Revolution Medicines, Inc. Price & Performance (RVMD)

This afternoon, we released financial results for the quarter ended 12/31/2020 and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. That, I'll turn the call over to Doctor. 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 RasOn 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 ten 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: [indiscernible] development and delivery. First, our innovative clinical stage RASON 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 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 by building strong commercialization capabilities in support of a successful launch, subject to regulatory approval, for duraxon RASib. Supporting our mission, is an ambitious strategic roadmap for maximizing the impact our RASON 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 Revolution. We've been pioneers in the RAS space. Scientific innovation within RevNet has resulted in the first three clinical stage RASON inhibitors. A RASON multi selective inhibitor a Rason G12C selective inhibitor and a RASON 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 RASP, that alludes to the novel RASIP mechanism of Revolution, for this new class of compounds. Dioraxon RACIB or RMC-six thousand two hundred and thirty six our groundbreaking multi selective RACON inhibitor Elioron RASib, or RMC-six thousand nine hundred and one our distinguished G12C selective covalent inhibitor and sold on RASib 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 RASP focused We reported compelling monotherapy clinical data with our first wave of RAV [indiscernible] Particularly, duraxon RASIV and pancreatic ductal adenocarcinoma or PDAG and non small cell lung cancer and ZOLDARMRASib 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 the combination of ileuron RASib with duraxon RASib 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 Rason inhibitor doublet ZOLD ONRASSIV combined [indiscernible] we will study both rasone 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 duraxon raspib in combination with pembrolizumab and Revolution rassib 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 Aethon Therapeutics. We also formed collaborations with leading industry academia Revolution research partners such as the Breakthrough Cancer Organization, that presents a valuable opportunity to uncover [indiscernible] 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 Drexon RASIV and strengthening our organizational capabilities in preparation for a potential first regulatory approval.

And 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 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 aiming to maximize the impact we can have for patients with RASK addictive 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 draxonRacib nonotherapy in patients with previously treated metastatic pancreatic cancer and non small cell lung cancer.

For the global Phase three Rasolute-three zero two 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 Warp 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 three RESOLVE-three zero one, randomized controlled trial comparing duraxon RASP to docetaxel in patients with previously treated metastatic RAS tumors.

Our second priority is to advance Droraxon RASib 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, Based on single agent data and preliminary chemotherapy combination data, we are optimistic that both treatment arms containing daraxon rasib 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 DraxonRacib 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 also very happy to share that we are actively designing a registrational trial with daraxon rasib as an adjuvant treatment, patients with resectable pancreatic cancer who have undergone surgery and perioperative therapy, often including chemotherapy. This population constitutes approximately fifteen percent 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 to generate sufficient data to inform development priorities for the mutant selective inhibitors ELLERON RASib and ZOLD ONRACIB, 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 ZOLD ONRASib, our innovative Rason 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 marker of progress against this priority is generating additional clinical data that help 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 twenty twenty five. Another example is our ongoing efforts to identify and advance rational combination strategies with our Rascon inhibitors. We are data driven and 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 duraxon rasib and Elearon racib 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 Elearon RASib with duraxon RASib and KRAS G12C colorectal cancer, that provide initial validation of this innovative approach. We are actively enrolling and evaluating this RASON 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 rascib with DORAXONE RASSID it's 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 aileron rasib or Zoldon rasib 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 [indiscernible] In particular, we currently expect to advance RMC-five 127 Our RASON 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 RASA inhibitor doublet [indiscernible] 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've 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. Continue to expand to expand key aspects of our organization to support a commercial launch by adding top talents 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.

Are resourcing our efforts to ensure that we have the best strategies, tactics operational capabilities and people to bring Durax on RASP 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, Jack? Thanks, Mark. We ended the fourth quarter of twenty twenty four with point three billion dollars in cash and investments. Which includes $823,000,000 in net proceeds from our upsized equity offering last December. We project that our cash and investment balance in fund planned operations into the second half of twenty twenty seven 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 and D expenses for the fourth quarter of twenty twenty four were $188,100,000 compared to $148,500,000 for the fourth quarter of twenty twenty three. Please note the prior year quarter included $13,100,000 in wind down cost associated with the EQRx acquisition. The increase in R and D expenses was primarily due to increases in clinical trial related expenses and personnel related expenses associated with additional headcount. G and A expense were $28,200,000 compared to 32,200,000.0 for the fourth quarter of twenty twenty three. The decrease in G and A expenses was due to $13,800,000 in EQRx wind down costs in the prior year quarter. Excluding these non recurring EQRx costs, G and A expenses increased in the fourth quarter of twenty twenty four was primarily due to increases in commercial preparation activities, and personnel related expenses associated with additional headcount. Net loss for the fourth quarter of twenty twenty four was 194,600,000.0 compared to $161,500,000 for the fourth quarter of twenty twenty three. Please note, net loss for the prior year quarter included a total of $26,900,000 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 ks was filed with the SEC this afternoon. Turning to financial guidance for 2025, we expect full year GAAP net loss to be between $840 and $900,000,000 which includes estimated non cash stock based compensation expense of $115 to $130,000,000 The increase in expected GAAP 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 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 financial capital to fuel our vision to create an industry leading targeted medicines franchise for patients with RASDICTICI 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 and A portion. Of the call. Our first question comes from the line of Ely Merlee 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 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 RAF 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 strong conviction that we are to try to own the entire PDAC space across whole lines of therapy.

So we've indicated that previously and this is just further 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 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 [indiscernible] and we'll further our goal of completely owning the PDX space with this 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 versus maybe like the advanced or metastatic disease and how you're thinking about the overall opportunity there?

I don't know that there's any evidence that those patients would have any different representation of brass drivers 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 [indiscernible] 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 [indiscernible] what we've generally thought about as being in scope in pancreatic cancer You noted, Mark, that resectable PDAC is about fifteen percent 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 [indiscernible] initiatives? And then as it relates to the pivotal study, how should we be thinking about the regulatory bar that would need to that would need to be satisfied for registration. Is it PFS OS? It would be great to hear your thoughts there. Thank you.

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. On the first question, I think I'll ask Doctor. Whaitland, our Chief Medical Officer, to comment along the estimated proportion of total PDAC cases that are currently considered receptible and whether that could evolve over time.

Thanks, Mark. It's a great question.

Think in the short term, we don't expect the number to change. Because that detection is largely driven by whether there is 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.

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 [indiscernible] we can show further benefit to patients who are [indiscernible] that I think will further promote those efforts [indiscernible] 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 receptacle 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 focus on the patients who are diagnosed and they do represent a significant fraction.

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

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

Thanks for taking my questions. I wanted to start just to follow-up on the question about adjuvant design.

Pancreatic docs also talk about borderline resectable disease, not just resectable. And then there's also within resectable, some patients get lipo 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 to pain point, which one you fall in? And then similarly, with the 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, Mark. Is the second question also relating to receptable or was that referring Well, it's adjuvant both in first line and adjuvant for for that second part of it. I see.

Okay.

Good. I think Wei can address both the definition of receptable and what we're thinking about right now and then also testing and whether or not to stratify Yes. So first question, regarding the patient population. So first of all, I just want to caveat by saying that we have not had any L4D interactions. So the final design is still pending those interactions. But we would certainly like to offer Drexel Racet less in new center care for patients very, very to the broadest patient population possible. So that would really 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 and regulatory interaction, but that's our goal is to define the largest population where we believe drug and rasp would be benefit. And then the second question about the mutation specifically, this is kind of it's piggyback on Mark's earlier comment. We do believe that RAS is the cancer initiating for our mutation And so first of all, I think the preference is as far as we know, it's pretty consistent throughout the lines of therapy.

And then in the ACT setting or the early disease setting, Our approach in developing duracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomiracomir is similar in the metastatic setting. Which is we aspire to cover as many lesions that's actually eligible for our trial. And then that's including a potential for our ocular approach. To the entire population of pancreatic cancer patients.

Okay.

That's really helpful. And then maybe just 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.

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.

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, and see what we might offer that's better. In 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 making those prioritization decisions. But But there could be certainly circumstances where we can't make such a decision we wouldn't hold off on pursuing a a Phase three registration trial because that would lead patients unserved and or it would lead 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 Revolution, I think it's ours to lose. If we don't pursue these things, we will be setting ourselves up for for a different scenario. We'd rather be first to the table where we can't be. So it's a challenging challenging topic.

Falls into the category of an embarrassment, but riches to a large degree because we can define multiple potential solutions to each of these situations. And but we have to work in real time because for patients, this isn't 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 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 one work needs to be done with the chemotherapy combination, the initiating the study?

And 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 SOD and RASM into your pancreatic cancer registration strategy, perhaps relative to thoraxone racid Thanks so much. Thank you, Michael.

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 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 and third lines data that we've already shared. So this is really just about safety and making sure that we can assure high enough [indiscernible] 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 of grade three 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 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 and regimens to go forward with and we need some more data to drive that.

But it still is our intention in 2025 to initiate that that trial. So we're are moving swiftly as we can to support that decision.

The second question is Soloprazole. Do you want to comment weigh on ZolomRacid and pancreatic cancer? And we think about that relative to direct cell unrest? I'm sure. Thermolysis, as you know, G12B has a prevalence of about forty percent of pancreatic cancer. So it's the most common graft mutation or specific mutation in general that's a driver of pancreatic cancer. So we had shared earlier Phase one data and showing that it's a highly active agent, we're actually following on those results looking for the durability of these activities. And then I think our initial thinking is probably end up being a separate registration trial with a standalone registration path. And we're currently evaluating the combination with [indiscernible] best in class option that could be a substantial improvement on either monotherapy. As well as the chemotherapy plus TENACARE with Soloz oral acid. So those are Thank you. Thank you. Our next question comes from the line of Ben Burnett of Stifel. Your line is now open.

Great. Thank you. Just wanted another quick question on ZOLDINRASSE. I guess, is there any more color you can provide on that data update being contemplated in second quarter? Specifically, what are the key learnings that you have to glean from these data? Yes. Hi, Ben. Thanks for your question. Don't have any more color to provide on that today. We do intend to provide additional data on Solvaughn RASID in the second quarter of this year. And I think we'll just have to wait until those data are available. Okay, understood. If I can 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 combinability of doxiniracib with chemo. Sounds like you guys are pretty confident there is some combinability potential here given the design that you're proposing. In the frontline metastatic cancer study. But I guess the question is like what are the overlapping talk signals that one should be concerned with when thinking about DUXENRASSEB and the data that's been provided thus far with the various chemos being contemplated. Yes, 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 has 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 chemotherapy has to be aggressive to go with it.

And that that chemotherapy already today drives substantial side effects, adverse events [indiscernible] often results in holding the drug for some period of time and or hospitalization.

And that in and of itself just for the chemotherapy, the standard of care chemotherapy alone could have implications for the ultimate efficacy of a combination of chemotherapy with daraxone or with any any other targeted agent, to be honest. So that's really the issue that we raised. We haven't not sure that there really has been any meaningful public debate about whether or not they are combinable. And so I don't think we have anything to add to that, because that hasn't really been the core issue course, we're evaluating that now And optimistic that we can develop for regimen that combines them But we're keeping in mind this fundamental issue that the chemotherapy itself is already essentially barely tolerated. And in fact, in most cases, not only results in some dose holes, but typically results in dose reductions as one moves from one cycle to the next.

So that's the context for that.

Thank you.

Our next question comes from 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? 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 ks rast driven tumors as well?

Yes. 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 a leiron RACED with daraxone RACED in patients quite advanced colorectal cancer patients who have been previously treated with a G12C inhibitor and really had no other options than we showed significant activity from the combination of ilearnracib with draxoneracib. So 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 be that might prove to be interesting. And we're evaluating them. And 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 Shee of Jefferies. This is Clara on for Kelly. Thanks for taking our questions. So for the Phase one study in PDAC, as of the last update, the median overall survival was so immature at their opportunity. So just wondering do you have any plans to update the overall survival data this year?

Hi, Clara. Thanks for your question. Yes. What we showed before was two different of looking at the data. One was from an aggregate of multiple dose levels up to and including the three hundred milligram cohort And there we did show an overall survival estimate from the curves that was fourteen point five months.

When we took just the subset of that, that was the three hundred milligram subset, if you will, that particular dose cohort because those patients have been enrolled more recently than had the patients on the earlier [indiscernible] that dose curves were not very mature. And so didn't have an estimate of 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 ninety seven percent to one hundred percent range.

Which I think provided some pretty good look about what's going to come as we as the estate mature. But don't. 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.

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. In terms of your priorities here, would you potentially also pursue a non G12 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, Kevin. I think we have Steve Kelsey, our President of R and D. Maybe he could comment on how we think about the first line [indiscernible] there are multiple subsets as you alluded to. Essentially, GTROC is now been defined as it sort of a disease in and of itself. And then there's everything other than GECO. Steve, 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 Revolution. 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 are acquiring and have presented preliminary data on the combination of a neuron acid with the axon acid in G12C cancers, we would plan to move that chemo-three triplet into the G12C lung cancer space and then the daraxone, racib would be prioritized for all other RAS mutant lung cancer without a G12C mutation, which is about [indiscernible] Somewhere in the region of seventeen percent to eighteen percent 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 that Data, yes, will we release yes, I don't think we've specifically guided with regards to 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 is an almost map absolute prerequisite now for the start in trials in first line non small cell lung cancer. And we can No. Only can we combine our rats on 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 combined with [indiscernible] some of the other RAS inhibitors have have had to do. So the ultimately, we are, as you know, still aggressively enrolling the combination of ILIRONRACID with DrexonRACID in both colorectal cancer and non small cell lung cancer and waiting for the the sort of durability to mature.

As soon as that has matured, then we can tell you about it. But of course, I think Because it's durability data, I can't really give you a timeline for the MAC maturation of that data. And of course, just behind that data set will be the combination of [indiscernible] in Ras mutant tumors as well. That was 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 Great. That's really helpful. Thanks. I'll hop back in the queue.

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

Hey, congrats on the progress and thank you for the update.

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 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 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 you just talk about what your strategy might be there?

Well, answer the first part of your question. Yes, we're very interested. I mean, we're we obviously have a very rich pipeline that's going to be very relevant to RAS the RAS mutant portion of lung cancer, which represents about thirty percent of non small cell lung cancer, and 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 intention to pursue an adjuvant trial in pancreatic cancer that we are committed to moving 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 well articulated, well thought through. And the pancreatic cancer is just a little bit ahead of lung cancer because it it really has taken off and the unmet need is so substantial and urgent that we're in a better position really to to push things in all directions there. But you'll hear about lung cancer over time as we 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 both data and then the strategy that supports the data for various earlier lines. We will 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 question. Maybe one quick one for me as it relates to your comment, Mark.

That chemo alone in 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 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 regular interactions 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 combinations really combining adding braxane rasp to the current standard of care chemotherapy either Janabroxine or Fofuranox, right? I think as we've discussed, earlier, our primary goal is really to protect the dose and intensity of Drexel and Lassiter because we think that's going to deliver a maximum chemical benefit for patients. And so how one way or the other, what the final regimen that we develop will move into the first line setting. So other than that, I think maybe two or three [indiscernible] Yes. Maybe if I could add a little bit to that. We do expect that one arm of that trial will be monotherapy directs on RASID 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 of whether you call that induction and maintenance or not. It's [indiscernible] Doesn't 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 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 their initial period, whatever that is, because the potential for having long term benefit from direct on mastoid is implied by or suggested by the data from the previously treated patients. So again, we come back 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 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 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 Draxon RASIV arm to which we've added some chemotherapy as opposed to the chemotherapy arm to which we've added some Drexon RASIV 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 then of course we'll have to engage with regulators. Right now we're talking with 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 Strawnahan of Think of America. Your line is now open.

Hey, guys. This is Matthew on for Alex. Thanks for taking our questions. Maybe first quick one from us. I think in 3Q, you mentioned that you [indiscernible] I know you had safety tolerability data in December. Just curious if there were any updates planned still for 1Q or whether the next updates would come in the mutant selector inhibitor update in 2Q or 3Q. Okay. I was processing your question and I realized now what you're alluding to. We actually moved that update from Q1 of twenty twenty five into Q4 of twenty twenty four. And so that was the update. We provided it [indiscernible] we weren't sure if we were going to be able to do that, which is why we alerted folks that might come in [indiscernible] 2025, but it actually came in 2024. And it is 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 [indiscernible] who have already experienced pembrolizumab So there really wasn't much potential for them to get a new boost antitumor activity by retreating them with pembrolizumab. And so looking at efficacy in that context, if you're thinking about it as additive pembro plus duraxone racid, what you'd really just be seeing is the Diraxon RACID activity.

This contrasts with where it would actually be used, which is in first line patients who have not seen direct sunRascib or pembrolizumab before and that would be a more appropriate setting for assessing the efficacy Makes sense. And then maybe a quick one on how you think about entertaining potential collaboration opportunities with the rest on RASIV 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. So 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 direct cell And that's a 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 Fadia of Needham and Company. Your line is now open. Hi. This is Puna on for Ami. Thank you for taking my question. On dose and rafib, what additional data do you need see that would give you confidence to initiate the pivotal combination trial? And anything update into 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 Could you repeat that and maybe if we could get the volume adjusted up, that would be helpful. [indiscernible] I was asking what additional data do you need to see for result on gas that would give you confidence to initiate the pivotal combination trial? 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 Zoloft on RASID in the combination context Well, We are currently evaluating sold on RASM in combination with duraxon rassib which we think is justified by the previous observations that Elirom Racine plus Deraxon Racine delivered compelling differentiated initial evidence of antitumor activity. So we believe that same concept may hold for ZULRESSO and we're evaluating it We're also evaluating ZULRASID in combination with other 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 zolzomirasib mid year And we expect to develop at least one pivotal trial concept based on a new selective inhibitor which could as well be a soluble acid 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. Ed, so I joined late, so sorry if this was addressed already. But 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. 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 [indiscernible] which we believe is a credible thing based on the [indiscernible] Data that we've shown so far. There's broad interest in this study You're now talking about the three zero two of ESOLU study. There's broad interest in that study by patients and investigators The currently active sites and rolling sites are enrolling quite actively. We're very pleased with the progress there. Also opening new sites in The U. S. According to our plan, consistent with our plan, we're opening sites in The U. S. Right now We do expect and are highly confident that we can complete enrollments of this study in 2025. There may be some stragglers from from countries outside The U. S. That could roll over into 2026, but largely we do expect to complete enrollment in that trial with CRM. We're moving as fast as we possibly can.

As you point out, it does put pressure on that first line trial And frankly, we think it will put pressure on every future first line trial. That's sort of part of the 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 a trial By the end of this year.

Okay.

Thank you. 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 wild about accelerated approval in pancreatic cancer for a number of reasons. One of which is that the OS readout doesn't come that long after the PFS readout. And so they're not particularly enthusiastic about 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. So 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 and our ambition is to be able to deliver such data. That will be determined by what the data show. Based on the Phase onetwo data, which we've shown so far, we're encouraged by that possibility. A regulatory body might look at those results we don't we of course can't predict We designed the trial really around the OS which means that it's overpowered for PFS, And the timing of the [indiscernible] 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, but having reached it yet, which case there would be a subsequent assessment of the data after with a greater chance of achieving the OSF1 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.