Good day, and thank you for standing by. Welcome to Revolution Medicines Fourth Quarter 2025 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Ryan, please go ahead.

Thank you, and welcome, everyone, to our fourth quarter and full year 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, our Chairman and Chief Executive Officer; and Jack Anders, our Chief Financial Officer; Dr. Steve Kelsey, our President of Research and Development, Dr. Alan Sandler, our Chief Development Officer; Dr. Wei Lin, our Chief Medical Officer; and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call. Before we begin, I'd like to remind everyone that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K that is filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter and full year ended December 31, 2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. Good afternoon, and thank you for joining us. We will keep our prepared remarks brief today highlighting the substantial progress and growing momentum for our pioneering RAS(ON) inhibitor pipeline and outlining several important priorities for the year ahead. Jack Anders will summarize our financial results, along with financial guidance for the year ahead. At Revolution Medicines, we remain steadfast in our commitment to revolutionizing treatment globally for patients living with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines directed against these common mutational drivers of human cancers. As pioneers in the RAS targeting field, with a singular focus on RAS-addicted cancers and a great deal of validating data behind us, we are well positioned to continue building on important scientific drug discovery and clinical breakthroughs that have the potential to change standards of care for patients. Our efforts throughout 2025 strengthened our leadership position as we advanced our robust pipeline that includes four novel investigational drugs that target the major oncogenic RAS drivers: daraxonrasib, our most advanced program, a groundbreaking RAS(ON) multi-selective inhibitor; elironrasib, a differentiated, highly active and well-tolerated RAS(ON) G12C selective inhibitor; zoldonrasib, an innovative, highly active and well-tolerated RAS(ON) [ G12C ] selective inhibitors; and our newest clinical compound, RMC-5127, a promising RAS(ON) G12V selective inhibitor. We have 8 ongoing or planned Phase III registrational trials and extensive clinical experience to date with more than 2,500 patients having received one or more of our RAS(ON) inhibitors in the aggregate. This clinical work has built upon the foundation of a strong discovery and preclinical platform that continues pushing the boundaries. Our virtuous cycle of innovation fuels how we discover new ways of targeting RAS through our highly productive tri-complex platform, develop novel investigational drugs through robust and parallel clinical development plans and…

Thank you, Mark. We ended the fourth quarter of 2025 with $2.03 billion in cash and investments. In 2025, we entered into our innovative and flexible strategic partnership with Royalty Pharma, which provided us access to up to $2 billion in committed capital under the terms of the agreement. We received the first royalty monetization tranche of $250 million in June 2025, and there remains an additional $1.75 billion and future committed capital under this arrangement. Turning to expenses. R&D expenses for the fourth quarter of 2025 were $294.9 million compared to $188.1 million for the fourth quarter of 2024. The increase in R&D expenses was primarily due to increases in clinical trial and manufacturing expenses related to our multiple ongoing clinical development programs and an increase in personnel-related expenses and stock-based compensation expense associated with additional headcount. G&A expenses for the fourth quarter of 2025 were $66.7 million compared to $28.2 million for the fourth quarter of 2024. The increase in G&A expenses was primarily due to increases in commercial preparation activities and personnel-related expenses and stock-based compensation expense associated with additional headcount. Net loss for the fourth quarter of 2025 was $364.9 million compared to $194.6 million for the fourth quarter of 2024. The increase in net loss was primarily due to higher operating expenses as described earlier. Net loss for the fourth quarter of 2025 also included specific noncash charges of $33.7 million in stock-based compensation expense, $12.6 million in noncash warrant expense related to a mark-to-market change in the fair value of warrants we inherited as part of our EQRx acquisition and $11.9 million in noncash interest expense related to the accounting treatment for our Royalty Pharma arrangement. Full year 2025 financial results are available in our corresponding press release and also included in our Form…

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

[Operator Instructions] Our first question comes from Jonathan Chang of Leerink Partners.

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

Thanks, Albert, for your question. So I think you're asking about our plans for daraxonrasib in first-line lung cancer. We still have a high commitment to continue developing daraxonrasib in lung cancer, particularly in first line. Maybe Dr. Kelsey could comment on prior resolution answer to that.

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

Yes. And if I could just add, I think the other element to this, of course, is that we just started dosing patients with Ivonescimab in combination with our RAS(ON) inhibitors that obviously has fairly act on how we think about lung cancer.

Our next question comes from Brian Cheng of JPMorgan.

As we get closer to the top line for the second-line PDAC trial, what is your latest thought on the efficacy measure that we could get at the time of the top line and just curious if you can provide a bit more color on the rate of events towards this upcoming top line.

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

Our next question comes from Michael Schmidt of Guggenheim.

Congrats on all the progress. Mark, I had one on your ongoing implant studies in first-line pancreatic cancer. So obviously, there's a lot of excitement among physicians and patients in the pancreatic cancer community around daraxonrasib. We've heard from docs more recently that if approved, they think that over 90% of their second-line indications could go on daraxonrasib within months of approval. And so when you think about that, to what degree do you think daraxonrasib use in your first-line studies post-progression in the control arm could potentially impact outcomes in RASolute 303 and 305? And how important is it to demonstrate OS in these studies in the first place?

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

Our next question comes from Charles Zhu of LifeSci Capital.

Congrats on the progress. I have a couple regarding some of your ongoing partnered collaborations. First, can you talk about your decision to also combine your pipeline assets with Bristol's PRMT5 inhibitor and how this kind of fits in context with your ongoing collaboration with Tango. And second, your collaboration with Ivonescimab, at what point might you make go, no-go to decisions on later-stage clinical development with your pipeline assets? And how do you weigh not only the emerging combination data that you're generating, but also the broader landscape among the various HARMONY trials shaping out?

Thanks, Charles. I appreciate those questions. Really two different topics. One is PRMT5 inhibitors and why is this or support assessment of RAS(ON) inhibitors in combination with more than 1 PRMT5 inhibitor. To some extent, we had already established that precedence because we have an ongoing collaboration with both Amgen and Tango and the PRMT5 inhibitors appear to be emerging as a potentially important new target class of therapies for patients with MTAP gene deletion, so it makes sense for us to make that -- to make our compounds, which are differentiated and compelling and make them available to others who have PRMT5 inhibitors. This isn't really a signal or a vote on our part about any particular inhibitor. It doesn't speak at all to the work that's ongoing with Tango or Amgen. It's rather more of an inclusive approach and to allow our compounds to be considered in other context as well. With regard to the second question, which is Ivonescimab and how will we make decisions about when to advance into a late-stage trial probably the same way we make all such decisions. So it will be data driven. It will depend on the context, potentially this class of inhibitors could offer a significant advantage over the first-generation PD-1 inhibitors. There is growing value derivatives to support that. We don't have the definitive data yet and we are staying very much on the front lines of a combination of strategies involving IVO with our RAS(ON) inhibitors. So I think we'll be in a great position to make the decision with some data in hand.

Our next question comes from Marc Frahm of TD Cowen.

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

Thanks for your question, Marc. I think I'll comment on the first one and then maybe Alan Sandler can comment on your question about sort of future landscape and future expectations for treatment paradigms. My comment is I don't really have any answer to your question. When the data are unblinded, that causes us to do an analysis, which then leads to a disclosure. And that's about all I can say to that. On your question about how does pancreatic cancer look a few years from now, Alan?

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

Our next question comes from Alec Stranahan of Bank of America.

With the Ivonescimab study now dosing patients, I guess could you maybe speak a bit about the study design and which tumor types and lines of therapy you expect might enrich in the study as it enrolls and longer term, how is this combo maybe emblematic of how you're hedging your RAS therapies alongside potential shifts in standard of care.

I think Dr. Lin, our Chief Medical Officer, can comment on what's our approach to ivo and the initial Phase I context.

Thanks for the question. So like before been pointed out has been initiated, and that's the [indiscernible] study and involve all three kind of stage RAS(ON) inhibitors, that's daraxonrasib, zoldonrasib as well as elironrasib that covers all RAS, the G12D as well as the G12C population. There's a standard dose escalation involving Ivonescimab in combination with daraxonrasib, in combination zoldon and in combination with elironrasib, and the dose escalation is standard all solid tumors and will be helped to define the safety and preliminary activity across some major solid tumors that's going to be seen. And then once the dose has been defined and safety has been cleared, there is dedicated expansion cohort across the three major DCs of interest both Summit as well Revolution Medicine side. And it really is focusing on the three diseases that we have focused on today that include pancreatic cancer, non-small cell lung cancer and colorectal cancer.

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

Yes, just broadly, how you're thinking about combos as standard of care across these treatment setting.

Yes. Well, I think we're not holding anything up. We're certainly developing things in combination with pembro to the extent that, that makes sense to do, but we also have to recognize that field is evolving. And so we're right on the leading edge of it in collaboration with Summit to make sure that we're the first to evaluate RAS inhibitors and particularly class leading RAS(ON) inhibitors in combination with ivo, and we'll learn a lot. With regard to non-small cell lung cancer, where pembro really is a dominant standard of care in most parts of the world, it will take more to knock that off and for that -- for there to be a real change and that will be up to, go to prove itself, which is currently work that's underway. In the GI tumors, there's much less of a precedent here and the combination of a PD-1 and a VEGF inhibitor in the same molecule really opens up a real significant opportunity there. And again, to be the first RAS inhibitors for the RAS versions of those tumors in combination with ivos is an exciting thing to do. So we're playing all the time sort of like our overall strategy, everything everywhere all at once. And that's pretty much what we have to do in a rapidly evolving environment.

Our next question comes from Asthika Goonewardene from Truist.

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

I think that was really in reference to first-line lung daraxonrasib and whether it should be combined with pembro and chemo or whether potentially ivo emerges during that period of time. I think that was the context for that narrow answer that we're now evaluating ivo, and so we'll have some of that information. But in the meantime, as Steve had articulated, we are doing -- continuing the dose optimization and efficacy analysis of daraxon plus pembro plus chemo, the KEYNOTE-189 context. So those are running in parallel, and that will put us in a good position to to make the best decision.

Got it. If you can speak a quick one in. Any thoughts on whether you would use your commissions prior to review voucher for second-line PDAC when we had the RASolute 302 data in hand?

What's the question?

[ CMPV ] will be used for second-line PDAC?

I see. Yes, I think that's been made clear that it wouldn't really make sense to hold back. The [ CMPV ] was awarded on the basis of largely second-line and third-line data that we have shown publicly and shared with the FDA. And so I can't really see a scenario in which we wouldn't be operating under the CMPV in that second-line 302 data readout context.

Our next question comes from Laura Prendergast at Stifel.

In a recent public appearance, Mark, you brought up the concept of treating beyond progression in PDAC from the angle of patients progressing under daraxonrasib and [indiscernible] amplification of the RAS target. Considering a pretty unique consideration in oncology where [indiscernible] the drug upon progression of PDAC [indiscernible] in the patients. [indiscernible] you go for some questions at our end. First, our investigators on the Phase III studies, the first and second line PDAC encouraged [indiscernible] is allowed for any protocols and you...

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

Yes. So specifically, as it relates to study protocols, was there any restrictions on how much -- on whether or not this is a possibility on the first line or second line Phase III? And then how you guys think this could impact overall survival of those studies?

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

Our next question comes from Jay Olson of Oppenheimer.

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

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

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

I think your answer covered it pretty darn well. Maybe the one last little piece is would we bring in additional compounds into our pipeline. And that's always possible. We have a very robust process by which we evaluate other people's assets. We receive a lot of inbound proposals. And occasionally, we reach out to somebody else to look to learn more. So that's all just the practical considerations. The fundamental points I think Steve made are the fundamental points.

Our next question comes from Leo Timashev from RBC.

I wanted to ask a little bit on RM-055 in that class of molecules. I guess does this address secondary mutations? Or is it really only work directly on RAS mutations themselves. And I guess said another way, do you think you'll ultimately need to be selecting patients that might be amenable to this? And then just based on some of the preclinical work you've shown, it looks like it drives a very deep responses even relative to daraxonrasib. So are you seeing this ultimately be positioned as a next line option? Or can this be something that ultimately replaces and is a better daraxonrasib?

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

Our next question comes from Ami Fadia from Needham & Company.

This is Poorna on for Ami. Just wanted to understand how soon can you get to commercialization of data in case the first interim is positive? What are some of the aspects within the commercialization preparations that you still need to work through.

Thank you for those questions. So I think you're asking about what if we don't repair and what does the timeline look like? I think Anthony can step into that.

Yes. Thanks for the question. I think we're really pleased with how our launch ready as planned, we are advancing, and we continue to add highly experienced and talented members of the team, and we're really achieving broad organizational readiness led by the U.S., but also in Europe and in Japan. So we're really pleased with the launch readiness across the board. As Mark alluded to in his prepared remarks, that launch readiness in terms of the U.S. The first launch is actually proceeding quite well with leadership teams in place across commercialization and cross functions field-based leaders across med affairs, market access, marketing and sales. And as Mark mentioned as well, we've now initiated the posting of our further extension of our field-based teams, our sales team. So we're really going to be pleased with how with how the launch readiness overall is coming together. And certainly, as we get closer to filing and launch, we'll provide some more color there.

Our next question comes from Kalpit Patel of Wolfe Research.

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

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

Our next question comes from Sean McCutcheon of Raymond James.

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

Okay. I got the general idea. There were a lot of specifics in that, maybe just the staggering of enrollment, just to make sure we understood your question, were you linking the staggering of enrollment to the mutation representation? Or was that more of a broad question about getting access to patients and enrolling patients? I didn't quite follow that.

Yes. Linking is obviously 303 is all comers, there versus 305, 309 being G12D. So the staggering as it relates to kind of shuttling the patients -- avoiding struggling digital G12D patients to the 305 and 309 studies?

Do you want to comment on that?

Sure. I think some of this will be managed by the site selection, all 3 global trials. We're certainly mindful that we want to have a fair and equitable representation of RAS mutant in the RAS all-comer population in the 303 study and the G12D mutant population in 305 as well as 309 and the control arm do vary among these 3 trials. So 305, specifically does offer both GMP as well as FOLFIRINOX versus 309 and 303 offers GMP as a control. So -- and as you know, there are local regional practices as saw in [indiscernible] practices when it comes to preference for GMP and FOLFIRINOX. So we have a variety of sites region, country to select from. The PDAC patients are certainly -- they are very common. As you know, there's about nearly 60,000 Americans with PDAC every year, half of those are probably first-line metastatic patients in U.S. alone would account for about 30,000 in a year. And globally, certainly many more. So I don't think there'll be a lack of patients, they'll be selecting from. It's really trying to identify sites based on their local factors and investor interest in these trials and then offering these trials as option to their patients. So -- and we're so mindful about the site footprint overlap around these three studies to ensure that there say, the competition across these three studies are not going to be at individual site level.

Maybe mutations in their representation, 85% of PDAC cases have a G12 mutation. Things could be hard to bias that dramatically just from a few ongoing trials. And so there should be fairly similar representation across any of the multi-RAS inhibitor trials. And then in a G12D trial, it's going to be G12D mutation is going to be very specific for that. And then within any given trial, there should be balanced between the control groups and the treatment groups because there will be randomization after patients designated for particular chemo type, if it's a chemo bearing the trial, then they would be randomized to treatment arm versus chemo. So this should be balanced throughout these. I'm not sure that there's any inherent bias that would lead towards anything unusual.

Understood. Yes. And just on the expectation for it in the 303 study for G12D performance relative to G12V and G12R, given the respective expectations for each of those mutations being treated with GMP.

Well, you're asking a question as to -- the question is posed -- presuppose that there are very well-established differences amongst these mutations and how patients perform in a given treatment. I don't think that's so well established. In fact, if you look at multiple studies, you can find very conflicting results, it's just not particularly well established. So again, though, whatever it is, whatever the underlying biology is will be randomized and balanced in a given trial. So whatever that representation is should not -- shouldn't put a figure on the scale on control arm versus experimental.

Our next question comes from [ Faisal Khurshid ] of Jefferies.

I just want to ask now that you've had the commissioner priority review voucher for a little bit. Can you speak to what benefits you are either seeing now or expect to receive from that above and beyond what you'd otherwise get from programs like breakthrough designation in the real-time oncology review.

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

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

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

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