQRx wind-down costs in the prior year quarter. Excluding these nonrecurring EQRx costs, G&A expenses increased in the fourth quarter of 2024, which was primarily due to increases in commercial preparation activities and personnel-related expenses associated with additional headcount. Net loss for the fourth quarter of 2024 was $194.6 million compared to $161.5 million for the fourth quarter of 2023. Please note, net loss for the prior year quarter included a total of $26.9 million in EQRx wind-down costs. The increase in net loss was due to higher operating expenses as described earlier. Full year 2024 financial results are available in our corresponding press release and also in our Form 10-K that was filed with the SEC this afternoon. Turning to financial guidance for 2025. We expect full year GAAP net loss to be between $840 million and $900 million, which includes estimated non-cash, stock-based compensation expense of $115 million to $130 million. The increase in expected GAAP net loss for 2025 is as a result of increased expenses associated with 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 2025 as a result of increased commercial preparation efforts as we continue to build and expand our organizational capabilities in preparation for becoming a commercial stage company. That concludes the financial portion. I'll now turn the call back over to Mark.

Thank you, Jack. In 2024, we continued to deliver compelling clinical observations and to build on our track record of effective execution. We have begun 2025 with the talent, capabilities, and financial capital to fuel our vision to create an industry-leading targeted medicines franchise for patients with RAS-addicted cancers and to fulfill our responsibilities to patients, investors, and employees. The foundation we have established sets us up for long-term sustainable growth in support of our aim to revolutionize treatment for patients with RAS-addicted cancers. With that, I'll turn the call over to the operator for the Q&A portion of the call.

Our first question comes from Ellie Merle of UBS. Your line is now open.

Hi, guys. It's Sam on for Ellie. Thanks for taking our question. I guess can you walk us through the decision to move forward with the two Phase III studies in the earlier line PDAC? And I guess, specifically, what gives you conviction on the Phase III in the adjuvant setting? And can you talk a little bit about the role of RAS in this earlier line setting?

Yes. Thanks very much for your question. I think based on the data that we've already reported in pancreatic cancer, the monotherapy data, I think we have a strong conviction that we ought to try to own the entire PDAC space across all lines of therapy. So we've indicated that previously, and this is just furthering towards that goal. We've already previous announced that we intended to pursue a first-line metastatic study. The question has always been what will be the composition of the various cohorts in that trial, and we've provided a little bit of clarity around that today, and we'll continue doing so as the year progresses. The adjuvant is basically a study of patients who will have had their disease resected and represents an important opportunity to provide very significant long-term clinical impact for those patients. The proof-of-concept that supports pursuing that particular indication is already provided by the second line and third data that we've shown previously with monotherapy. So I think both of these are very rational and appropriate things for us to pursue, and we'll further our goal of completely owning the PDAC space with this compound.

Yes. That makes a lot of sense. That's really helpful. And then I guess just a quick follow-up. Can you just touch on how the frequency of RAS mutations might differ in the adjuvant setting versus maybe like the advanced or metastatic disease and how you're thinking about the overall opportunity there?

Oh, I don't know that there's any evidence that those patients would have any different representation of RAS drivers and all other patients, which is essentially almost all pancreatic cancer patients have a RAS driver. And so there's no reason to believe that those patients would behave any differently in response to daraxonrasib.

Thank you so much.

Our next question will come from the line of Eric Joseph of JPMorgan. Your line is now open.

Thank you. Thanks for taking the questions. The proposed pivotal study in the adjuvant setting is also interesting to us and expansive to what we've generally thought about as being in-scope in pancreatic cancer. You noted, Mark, that resectable PDAC is about 15% of overall cases, if I heard that correctly. Has this been a static metric? I wonder if you see this proportion sort of expanding at all with perhaps early detection initiatives? And then as it relates to the pivotal study, I guess how should we be thinking about the regulatory bar that would need to be satisfied for registration? Is it PFS OS? It would be great to hear your thoughts there. Thank you.

Yes. Eric, thanks for your question. I don't think that we can comment today on the second part of the question since we really haven't engaged with regulatory authorities at the moment. So that will be something that we address in the future. But on the first question, I think I'll ask Dr. Wei Lin, our Chief Medical Officer, to comment on the estimated proportion of total PDAC cases that are currently considered resectable and whether that could evolve over time.

Thanks, Mark. It's a great question. I think in the short term, we don't expect the number to change because that detection is largely driven by whether there's any screening. Unlike breast cancer, colorectal cancer, there's no mammography or colonoscopy, and there's no pending test evaluating patients with pancreatic cancer. Now with blood tests for ctDNA and so on, that's a much more long-term to be established before it becomes standard of care. That's why we don't, probably in the short term, see that number changing.

Yes. And if I could just add that, of course, there are efforts underway to try to develop such screening tools that are largely based on circulating tumor DNA. And to the extent that we can show further benefit to patients who are diagnosed earlier in their disease, that I think will further promote those efforts, but those are future events to occur. And of course, the possibility of even clearing a tumor to the point of cures becomes credible in the context of resectable disease. So if it's become possible to diagnose patients much earlier than, the possibility of even greater impact, as you point out, becomes much higher. But as of now, we just have to focus on the patients who are diagnosed, and they do represent a significant fraction.

Okay, great. Thanks for taking the questions. I appreciate the color.

Thank you. Our next question comes from the line of Marc Frahm of TD Cowen. Your line is now open.

Thanks for taking my questions. Maybe I wanted to start just a follow-up on the questions about adjuvant design. Pancreatic attacks also talk about borderline resectable disease, not just resectable. And then there's also, within resectable, some patients get Whipple procedures, others don't get Whipple. Would you be looking to go after all surgeries or just kind of certain subsets there because there are some varying outcomes depending upon which one you fall in? And then similarly, with the current trial in late-line disease, you have this hierarchical analysis based on different RAS mutations. Would you also do that and enroll broadly? Or is that kind of introducing too much risk when you're moving lines, different subsets, and different mutations in there?

Thanks, Marc. Is the second question also relating to resectable? Or was that referring to...

Well, it's adjuvant. Both first-line and adjuvant for that second part of that.

I see. Okay. Good. I think Wei can address both the definition of resectable and what we're thinking about right now and then also testing and whether or not to stratify.

The first question is about the patient population. To begin with, I want to clarify that we have not gained any traction yet, so the final design is still awaiting further interactions. However, we would like to position daraxonrasib as a new standard of care for patients who have undergone resection of their primary disease and have any form of preoperative disease, generally chemotherapy, as broadly defined. The final design is still pending, but our objective is to identify the largest patient population that could significantly benefit from daraxonrasib. Regarding the mutation specifically, this aligns with Mark’s earlier point. We believe that RAS is a key initiating driver mutation for cancer. It appears that the preference for this mutation remains consistent across various lines of therapy, including the adjuvant or early disease settings. Our strategy for developing daraxonrasib mirrors our approach in the metastatic setting, aiming to include as many eligible patients for our trial as possible, embracing a potential all-comer strategy for the entire population of pancreatic cancer patients.

Okay. That's really helpful. And then maybe just a more strategic if you, Mark, based on how you balance with all of these different combinations, also monotherapy opportunities to move forward into earlier lines, just how do you balance moving quickly versus making sure you don't end up having to run too many redundant trials or setting bars that then make it difficult to get the best option for patients over the long term?

Yes. Well, that's a hard question. That's what we grapple with every day in our strategic considerations. I think our primary motivation here is to serve patients. And that means moving swiftly. When we have something that we think will move the needle for patients, we really need to do so. Given also the competitive environment from a business point of view, there's not a lot of opportunity for us to pause things and wait and see what we might offer that's better in that place of that. I think we just have to move swiftly to try to deliver against the unmet needs. Of course, to the extent that we generate data that tells us what to prioritize, we'll use that information in making these prioritization decisions. But there could be certainly circumstances where we can't make such a decision, but we wouldn't hold off on pursuing a Phase III registration trial because that could lead patients unserved and/or would leave opportunities for competition to step in and just to create new bars for us. We'd rather be the ones to create the bar and then try to beat the bar ourselves rather than chasing someone else. And given our current position, I think it's ours to lose. If we don't pursue these things, we will be setting ourselves up for a different scenario. We'd rather be first to the table where we can't be. So it's a challenging topic that falls into the category of an embarrassment of riches to a large degree because we can define multiple potential solutions to each of these situations. But we have to work in real time because for patients, this is a pressing matter. It's not something that they can wait years for us to sort out.

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

Hey, thanks for taking my questions and congrats on all the progress. I had a follow-up on your first-line metastatic pancreatic cancer strategy. So it sounds like you've now committed to doing a single three-arm trial there for registration as opposed to two separate trials. How much more Phase I work needs to be done with the chemotherapy combination before initiating the study? And will you be able to share some of that data perhaps later this year being as a monotherapy perhaps in first line or in combination? And secondly, what are your latest thoughts on how to incorporate zoldonrasib into your pancreatic cancer registration strategy perhaps relative to daraxonrasib? Thanks so much.

Thank you, Michael. So the first question is, are we continuing evaluation of chemotherapy combination to support that third arm in the trial? And the answer to that is straightforward: yes, we're doing that work now. We've collected some data, but we need more, and it mainly has to do with what regimen we select to move forward with. It's really not a good stage but is primarily driven by efficacy because we already have confidence in the efficacy based on the monotherapy second and third line data that we've already shared. So this is really just about safety and making sure that we can assure high enough relative dose intensity during treatment that there aren't long breaks. As you may know, both major forms of chemotherapy for pancreatic cancer often incur the liability of Grade 3 or higher adverse events that drive hospitalization that often results in discontinuation of anticancer treatment for some period of time. And that's not ideal, particularly for a targeted therapy, whereas continuous coverage as possible is likely to result in the greatest efficacy in the long run. So we just want to choose the best regimen or regimens to move forward with, and we need some more data to drive that, but it still is our intention in 2025 to initiate that trial. So we're moving as swiftly as we can to support that decision. The second question is zoldonrasib; do you want to comment, Wei, on zoldonrasib, pancreatic cancer and how we think about that relative to daraxonrasib?

Sure. Zoldonrasib, as you know, G12D has a prevalence of about 40% of pancreatic cancer. So it's the most common RAS mutation or specific mutation in general that's a driver of pancreatic cancer. We had shared earlier Phase I data showing that it is a highly active agent, and we're actually following on those results, looking for the durability of these activities. Our initial thinking is we will probably end up with a separate registration trial with a standalone registrational path. We’re currently evaluating a combination with daraxonrasib as a potential RAS(ON) doublet, the best-in-class option that could substantially improve on either monotherapy as well as the chemotherapy plus standard of care, with zoldonrasib. So those are potentially two options we could develop.

Thank you.

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

Great. Thank you. First, I just want to have another quick question on zoldonrasib. I guess is there any more color you can provide on the data update being contemplated in the second quarter? Specifically, what are the key learnings that you have to glean from these data?

Yes, Ben, thanks for your question. We don't have any more color to provide on that today. We do intend to provide additional data on zoldonrasib in the second quarter of this year. I think we'll just have to wait until those data are available.

Okay. Understood. And if I could maybe go back to sort of a previous question on frontline metastatic pancreatic cancer, it feels like there's been some debate as to the combined ability of daraxonrasib with chemo. Sounds like you guys are pretty confident that there is some combinability potential here given the design that you're proposing in the frontline metastatic cancer setting. But I guess the question is like what are the overlapping talk signals that one should be concerned with when thinking about daraxonrasib and the data that's been provided thus far with the various chemos being contemplated?

Yes, Ben, let me clarify. I don't believe there has been a debate about the potential for combining therapies. This point has been made several times, but I haven't encountered any real discussion on the matter. The issue we highlighted earlier this year is that chemotherapy alone poses significant challenges for pancreatic cancer patients due to the aggressive nature of the disease. The chemotherapy administered must also be aggressive, leading to considerable side effects and adverse events that frequently necessitate holding the drug temporarily or hospitalization. This alone could impact the ultimate effectiveness of combining chemotherapy with daraxonrasib or any other targeted agents. That is really the concern we've raised. I'm not sure there's been any substantial public debate regarding their combinability. Therefore, I don’t think we have additional insights on that since it hasn't been the main issue. We are currently evaluating this and remain optimistic about developing a regimen that successfully combines them, while being mindful of the fact that chemotherapy is often poorly tolerated. In many cases, this results in dose holds and typically causes dose reductions as one progresses through treatment cycles. This provides context for our position.

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

Hey guys, I was wondering if you could provide a little bit more colorectal cancer data disclosure cadence. Should we be expecting any chemo combo data, EGFR inhibitor combo double data this year? And then just any guidance on if or when there will be a registrational path for colorectal cancer and then maybe beyond the big three KRAS-driven tumors as well?

Yes. Laura, thanks for your question. We don't have any guidance provided yet on next disclosures about colorectal cancer. We, of course, are studying colorectal cancer. In fact, just in December, we disclosed data from a study of the combination of elironrasib with daraxonrasib in patients, quite advanced colorectal cancer patients who have been previously treated with a G12C inhibitor and really had no other options, and we showed significant activity from the combination of elironrasib with daraxonrasib. That was just six weeks ago or two months ago, but we don't have any guidance to provide. We continue to study this. There are a variety of different combination strategies that might prove to be interesting, and we're evaluating them. I think when we have information that starts to point to future strategies, we'll share that.

Thank you. Our next question comes from the line of Kelly Shi of Jefferies. Your line is valid.

Hey, guys. This is Clara on for Kelly. Thanks for taking our questions. So Phase I study in PDAC. As of the last update, the median overall survival was still immature at the opportunity. So just wondering, do you have any plans to update the overall survival data this year?

Yes. Clara, thanks for your question. Yes, what we showed before was two different ways of looking at the data. One was from an aggregate of multiple dose levels up to and including the 300-milligram cohort. There, we did show an overall survival estimate from the curves that was 14.5 months. When we took just the subset of that, that was the 300-milligram sort of subset, if you will, that particular dose cohort because those patients have been enrolled more recently than those patients with the earlier doses, those curves were not very mature. We therefore didn't have an estimate of OS per se, but we did have information regarding the 6-month OS which was quite high, depending on which safety looked at it was in the 97% to 100% range, which I think provided a pretty good look about what's going to come as these state mature. But of course, we don't have those data. So those do continue to mature. I'm sure at one point we'll have an estimate of that. We don't have that today, and we don't have any information to share, but I would imagine at some point, we'll share that information. We don't have a specific plan around it right now.

Thank you. Appreciate it.

Thank you. Our next question comes from the line of Chris Shibutani of Goldman Sachs. Your line is now open.

Hi. This is Kevin on for Chris. Thanks for taking our questions. I just wanted to clarify on the first-line lung opportunity. You noted that you're exploring the potential for a chemotherapy-free triplet combination here. Just in terms of your priorities, would you potentially also pursue a non-G12C frontline indication? Or do you still have plans to explore that? And then for the triplet, could that be one of the updates that we could expect in the second quarter or third quarter of this year? Thanks.

Thanks, Kevin. I think we have Steve Kelsey, our President of R&D. Maybe you could comment on how we think about the first-line lung cancer. Certainly, there are kind of multiple subsets, as you alluded to, essentially, G12C has now been defined as a sort of a disease in and of itself. Everything other than G12C, maybe Steve could comment on that.

Sure. We definitely divide the world of RAS-mutant lung cancer into distinct sets depending on the type of RAS mutation. I think that now G12C mutant lung cancer has established itself as a completely separate disease, probably requiring a G12C selective inhibitor. As of now, because we are acquiring and have presented preliminary data on the combination of elironrasib with daraxonrasib in G12C cancers, we would plan to move that chemo-free triplet into the G12C lung cancer space. Daraxonrasib would be prioritized for all other RAS mutant lung cancer without a G12C mutation, which is about somewhere in the region of 17% to 18% of all non-small cell lung cancer right now. So I think that addresses your first question. Can you remind me your second question?

Just following up on that. So does that mean...

Yes, we will release the data. However, I don't think we have specifically indicated when the comprehensive data supporting those clinical trials will be finalized. We are issuing data in segments as we gather it. We’ve already attempted to demonstrate that our RAS(ON) inhibitors can be combined with pembrolizumab, which is a significant step toward initiating first-line trials in non-small cell lung cancer. Not only can we combine our RAS(ON) inhibitors with pembrolizumab without increasing toxicity, but we can use what we believe to be the full recommended Phase III dose. We don’t need to reduce the dose to combine it with pembrolizumab like some other RAS inhibitors have had to do. We are actively enrolling patients in the combination of elironrasib and daraxonrasib for both colorectal cancer and non-small cell lung cancer while we wait for the durability to mature. Once that data is mature, we will provide you with updates. However, since it pertains to durability data, I cannot specify a timeline for when that will occur.

Great. That's really helpful. Thanks. I'll hop back into queue.

Thank you. Our next question comes from the line of Jay Olson of Oppenheimer. Your line is now open.

Oh hey. Congrats on the progress. For the study of daraxonrasib in the adjuvant setting for resectable PDAC, how are you thinking about the dosing duration? And could that be guided by ctDNA? And then I have a follow-up question on non-small cell lung cancer.

I think it's just a little bit early for us to get into the details of trial design since, as we indicated, we're now committed to working on the trial design. Those are obviously questions that we'll be addressing, but they are core elements of the trial design. So I would say hold that question, and we ought to be addressing it in due course.

Okay. Understood. And then in non-small cell lung cancer, are you interested in earlier lines of therapy like the adjuvant setting or even neoadjuvant? And can you just talk about what your strategy might be there?

Well, I can answer the first part of your question. Yes, we're very interested. I mean we're obviously have a very rich pipeline that's going to be very relevant to the RAS mutant portion of lung cancer, which represents about 30% of non-small cell lung cancer and in all lines of treatment. You've heard about our strategy around first line, and I think we've just shown with our disclosure about our intention to pursue an adjuvant trial in pancreatic cancer that we're committed to moving to these earlier lines. We don't have specificity around that right now, so it's a little hard to explain the strategy until we have it well sort of articulated and thought through. The pancreatic cancer is just a little bit ahead of lung cancer because it really has taken off, and the unmet need is so substantial and urgent that we're in a better position really to push things in all directions there. But you'll hear about lung cancer over time as we're able to do so. Of course, importantly, we just announced today that we've initiated our second-line, third-line non-small cell lung cancer study as we expected to do in the first quarter of this year, but we're there now, and that's happening. So that's the first step in the right direction. As we develop both data and then the strategy that supports the data for various earlier lines, we will share that.

Thank you. Our next question comes from the line of Joe Catanzaro of Piper Sandler. Your line is now open.

Great. Thanks so much for taking my questions. Maybe one quick one for me as it relates to your comment, Mark, that chemo alone in front-line PDAC is an aggressive regimen. So for the frontline chemo combo, are you thinking that you'll design the regimen as just continuous combination therapy until progression? Or is there potential to use an induction maintenance idea? And maybe what the pros and cons of each approach could be?

Thanks for your question, Joe. I think Wei can comment on that question.

Yes. Again, because we have not had the regulatory interactions, I think right now, we do not have the final study design. I think what we're doing right now in the exploratory studies in evaluating the combinations is really combining adding daraxonrasib to the current standard care chemotherapy either GEM/abraxane or FOLFIRINOX, right? Our primary goal is really to protect the dose and intensity of daraxonrasib because we think that's going to deliver the maximum clinical benefit to patients. How one way or the other, what the final regimen we develop will move into the first-line setting. Other than that, I think maybe it's a little too early to share.

Yes. Maybe if I could add a little bit to that. We do expect that one arm of that trial will be monotherapy daraxonrasib. And so there really isn't an induction and maintenance phase; there's just a treatment phase, and patients will be treated as long as they're clinically benefiting from it. With the chemotherapy added, it does raise the question of whether there's an initial phase and then a follow-up phase of induction and maintenance or not as matter so much, that's just nomenclature. But currently, pancreatic cancer patients, first on pancreatic cancer patients, typically try to pursue four to six cycles of chemotherapy, but many patients don't make it through four or six cycles in chemotherapy, either because they can't tolerate it and so they stop or because their disease progresses and they stop. That's just something to keep in mind; we want to make sure that patients actually get through their initial period, whatever that is, because the potential for having long-term benefit from daraxonrasib is implied by or suggested by the data from the previously treated patients. So again, we come to the notion that based on the history of that disease and how it's treated and the fact that we're now moving from a generalized chemotherapy attempt to just kill cells to a more biologically driven disease-modifying strategy that will require a bit of a paradigm shift or should require a paradigm shift in how we think about treating those patients. Effectively, we'll think of that combination arm as the daraxonrasib arm to which we've added some chemotherapy as opposed to the chemotherapy arm to which we've added some daraxonrasib, and that’s conceptually a very important thing to think about. It may not conform to the nomenclature we're using earlier. But again, as Wei said, we're actively engaged in thinking through this, and we'll have to engage with regulators. We're currently talking with advisers and trying to devise the most appropriate strategy.

Thank you. Our next question comes from the line of Alec Stranahan of Bank of America. Your line is now open.

Hey guys. This is Matthew on for Alec. Thanks for taking my questions. Maybe a first quick one from us. I think in 3Q, you mentioned that you expect to disclose data from the elironrasib/pembrolizumab combo in 1Q. I know you had safety tolerability data in December. Just curious if there were any updated plans still for 1Q or whether the next update would come in the mutant selector inhibitor update in 2Q or 3Q?

Okay. I was processing your question, and I realized that what you're alluding to. We actually moved that update from Q1 of 2025 into Q4 of 2024. And so that was the update. We provided it earlier. We weren't sure if we were going to be able to do that, which is why we alerted folks that might come in 2025, but it actually came in 2024. It was primarily—and it is primarily a safety assessment, the issue with efficacy is that the patients who were treated, the vast majority of those patients, were actually previously treated patients who had already experienced pembrolizumab. So there really wasn't much potential for them to get a new boost of antitumor activity by retreating them with pembrolizumab. And looking at efficacy in that context, if you're thinking about it as additive pembro plus daraxonrasib, what you could really just be seeing is the daraxonrasib activity. This contrasts with where it would actually be used, which is in first-line patients who have not seen daraxonrasib or pembrolizumab before. That would be a more appropriate setting for assessing efficacy.

Makes sense. And then maybe a quick one on how you think about entertaining potential collaboration opportunities with daraxonrasib or any of your other assets?

Yes. I mean we certainly are both entertaining and actually engaged in collaborations. There have been many years of preclinical collaborations that have been underway and continue and have published papers and so on. There are actually active clinical collaborations. We've mentioned, for example, that Tango Therapeutics will conduct a study of their PRMT5 inhibitor with one or several of our RAS inhibitors, including daraxonrasib asset, and that is a clinical collaboration. We would imagine that, that range of combinations will be expanded over time.

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

Hi. This is Poorna on for Ami. Thank you for taking our question. On zoldonrasib, what additional data do you need to see that will give you confidence to initiate the pivotal combination trials? And any big updates include data from other indications such as gastric and CRC?

Unfortunately, we can't hear you very well. So we're not sure what those two questions were. Could you repeat that? And maybe if we could get the volume adjusted up, that would be helpful.

Sorry, I was asking what additional data do you need to see for zoldonrasib? Does it give you confidence to initiate the pivotal combination trials? And would any of these updates include data from other indications such as gastric and CRC?

Okay. So the question is really about pivotal trials of zoldonrasib raised in the combination context. Well, we are currently evaluating zoldonrasib in combination with daraxonrasib, which we think is justified by the previous observations that elironrasib plus daraxonrasib delivered compelling differentiated initial evidence of antitumor activity. We believe that same concept may hold for zoldonrasib, and we're evaluating it. We're also evaluating zoldonrasib in combination with other agents that would be appropriate for lung cancer or for colorectal cancer or for pancreatic cancer. So I think we have to generate that information. We've indicated that this is a high priority for this year. Much of that work is already underway. We expect to share some additional clinical data on zoldonrasib mid-year, and we expect to develop at least one pivotal trial concept based on a new selective inhibitor, which could well be zoldonrasib for 2026 and beyond.

Okay, thank you.

Thank you. Our next question comes from the line of Peter Lawson of Barclays. Your line is now open.

Hey, good afternoon. This is Alex on for Peter. Thanks for taking my question. I joined late, so sorry if this was addressed already. But how are you thinking about completion of the second-line PDAC study and potential approval? And how could that impact—if that could impact the control arm in your first-line trial and the ability to show an OS benefit?

Yes. Thanks for your question. There's always a downside to anything that has an upside. Rapidly completing that trial does create new barriers for a different trial. That doesn't stop us, though. We want to move forward as quickly as possible to complete that trial. It is a very important opportunity for us to demonstrate an OS benefit from daraxonrasib which we believe is a credible thing based on the data that we've shown so far. There's broad interest in this study. You're now talking about the 302 or RASolute study. There's broad interest in that setting by patients and investigators. The currently active sites and rolling sites are enrolling quite actively. We're very pleased with the progress there. We're also opening new sites in the U.S. according to our plan, consistent with our plan. We do expect and are highly confident that we can complete enrollment in this study in 2025. There may be some stragglers from countries outside the U.S. that could roll over into 2026, but largely, we do expect to complete enrollment in that trial this year, and we're moving as fast as we possibly can. As you point out, it does put pressure on that first-line trial. We think it will put pressure on every future first-line trial. That's sort of part of the intention here, to deliver changes in treatment benefit for patients that truly moves the needle. That's what we want to achieve. We feel that urgency, and we currently expect to be able to do so to initiate the trial by the end of this year.

Okay. And do you see any potential for an accelerated approval of some sort based on PFS in the first-line setting?

Yes. That’s a question probably best addressed to regulators. I think that there is a widespread belief and understanding that the FDA is not enthusiastic about accelerated approval in pancreatic cancer for a number of reasons, one of which is that the OS readout doesn’t come long after the PFS readout. They're not particularly enthusiastic about giving somebody an approval and then finding out a month later that it does or doesn’t meet the OS bar, just to exaggerate a little bit. I think generally speaking, we don't assume that there's an accelerated approval path based on PFS. On the other hand, there hasn't really been a drug that's moved the needle based on PFS, really, ever, in any meaningful way. Our ambition is to be able to deliver such data. How a regulatory body might look at those results, we don't, of course, predict. We designed the trial really around OS, which means that it’s overpowered for PFS. The timing of the analysis—the first analysis—is actually driven by the number of OS events and it’s an OS event-driven trial, but it is possible to achieve success on the PFS without having reached the mark on OS or maybe being partially on the way there, with evidence of a trend towards it, without having reached it yet, in which case there would be a subsequent assessment of the data after—where we could have a greater chance of achieving the OS at that point. What happens in that interim period? I think we’ll just have to leave dangling because that’s not really entirely up to us, in fact, it’s not really up to us very much at all.

Thank you. I am showing no further questions at this time. So I would like to turn it back to management for closing remarks.

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

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