Revolution Medicines, Inc.

Welcome to the Revolution Medicine's Q4 2024 earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 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 Asey. 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 at 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 investor section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's chairman and chief executive officer. Mark?

Thanks, Ryan. 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 Medicine is 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. Our 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 -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 Daraxon RAS-ib. 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. And our commitment to this level of ambition is reinforced by our track record of productivity and successful execution. We've been pioneers in the RAS space. Scientific innovation within RevNet has resulted in the first three clinical-stage RAS-on inhibitors, a RAS-on multiselective 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 nonproprietary or generic names for these three compounds, each of which is centered on the shared phrase on RAS-ib that alludes to the novel RAS-on mechanism of action for this new class of compounds. Daraxon RAS-ib or RMC6236, our groundbreaking multiselective RAS-on inhibitor, Eliron RAS-ib or RMC6291, our distinguished G12C-selective covalent inhibitor, and Zoldon RAS-ib or RMC9805, 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 daraxon RAS-ib and pancreatic ductal adenocarcinoma or PDAC and non-small cell lung cancer and Zoldon RAS-ib in PDAC. We also reported initial evidence of two promising combination strategies. First, we reported initial clinical proof of concept for the first of its kind RAS inhibitor doublet with a combination of Eliron RAS-ib with daraxon RAS-ib. These data are highly encouraging and increased our confidence in the innovative RAS doublet concept more broadly. We've already completed dose escalation on a second RAS-on inhibitor doublet, Zoldon RAS-ib combined with daraxon RAS-ib. We will study both RAS-on inhibitor doublets further as potentially compelling options for patients, particularly as we move into earlier lines of treatment. Second, we reported early safety and tolerability data for both daraxon RAS-ib in combination with pembrolizumab and Eliron RAS-ib 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 also 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 a-thon therapeutics. We also formed collaborations with leading industry, 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 three registrational trial, reaching commercial scale manufacturing of daraxon RAS-ib and strengthening our organizational capabilities in preparation for a potential first regulatory approval. And 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 Pancreatic Cancer Action Network or PANCAN, a distinguished organization devoted to improving the lives of people living with pancreatic cancer. And 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 RevNet 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 daraxon RAS-ib monotherapy in patients with previously treated metastatic pancreatic cancer and non-smell cell lung cancer. For the global Phase III, RAS-olute 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. investigation 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 -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, RAS-olute 301 randomized controlled trial comparing daraxon RAS-ib to docetaxel in patients with previously treated metastatic RAS tumors. Our second priority is to advance daraxon RAS-ib 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 daraxon RAS-ib monotherapy and one with patients treated with daraxon RAS-ib plus chemotherapy. Based on single agent data and preliminary chemotherapy combination data, we are optimistic that both treatment arms containing daraxon RAS-ib 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 daraxon RAS-ib plus chemotherapy safety cohorts. Of course, we'll need to align with the relevant regulatory authorities, including the EU, the US FDA before we can initiate the global randomized case-free trial in patients with first-line metastatic PDAC. As a further step in our ambition to serve patients with earlier stage disease, I'm also very happy to share that we are actively designing a registrational trial with daraxon RAS-ib as an adjuvant treatment, patients with respectable pancreatic cancer who have undergone surgery and perioperative therapy, often including chemotherapy. This population constitutes approximately 15 percent of newly diagnosed pancreatic cancer cases in the US 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, ileuron RAS-ib and zoldon RAS-ib, 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 continue development of zoldon RAS-ib, our innovative RAS-on G12D selective inhibitor for which the first in human clinical data, including a favorable tolerability profile and encouraging anti-tumor activity in RAS G12D PDAC were reported at the triple meeting last quarter. A key marker 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 anti-tumor 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 diraxon RAS-ib and ileuron RAS-ib 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 ileuron RAS-ib with diraxon RAS-ib 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, that is, as a triplet regimen in KRAS G12C non-small cell lung cancer as a potential chemotherapy sparing first line treatment. And a trial evaluating a doublet of zoldon RAS-ib with diraxon RAS-ib is currently in an expansion phase across a range of solid tumors at the anticipated single agent recommended phase two dose for each agent. We plan to evaluate emerging data for 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 ileuron RAS-ib or zoldon RAS-ib 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 RMC5127, a RAS-on G12V selective inhibitor, to a clinic-ready stage this year. This will enable initiation of a first in human dose escalation phase one clinical trial in 2026 and a subsequent evaluation of a RAS-on inhibitor doublet with Dirac's on RAS-ib. 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 precommercial 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 strategy, tactics, operational capabilities, and people to bring Dirac's on RAS-ib 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 are 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 will now turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance. Jack?

Jack? 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. GNA 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 GNA expenses was due to $13.8 million in EQRX wind down costs in the prior year quarter. Excluding these non-recurring EQRX costs, GNA 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 10K that was filed with the SEC this afternoon. Turning to financial guidance for 2025, we expect full year gap net loss to be between $840 and $900 million, which includes estimated non-cash stock-based compensation expense of $115 to $130 million. The increase in expected gap net loss for 2025 is 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 continue 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 rastidictive cancers and to fulfill our responsibilities to patients, investors, and employees. The foundation we've established sets us up for long-term sustainable growth in support of our aim to revolutionize treatment for patients with rastidictive cancers. With that, I'll turn the call over to the operator for the Q&A portion of the call.

Thank you. At this time, we will conduct the question and answer session. Each participant is encouraged to ask one question and a follow-up. 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. Our first question. Comes from the line of Ellie Merlie 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 three studies in the earlier line PDAC? And I guess, specifically, what gives you conviction on the phase three in the adjuvant setting? And can you talk a little bit about the role of RAS in this earlier line setting?

Yeah, 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 strong conviction that we ought to try to own the entire PDAC space across whole lines of therapy. So we've indicated that previously, and this is just a furtherance towards that goal. We've already previously announced that we intended to pursue a first line metastatic study. And the question has always been, what will be the composition of the various cohorts in that trial? And we provide 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. And the proof of concept that supports pursuing that particular indication is already provided by the second line and third line 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

I think that's a good comment.

Yeah, 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 than 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 diraxon racin.

Thank you so much.

Thank you. 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 respectable PDAC is about 15% of overall cases. 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, how should we be thinking about the regulatory bar that would need to be satisfied for registration? Is it PFS OS? It'd be great to hear your thoughts there. Thank you.

Yeah, hi 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 have to be something that we address in the future. But on the first question, I think I'll ask Dr. Wailey and our chief medical officer to comment on the estimated proportion of total PDAC cases that are currently considered respectable 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 CTNA and so on, that's a much more long term to be established before it becomes standard care. That's why we don't, probably in the short term, we don't see that number change.

Yeah, 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 respectable disease. And so if it becomes possible to diagnose patients much earlier, then the possibility of even greater impact, as you point out, becomes much higher. But at the moment, we just have to focus on the patients who are diagnosed and they do represent a significant

fraction.

Great. Thanks for taking the questions. I appreciate the caller.

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

Thanks for taking my questions. I wanted to start to follow up on the questions about adjuvant design. Pancreatic docs also talk about borderline respectable disease, not just respectable. And then there's also within respectable, some patients get whipple procedures, others don't get whipples. 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. 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 roll broadly or is that kind of introducing too much risk when you're moving lines, different subsets, and different mutations in there?

Thanks, Mark. Is the second question also relating to respectable or was that referring to- Well, both

first line and adjuvant for that second part of it.

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

Yeah. So first question regarding the patient population. So first of all, I just want to caveat by saying that we have not had any health-oriented interactions. So the final design is still pending those interactions. But we would certainly like to offer Drax and Rassiv as a new standard care for patients very, very to the broadest patient population possible. So that would really include as many patients that have had resection of their primary disease and then have any type of perioperative disease, typically chemotherapy, and that defined as broadly as possible now. I think the final design is still pending health-oriented interaction, but that's our goal is to define the largest population where we believe Drax and Rassiv can really benefit. And then the second question about the mutation specifically, this is kind of- So first of all, I think the preference is as far as we know, it's fairly consistent throughout the lines of therapy. And then in the accident setting or the early disease setting, our approach in developing Drax and Rassiv is similar in the metastatic setting, which is we aspire to cover as many patients that's actually eligible for our trial. And then that's including a potential for an old comor approach to the entire population of hepatic

cancer patients.

Okay, that's really helpful. And then maybe just a more strategic view, Mark, just 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?

Yeah, 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 assert 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 place of 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 those 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 three registration trial because that would leave 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 be. So it's a challenging topic. It 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 will come 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're now committed to doing a single three-arm trial there for registration as opposed to two separate trials. How much more 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, be it as a monotherapy perhaps in first line or in combination? And secondly, what are your latest thoughts on how to incorporate sodium rasic into your pancreatic cancer registration strategy perhaps relative to that? 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. And that's primarily around safety. It's really not at this stage about primarily driven by efficacy because we already have confidence in the efficacy based on the monotherapy second, third lines 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 treatments that there aren't long breaks. As you may know, even both forms, major forms of chemotherapy

and pancreatic cancer often incur the liability of grade three

or higher adverse events that drive hospitalization that often results in discontinuation of anti-cancer treatment for some period of time. And that's not ideal, particularly for a target therapy where as continuous coverage as possible is likely to have the greatest efficacy in the long run. So we just want to choose the best regimen or regimens to go forward with. And we need some more data to drive that. But it still needs to be a good decision. So we're

moving as swiftly as we can to support that decision. The second question is Zola and Rasset. Do you want

to comment away on Zola and Rasset and pancreatic cancer and how we think about that relative to direct Zola and Rasset? Sure.

Zola and Rasset, as you know, G12b has a problem rate of about 40% of pancreatic cancer. It's the most common Rass mutation or specific mutation in general that's a driver of pancreatic cancer. So we have shared our earlier Phase 1 data showing that it's a highly active agent where we follow along those results looking for the durability of these activities. And then I think our initial thinking is it will probably end up being a separate registration trial with a standalone registration path. And we're currently evaluating a combination with Diraxon Rasset, a potential Rasson doublet, a -in-class option that could be substantially improved upon by their monotherapy. As well as the chemotherapy plus standard care with Zola Zola and Rasset. So those are potentially

two options we could develop. Thank

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

Great. Thank you. First, just want to add another quick question on Zola and Rasset. 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 hope to glean from these data?

Yeah. Hi, 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 Zola and Rasset in the second quarter of this year. And I think we'll just have to wait until those data are available.

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

Okay. Yeah. Ben, let me just clarify, though. I don't know that there's been a debate about the combinability. That really, I think, is that statement's been made a number of times, but I haven't heard that debate. Really, the topic that we raised earlier this year is the one that I alluded to in one of the earlier questions, which is that chemotherapy alone is a very difficult thing for pancreatic cancer patients to go through because the disease is so aggressive, the chemotherapy has to be aggressive to go with it. That chemotherapy already today drives substantial side effects, adverse events that often result in holding the drug for some period of time and or hospitalization. That, in and of itself, just for the chemotherapy, the standard chemotherapy alone could have implications for the ultimate efficacy of a combination of chemotherapy with the diraxone acid or with any other targeted agent, to be honest. That's really the issue that we've raised. We haven't. I'm not sure that there really has been any meaningful public debate about whether or not they are combinable. I don't think we have to add to that because that hasn't really been the core issue. Of course, we're evaluating that now and we're optimistic that we can develop a regimen that combines them, but we're keeping in mind this fundamental issue that the chemotherapy itself is already essentially barely tolerated. In fact, in most cases, not only results in some dose holds, but typically results in dose reductions as one moves from one

cycle to the next.

That's

the context for that.

Thank

you.

Our next question comes from Laura Prendergast of Freeman 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, ATFR inhibitor combo, double data this year? Then just a few, any guidance on if or when there will be a registrational path for colorectal cancer and then maybe beyond the big 3K rast-driven tumors as well?

Yeah. Hi, 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 aileron racid with diraxon racid in patients, quite advanced colorectal cancer patients who had been previously treated with a G12C inhibitor and really had no other options. We showed significant activity from the combination of aileron racid with diraxon racid. That was just six weeks ago or two months ago. But we don't have any guides 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.

Great. Thank you.

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

Hey, guys. This is Clara. I'm for Kelly. Thanks for taking our questions. So for the Phase 1 study in PDAC, as of the last update, the median overall survival was so immature at their output QD. So just wondering, do you have any plans to update the overall survival data this year?

Yeah. Hi, 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 including the 300-milligram cohort. And 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 had been enrolled more recently than had the patients with the earlier doses, that those curves were not very mature. And so we didn't have an estimate of OS per se, but we did have information regarding the six-month OS, which was quite high, depending on which subset you looked at. It was in the 97 to 100 percent range, which I think provided some pretty good look about what's going to come as we, as these data mature. But of course, we didn't have those data. So those do continue to mature. And I'm sure at one point, at some point, we will 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 Onfrakris. 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 here, would you potentially also pursue a non-G12C frontline indication, or do you still have plans to explore that? And then for the, you know, 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 he 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. And then there's 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. And I think that now G12C mutant lung cancer has established itself as a completely separate disease, probably requiring a G12C selective inhibitor. So right now, because we are acquiring and have presented preliminary data on the combination of a neuromraceid with norexomraceid in G12C mutant cancers, we would plan to move that chemo-free triplet into the G12C lung cancer space. And then the diraxon racid would be prioritized for all other RAS mutant lung cancer without a G12C mutation, which is about probably somewhere in the region 17 to 18% of all non-small cell lung cancer right now. So I think that addresses your first question. Can you remind me of your second question?

Well, just following up on that. So does that mean that- Oh, data.

Data. Yeah. Will we

release

- So when the data that justifies those clinical trials will be put together in a complete package. I mean, we are releasing data in tranches as we accumulate that data. We've already, I think, tried to persuade you that our RASon inhibitors are combinable with pembrolizumab, which of course is a fairly significant step on the road to starting first line trials in non-small cell lung cancer. It's an almost an absolute prerequisite now for the starting trials in first line non-small cell lung cancer. And we can not only can we combine our RASon inhibitors with pembrolizumab without incurring additional toxicity, but we can combine them at what we believe to be the full recommended phase three dose. We don't have to take a haircut on the dose in order to combine with pembrolizumab like some of the other RAS inhibitors have had to do. So ultimately, we are, as you know, still aggressively enrolling the combination of the liron RASon and Drexon RASid in both colorectal cancer and non-small cell lung cancer and waiting for the sort of durability to mature. As soon as that is mature, then we can tell you about it. But of course, because it's durability data, I can't really give you a timeline for the maturation of that data. And of course, just behind that data set will be the combination of zolgone RASid with Drexon RASid in Rasputin tumors as well. That's a little bit behind and again, I don't have any guidance on when we can report that. But as soon as we have the trials, the trial designs ready for public disclosure, we will also have the supporting data ready for public disclosure.

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

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 and thank you for the update. For the study of Drexon RASid in the adjuvant setting for resectable PDAC, how are you thinking about the dosing duration? And could that be guided by CT DNA? And then I have a follow-up question on non-small cell lung cancer.

You know,

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 that 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 obviously have a very rich pipeline that's going to be very relevant to the rat's mutant portion of lung cancer, which represents about 30% of non-small cell lung cancer in all lines of treatment. And you've heard about, from Steve just a moment ago, about strategy around first line. And I think we've just shown with our disclosure about our attention 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 articulated, well thought through. And the pancreatic cancer is just a little bit ahead of lung cancer because it really is taken off of the unmet need. So it's 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. And 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 Cottonzaro of Piper Sandler. Your line is now open.

Great. Thanks so much for taking my question. Maybe one quick one for me as it relates to your comment, Mark, that chemo alone and frontline 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 to maybe what the pros and cons of each approach could be? Thanks.

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

question. Yeah. Again, because we have not had the regular interactions, I think right now we do not have the final studies. I think what we're doing right now in the exploratory studies in valuing the standard care of chemotherapy, either general vaccine or folio-nox. I think as we discussed earlier, our primary goal is really to protect the dose and intensity of graxon-glyceride because we think that's going to deliver the maximum chemical benefit of patients. And so how one way or the other, what the final regimen that we develop will move into the first-month setting. Other than that, I think maybe to go to or to share.

Yeah. Maybe if I could add a little bit to that. We do expect that one arm of that trial will be monotherapy, directs on racet. 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 whether there's an initial phase and then a follow-up phase. Whether you call that induction and maintenance or not, doesn't matter so much. That's just nomenclature. But currently, pancreatic cancer patients, first-line pancreatic cancer patients typically try to pursue four to six cycles of chemotherapy. But many patients don't make it through four to six cycles of chemotherapy, either because they can't tolerate it and so they stop

or

because their disease progresses and they stop. And so that's just something to keep in mind is 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 directs on racet is implied by or suggested by the data from the previously treated patients. So again, we come back to the notion that, you know, based on the history of that disease and how it's treated and the fact that we're now moving from sort of a generalized chemotherapy attempt to just kill cells to a more biologically driven disease modifying kind of strategy, that that will require a bit of a paradigm shift or it should require a paradigm shift in thinking about how you go about treating those patients. And effectively, we'll think of that combination arm as the drafts on massive arm to which we've added some chemotherapy as opposed to the chemotherapy arm to which we've added some directs on massive. And that's conceptually a very important thing to think about and may not may or may not conform to the nomenclature we were using earlier. But that's again, as we said, those are things that we're actively engaged in thinking through. And then of course, we'll have to engage with regulators. Right now, talking advisors and trying

to devise the most appropriate strategy.

Okay, got it. That's helpful. That's all for me.

Thanks. Thank you. Our next question comes from the line of Alex Stronahan of Think of America. Your line is now open.

Hey, guys, it's Matthew on for Alex. Thanks for taking our questions. Maybe first quick one from us. I think in three Q, you mentioned that you expect to disclose data from the earlier on RASP-PAMBRO combo in one Q. I know you had safety tolerability data in December. Just curious if there were any updates plans still for one Q or whether the next updates would come in the mutant selector inhibitor update in two Q or three Q. Ah, okay. I was processing your question and I realized now 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. 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 have already experienced PEMBRALizumab. So there really wasn't much potential for them to get a new boost of antitumor activity by retreating them with PEMBRALizumab. And so looking at efficacy in that context, if you're thinking about it as additive PEMBRAL plus diraxonacid, what you'd just be seeing is the diraxonacid activity. This contrasts where it would actually be used, which is in first line patients who have not seen diraxonacid or PEMBRALizumab before. And 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 diraxonacid 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. And 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 diraxonacid. And that is a clinical collaboration. And we would imagine that that range of

combinations will be expanded over time.

Thank

you. Our next question comes from the line of Ami Fadiya of Neetam and Company. Your line is now open.

Hi, this is Poonam for Ami. Thank you for taking our question. On SOLD and RASF, what additional data do you need to see that will give you confidence to initiate the inhibitor combination trials? And would any of these updates include data from other indications such as gastric and CSU?

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 just enough, that would be helpful.

Oh, sorry. I was asking what additional data you need to see for SOLD on RASF that would give you confidence to initiate the inhibitor 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

inhibitor trials of SOLD on RASF in the combination context. Well, we are currently evaluating SOLD on RASF in combination with Diraxon RASF, which we think is justified by the previous observations that Eliron RASF plus Diraxon RASF delivered compelling, differentiated initial evidence of anti-tumor activity. And so we believe that same concept may hold for SOLD on RASF, and we're evaluating it. We're also evaluating SOLD on RASF in combination with other agents, other standard of care 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. The work, much of that work is already underway. We expect to share some additional clinical data

on SOLD on RASF mid-year, and we expect to develop at least one pivotal trial concept based on a new selective inhibitor, which could as well be SOLD on RASF 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. And so I joined late, so sorry if this was addressed already, but how are you thinking about completion of the second line PDUC 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. So 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, and it is a very important opportunity for us to demonstrate an OS benefit from Diraxon RASF, 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, a resolute study. There's broad interest in that study by patients and investigators. The currently active sites, enrolling sites, are enrolling quite actively. We're very pleased with the progress there. We're also opening new sites in the US, according to our plan, which is in their plan. We're opening sites in the US right now. We do expect and are highly confident that we can complete enrollment of this study in 2025. There may be some stragglers from countries outside the US that could roll over into 2026, but largely we do expect a complete enrollment in that trial this year. We're moving as fast as we possibly can. As you point out, it does put pressure on that first-line trial. Frankly, we think it'll put pressure on every future first-line trial. That's sort of part of the intention here is to deliver changes in treatment benefit for patients that moves the needle. That's what we want to achieve. We are fighting ourselves a little bit on this, which means getting to an answer on our final trial design for the first-line trial as quickly as possible is important to do. 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, thank you. Do you see any potential for an accelerated approval of some sort based on PFS in the first-line setting?

Yeah, that's a question probably best addressed to regulators. I think that there is a

widespread belief and understanding that the FDA is not wild about accelerated approval of that long after the PFS readout. They're not particularly enthusiastic about giving somebody an approval and then finding out a month later that 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 been approved based on PFS really ever in any meaningful way. Our ambition is to be able to deliver such data that will be determined by what the data show. But based on the phase one, two data we've shown so far, we're encouraged by that possibility and how a regulatory body might look at those results. We of course can't predict. We've designed a trial really around the OS, which means that it's overpowered for PFS. And the timing of the analyses, the first analysis, is actually driven by the number of OS events. And so 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 with 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.