All right, so good morning. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it is my great pleasure to welcome Mark Goldsmith, President and CEO of Revolution Medicines. Mark, welcome. Thanks for joining us. Thanks for having us. I'm just going to jump right into questions unless you want to provide a quick, quick overview of the story. Let's do it. All right. So daraxonrasib, obviously there's been a lot of focus on the upcoming phase, the first fully randomized phase III data to read out. You guided for top-line data in from the RASolute 302 study and second-line PDAC for the first half of 2026. My understanding is that PFS and OS are dual primary endpoint, which means I think you've said before the study could technically succeed on either being positive. But my understanding is the study will be triggered by a specific number of OS events. And so my first question is how similar compared to the prior phase I/II study do you expect patients in RASolute 302 to be? And what is your confidence that the data from the phase I/II study was already very positive will reproduce in a larger phase III trial? Yeah, thanks for the question. Well, let me clarify. So there are two primary endpoints, PFS and OS. The FDA has made it pretty clear publicly that they're seeking OS as the real driver because historically there have been examples of PFS not translating. And so we really look at OS as the main endpoint. And therefore the trial was designed as an OS event-driven program so that the readout is triggered by a certain number of deaths that are, of course, based on our modeling of what sort of effect size and accumulated events. Because it's powered for OS, it ends up effectively being overpowered for PFS. So once that number's hit, once we unblind the data, there are three possible scenarios. We may fail to cross statistical significance on both endpoints, conceivably. We could succeed on both endpoints, or we could pass significance on PFS but not yet be there on OS. So those are three different scenarios. That's why it's defined as an interim analysis. If it passes on both, well, then it's the final analysis. In terms of patients and reproducibility from the phase I data, we've really held the selection criteria, the eligibility criteria, consistent from the early phase I/II study into the phase III study. And we've compared those criteria to those of other phase III trials. We've done a lot of cross-trial comparisons. And we feel pretty confident that the patient population should be very similar, and therefore the results should be in the ballpark. Of course, we understand that there often is some sort of discount that occurs from phase I to phase III. I think that may often occur because of less careful matching of eligibility criteria. But we'll just have to see what the results show. Okay. What are your expectations for performance of the control arm, chemotherapy essentially in 302 study relative to the historic experience? Yeah, you know, there have been a lot of phase III trials. We've listed, we've put a table of trials that we've referenced on our website that's available. They consistently show that chemotherapy delivers a PFS in the range of three to four months in the previously treated pancreatic cancer patients and an OS in the six to seven month range. I think there's really no reason to believe that anything has changed suddenly in 2026 that would give us a different readout from that. There's some play in the data across different trials, but I think those numbers are pretty consistent. Right. Okay. And then obviously the vast majority of PDAC patients have a RAS mutation, but the study did include RAS wild type patients as well. How do you expect it to impact study outcomes in the ITT analysis? Yeah, this is a really important question. It's quite remarkable how consistently it appears that pancreatic cancer is driven by RAS. We consider it to be biologically a RAS-addicted disease, and that comes from a variety of sources of information. The vast majority of tumor cell lines from pancreatic cancer patients have a RAS mutation, and the vast majority of biopsy samples from pancreatic cancer patients have a RAS mutation. There are some patients who don't have a detectable RAS mutation but have other mutations in the RAS signaling pathway, either upstream, for example, RTK mutations or fusions, or downstream, Class I BRAF mutations. So it's pretty much telling us the biology is telling us that RAS is central to pancreatic cancer, whether or not you have a point mutation. And as far as we can tell, virtually all pancreatic cancer is a RAS-driven disease. We also know that daraxonrasib is active in third-line patients and later. It's active in second-line patients. It's active in first-line patients. So anybody who has the idea that RAS addiction is something that occurs after some early treatment with chemotherapy, it's just disproven by the facts. Pancreatic cancer is a RAS-driven disease. We haven't reported any clinical data on patients who have a so-called wild-type RAS genome. But in the pancreatic cancer cell lines, the few cell lines we can find that don't have a RAS mutation, they tend to still be sensitive to daraxonrasib, consistent with the idea that RAS is driving their disease, whether or not there's a point mutation in a RAS causing an oncogene. I'd also mention that, we do have the nested trial design, which means that in the core of the analysis, it will focus on patients with G12 mutations. So only patients with G12 mutations represents about 85% of pancreatic cancer. So it's not a minor subset, but it's a very well-defined, biomarker-defined subset. Those are the patients for whom we simply have the most data, therefore have the most confidence, and so we put it in the core of the analysis. In the outer ring, which then gets included in the secondary analysis, we then have patients who have anything other than a G12 mutation. They can have a G13 mutation, a Q61 mutation, or they might have no detectable mutation, and they're all included in that broader population. So we've designed the trial to optimize to make sure we have the highest probability of success in the core, but we also think it could well be successful in the broader group. One other comment. Not having a RAS mutation means that in testing, whether it's a biopsy sample or a liquid biopsy, no mutation was detected. That doesn't mean that there's no mutation in the tumor. It just means it wasn't detected. And there is a false negative rate in testing, either because the biopsy missed the tumor or because the liquid sample simply didn't have a high enough tumor DNA burden to be able to detect it. So sometimes on retesting you do find mutations. It's a RAS-addicted disease. It's the most addicted RAS-addicted of all cancers, and we think most pancreatic cancer patients have the potential to benefit from daraxonrasib. In order to receive a broad label in the ITT population. Yes. Do you think success in ITT alone is sufficient, or do you expect the FDA to look specifically at the non-G12C subset and to demonstrate benefit there? Well, the deal with the FDA is that they will, they can and will look at everything. So they will cut it 100 different ways, however they wish to. It is predefined the 100 ways in which we'll cut it for them, but then they'll get the raw data and they can cut it other ways. What they won't do is look for statistical significance in small populations. It's not meaningful. If it takes 500 patients to show a difference between treatment arms with G12 mutations, why would looking at 10 patients with wild type be able to tell you the difference between chemo and daraxonrasib? It doesn't; it wouldn't make any sense. What they'll look for is they'll do a sensitivity analysis. They'll look at the hazard ratios and see if something is really of concern such that you might be causing harm to patients. A hazard ratio of significantly greater than one typically becomes a yellow flag that they would then consider. But it's up to them. They'll make the determination. Okay. And so we get asked a lot, assuming the interim analysis is positive, how much information are you willing to share at that point in time, versus just announcing success of the study? Well, I think for a study as important as this, and it is being watched by every corner of the globe, people will want to see the data and want to see it in the most sort of rigorous context that you can do, which would be in a medical meeting. So I wouldn't necessarily expect that in an initial press release that we'd be releasing a lot of detailed data. But I'd expect the top-line results there and then a medical meeting of some sort, after that. Makes sense. And then assuming success, how quickly do you think you'll be able to submit an NDA, which obviously also incorporates a CMC package and other, other things? Yeah. I can't give you the specifics of that, but we'll move swiftly. Our organization is working really hard to set up the conditions for us to move efficiently once we unblind the data. But there's sort of built-in inefficiencies and there are just some things you can't do anything about. So we'll move swiftly after that. From the FDA's point of view, there's of course a lot of information that has to be provided. We're going to be on track with that, how they process it, handle it, and ultimately decide to accept a filing, which from their point of view is when the clock starts ticking. It's only after they accept the filing. And so you can pack a lot in before that, which they'll be trying to do in order to give themselves as much timeline for review as possible, even with the CNPV. All right. So I did want to speak now about your strategy for daraxonrasib in first-line metastatic pancreatic cancer patients, where you recently announced that the RASolute 303 study, which is your three-arm trial, is now open for enrollment. Maybe first question is how quickly do you think you'd be able to enroll this study, and to what degree can you leverage, I guess, clinical trial synergies from your 302 study here? Yeah, moving daraxonrasib to first line is a really important high priority for us, and that's why we've initiated the 303 trial already, because the data, the single-arm data that we've shown for daraxonrasib in second line and later lines was so encouraging, it actually even exceeded numerically the benchmarks for first line pancreatic cancer chemotherapy treatment. Therefore, patients, their families, and investigators are highly interested in getting access to daraxonrasib. So we expect from a patient and investigator point of view that there is and will be, you know, high engagement, high enthusiasm. On a global basis, we have a lot of investigators who are working really hard to get to the front of the line, to get onto the trial and to get slots allocated to them. Many of those are investigators who have had experience with daraxonrasib. Our typical observation is that once an investigator treats a patient or two with daraxonrasib, they become addicted to daraxonrasib. They really want more of it. They want access to it. They want to give it to their patients. If you're an investigator who's had a few patients, you'll want to be in the first line trial. Sounds like, so you expect swift enrollment. We would. You'd mentioned the importance of demonstrating overall survival in pancreatic cancer earlier. To what degree do you expect potential daraxonrasib post-progression use in a first-line study to become an issue in a way? And can you correct for that, if needed, to demonstrate OS in first line? Well, let me separate that into sort of two different concepts. One is should patients who progress on daraxonrasib continue on daraxonrasib? That's a, I don't think it's exactly what you were asking about, but I want to start with that. Meaning if you are doing well clinically, should you withdraw daraxonrasib just because the CT scan shows a small new lesion or a slight increase in one lesion? And we don't know the answer to that. But if you sort of pause and think about the biology, we've got the brakes on RAS signaling. We're pushing on it about as hard as we can. And if a tumor breaks through, it typically breaks through by increasing RAS signaling. If you take away the brake, that tumor's just going to have, you know, unfettered ability to grow. So it's not clear that you really should stop treating patients just because they've progressed, unless they've clinically progressed to the point where they can't take daraxonrasib any longer or where it's so obvious that you're not providing any benefit. And we have heard anecdotally from investigators that some have continued treatment for patients who are clinically doing well on daraxonrasib but have a CT scan that says that they've progressed under formal RECIST criteria and that some of those patients have stayed on for a very long time afterward and continued to do well. We have to study this. We have to quantitate it. So we really can't make any recommendations today. But we have in fact encouraged investigators, when they have such a situation to consider whether they should continue treating in order to collect more and more data about that. I think the thing you were asking about really was crossover and whether patients, who were randomized to chemotherapy in the second line trial, whether they would go seek access to daraxonrasib after they progress. And if they were to do that and got the benefit of daraxonrasib, would that affect their overall survival and therefore complicate interpretation? That's possible. And we are sort of in a race with ourselves here. We both want to get daraxonrasib out as quickly as possible, as many patients as possible from a humanistic point of view and to try to bend, you know, the mortality curve. At the same time, under a regulatory regime both in the United States and actually globally, every other country in the world wants to see OS results. So there's just this tension between those, and there's no obvious way to resolve those except we've just got to go as fast as we can on everything that we're doing. Now, because approval outside the U.S. would likely come after approval in the United States, we do have some additional time, there without sort of the complication of having, you know, prescription-based access to, daraxonrasib for patients who have progressed from chemotherapy. So I think we'll definitely utilize that to our advantage to try to accomplish both of our goals. But there's no question these are absolutely in tension with each other, and we don't have any magical solution to it except go as fast as you can on everything that we're doing. That makes sense. How will physicians weigh potentially using monotherapy daraxonrasib in first line versus the limited GNP combination, you know, regimen? What are some of the differences you expect to see in? Well, it's not a limited. It's a full GNP regimen. You mean the schedule being the every other week schedule for GNP. Yeah. Yeah. The word limited caught my attention. So, right now, the data we have shows that both monotherapy and combination with GNP deliver quite encouraging response rates. We haven't yet shown any durability data. Sometime this year at a scientific meeting, we'll show an update that gives an initial view of durability. But we're quite encouraged. We think both of these are very active regimens. Why bother doing both? It's funny. Sometimes I'm asked by, you know, an investor, "Well, if you're doing monotherapy, why bother doing chemo?" And I'll explain that, "Well, there may be some additivity between them. And also, a lot of doctors are very used to using chemotherapy and are uncomfortable, you know, giving up that backbone." And then that same investor will say, "Well, if you're doing the combination, why bother doing the monotherapy?" Well, there's some patients who can't take chemotherapy. There are many patients who will either self-declare that they're ineligible for chemo and just don't want it. What happens to those patients? They go to hospice care. I mean, it's really, it's a disaster. And so offering a pill that most patients can take quite easily and they can take it at home once a day, does create an option for patients who simply are ineligible or choose not to take chemotherapy. So from our point of view, we're really focused on primarily trying to provide credible options for patients. Every patient has his or her own characteristics. If we create all of those options, more patients will get access to and use daraxonrasib, which will, we hope, help their disease. Okay. So then I had a question: how you think about the first-line pancreatic cancer opportunity for your portfolio to play out long-term. You recently announced two new phase III studies in first-line PDAC for zoldonrasib, one in combination with chemotherapy, the other one in combination with daraxonrasib. First, remind us what what drove your decision to initiate two studies, the two separate studies, and then essentially a patient with a G12D mutation will have almost four choices, right, in terms of different combinations. Right. Yeah. How do you think this will play out longer term? More choices is better for the reasons that we just talked about. We don't yet have any preview of whether one regimen is superior to another. We're just comparing them to chemotherapy right now, and we think all of them are going to be superior to chemotherapy. But is there a rank order among those three or four options that you just talked about? We don't know. Tech might take years to figure that out. So why would we sort of arbitrarily just do one or the other back to our commitment to serving all patients and giving as many options as possible? Zoldonrasib seems to be a pretty remarkable compound. It is reported to be by investigators and patients extremely well tolerated. We see very little in the way of safety signals. The story I've heard multiple times now, by an investigator is patient comes in the office very ill with pancreatic cancer. They can barely make it into the office. They're emaciated. They have pain. They start on zoldonrasib, discharged from the office. They come back a month later feeling much better, walking in, looking a little healthier, saying, "Doc, I'm doing very well." Doctor says, "That's great." And then the patient says, "By the way, did you put me on placebo?" Because they experienced nothing from the drug that made them believe they had an active drug other than the fact that they're doing well, you know, in totality. So it's a very well tolerated drug. And because of that, we think it's the ideal drug to combine with other drugs that are poorly tolerated, chemotherapy being, you know, the poster child for poorly tolerated drugs. And whether you're talking about GNP or FOLFIRINOX, these are not pleasant experiences for patients. Adding anything on top of them that contributes to a side effect profile is a negative and might actually push them into having more dose interruptions and breaks in treatment. So zoldonrasib is a good idea. So we're combining zoldonrasib with FOLFIRINOX with GNP. We've shown initial data on the FOLFIRINOX combination. It's performing very well, tolerated well. It's tolerated at the limits of FOLFIRINOX but not at the limits of zoldonrasib. So that regimen makes a lot of sense to do. FOLFIRINOX is used in certain parts of the world, so we should try it. The combination with daraxonrasib is a really interesting different paradigm, which is taking a mutant selective inhibitor and combining it with the RAS multi-inhibitor. And they deliver really different properties to the tumor that seem to be additive. And I would say so far now, when we've done a RAS(ON) inhibitor doublet, meaning two different RAS(ON) inhibitors put together, one is a multi-inhibitor and one's a mutant selective inhibitor, in every experiment we've done, we've seen improved efficacy from that combination. And we believe it might be because the mutant selective inhibitor is very focused on the mutant, may do a very good job of suppressing that initial mutant. The multi-inhibitor sort of pours a cold wet blanket over all the other mutant forms that might otherwise emerge in the setting of the selective pressure of the mutant selective inhibitor. And so you get the benefit of the two. You also get increased total engagement of the tumor RAS mutations with the combination. So we're excited about that. That could be antitumor, a chemo-free regimen that would allow chemotherapy to be moved to later lines. So it's not as if we're displacing it entirely, but we push it back and maybe give patients a chemo-free regimen to begin with that may be superior to daraxonrasib or zoldonrasib given alone. So that's why we're pursuing all of those. Back to our earlier conversation, the longer we wait, the higher the barriers are to being successful in a trial. That will apply to every other competitor. Everybody else who has a compound, they're going to find it harder and harder to do a trial. But so are we. So we're in a race against ourselves to get all of these things done as quickly as we can before these drugs are so widely available that there's no, no study that anybody would ever be able to do. Okay. So, I did want to touch on colorectal cancer, actually. It sounds like you've been making some progress there internally based on your comments last month and so. Yeah. Yeah. Just what is your latest thinking on how to approach colorectal cancer and how much, or what could we learn this year from, your portfolio in terms of activity in that in that category? Yeah. Well, I can't give you much of a preview of what we'll learn until we share it. But, we're very active in patients with colorectal cancer. 50% of patients with colorectal cancer have a RAS mutation. It's obviously an important part of their disease. Unlike pancreatic cancer, where it's quite clear suppressing RAS alone can have a dramatic effect, there are lots of other things going on genetically in those tumors, multiple things that contribute to tumor progression. And, those tumors tend to be genetically and biochemically heterogeneous as well. So one part of the tumor may be driven by one collection, one, genotypic profile, and another part of the tumor might be driven by a different, set of genes. And so it's a very difficult thing to treat. and we believe it will take combination regimens. We've spent the last couple of years deeply into a variety of different combination regimens designed to suppress RAS, suppress RAS plus other non-RAS things going on. I think we're beginning to see the light. And sometime this year, we expect to share some additional data and some visibility into how we see registering in colorectal cancer. Okay. So, I just want to touch on another topic. I was really intrigued by your comments again last month about RM-055, actually, especially as I think about other pan-RAS inhibitors, pan-CARIS inhibitors entering the market or the space, the trials. Yeah. I don't know if they're entering the market, but they're entering the space. Trials, phase I trials. What can you tell us about RM-055 and how is it differentiated from daraxonrasib and perhaps other, pan-RAS inhibitors? Yeah. We're really excited about this, this new, innovative class of inhibitors. I realize we haven't really shared much about it. That will happen at an upcoming scientific meeting. Our scientists only would allow me to share what I shared. So I'm sort of limited to the information that we showed. But I think there was enough there to appreciate that the profile is dramatically different from really any other RAS inhibitor. And it comes out of some fantastic discovery science that was done at RevMed. We'll share that mechanistic information, more insights at an upcoming scientific meeting. And I think that will clear the path for an expected initiation of a clinical trial with the first compound from that class by the end of this year, which will be our fifth compound in the clinic once that enters. Okay. And then I just want to squeeze one more high-level question. And obviously, last summer, you announced this big $2 billion funding agreement with Royalty Pharma. And I know you did consider other strategic opportunities, ex-U.S. partnerships, for example. And you decided to do the global alone approach for now. And I guess my question is now one year later, or you know, eight months later. Yeah. As the development scale of your programs has evolved since, you're running a lot of phase III trials, a lot of, a lot more drugs, entering late stage, late stage development. At what point do you think revisiting this question of potentially having a global partnership may be value added relative to your assessment last year? I think we made the right decision. And I think, the evidence is increasing that we made the right decision. So I, I don't know what it is that would, would cause us to reevaluate that, to reevaluate that decision. I think, particularly with the pricing issues that have now arisen, the differentiation between U.S. and ex-U.S. markets and the complexities of those, trying to manage that through a partnership, would be actually a nightmare. I can't say that we made the decision because of that, but I'm sure glad we made the decision. So we're, we're all in on building the global capability and, don't see any, at least today, I don't have any idea what would drive us to reconsider that. We're, we're pleased with the decision. Okay. Great. Well, this is a good time to wrap up. So, Mark, thank you for your time this morning. Really appreciate it.