All right, so we'll get started right away. I'd like to welcome Mark Goldsmith for the next fireside chat here, President and CEO of Revolution Medicines. Mark, welcome. Thanks for joining us. We'll jump right into Q&A. Obviously, an exciting time for the company with pivotal studies underway for daraxonrasib and more to come. Just jumping right into a question, your most advanced registration study is the second line pancreatic cancer trial, RASolute 302, that's ongoing nearing completion of enrollment. As we look forward to the first registration data disclosure next year, the phase II data was obviously very promising. What have you done to ensure that the phase II data translates into the phase III study? Yeah, thanks for the question. I think that we found that the patient population in our phase I -II trial was very similar to the populations that have been studied in a variety of phase III trials in pancreatic cancer, very consistent across the board. We really did not find a risk profile that differed much. If anything, the patients in the phase I- II trial were slightly worse off, had worse prognostic factors than those in conventional phase III trials that have been reported. I think on that basis, we would assume that we had a representative population and therefore would expect it to be relatively similar in the phase III trial. Great. Can you talk a little bit about the mechanics of the trial itself? You have PFS and OS endpoints, and you also have built-in sequential analysis, rather, in different patient populations in this study. Just remind us how the analysis is done and sort of what triggers the unblinding of the study, so to speak. Yeah, so the main goal of this trial really is to demonstrate an OS benefit. That is something that the FDA has indicated that they would really prioritize in pancreatic cancer. We support that. We think that from a global perspective, having OS data will make the most difference for prescribers and for patients, of course. It is an OS-driven trial. There is a predefined number of OS events that is based on our statistical modeling. That event number, once we are fully enrolled and once we hit that number, we are enabled to look at the data. That could then lead to either just an interim analysis or it could be a final analysis. Of course, it depends on the outcome. In that analysis, we will be able to see both OS and PFS. Because the trial is powered for OS, that means the PFS is likely to be overpowered. The likelihood of reaching PFS significance is very high in that interim, that first interim analysis. The likelihood of OS is whatever we've powered it for. If we haven't reached OS, there's the opportunity to go on and continue to follow patients for an OS outcome later. The hierarchical testing that you alluded to is because there are multiple RAS mutations that drive pancreatic cancer, and the most common of which, 85% of which, are what we call G12 or G12X mutations, meaning some substitution at position G12, about 85%. It's clear from our preclinical studies that the G12 mutations showed the greatest sensitivity in tumor models to daraxonrasib, our RAS multi-inhibitor. Although actually every mutation that we've ever tested has shown sensitivity to daraxonrasib, just in terms of the totality of the evidence we had, it was just stronger evidence in the G12 population. On the basis of that, we have a hierarchical testing strategy where the first evaluation is in that G12 subset, that 85% subset. If we've reached statistical significance there, then a second analysis is done of the broader group that includes all RAS mutations as well as RAS wild type patients. It's a very small percentage of pancreatic cancer patients who have no detectable RAS mutation. Those are included in the broad secondary analysis to give the possibility of an all-comers label. Okay. Just to confirm, the analysis is triggered by the OS event rate in the G12X subset, is that correct? No, it's an overall event rate number. There's a single number, but it's largely driven by what we expect in the G12 population because we just have the deepest data set around that and therefore can make stronger predictions around it. It is an overall number that's a minimum threshold above which we can then begin to look at the data. Understood. Thanks. In terms of potential regulatory review, you obviously already have announced recently the breakthrough therapy designation. You also have received the commissioner's priority review voucher. What are the implications of that on the potential regulatory review process in your opinion? Yeah, daraxonrasib in pancreatic cancer is somewhat special in that it has breakthrough designation. It now has an orphan drug designation, and it was one of the first nine commissioner's national priority vouchers to be issued. It has the triple crown. Now it just has to deliver in terms of the data. All of those create some opportunities to accelerate the review process. Particularly, the breakthrough designation gives us access to greater communication. We're likely to end up with a priority review even without the voucher. With the voucher, the FDA has indicated that their intention is to work with us to try to streamline the review process so that it could happen in as short as one to two months after they accept an NDA filing. That's an important consideration. That one to two month number that Dr. McCarrey has used is really relevant only after they've accepted an NDA filing, which we won't be able to do until we've completed analysis of the data. There are some steps that take place that really nobody can accelerate. They're just sort of the physics of running the trial. Once we have those data, of course, we'll move as swiftly as possible to get it in the hands of the FDA. Right. And then perhaps moving to first line pancreatic cancer, you obviously recently announced plans to initiate the RASolute 303 study there, which is a three-arm trial. And so maybe just remind us of the decision process that went into designing that trial and how you're tracking towards initiating the study. We're on track to initiate that study in 2025, and we have about seven weeks left to deliver on that promise. Now, the first line data or first line trial is supported by really two completely different sets of data. We have the second line data that really is the foundation of the RASolute 302 trial. The phase I- II data showed very strong initial both tolerability, safety, as well as efficacy, with the results of both PFS and OS not only exceeding the benchmarks in the field for second line pancreatic cancer, but also exceeding the benchmarks, significantly exceeding the benchmarks for first line pancreatic cancer. Those data alone are sufficient to drive our conviction that a first line trial should be pursued. In addition, we recently disclosed data actually in first line patients, and we had two sets of data. One is patients who received monotherapy daraxonrasib, and those data are quite encouraging from an ORR point of view. We do not have durability data yet, but the ORR in that patient population was roughly 47%, again, exceeding the best reported results in first line patients with standard cytotoxic chemotherapy. In addition, we reported a reasonably sized cohort of patients who were treated concurrently with gemcitabine, one of the two major standards of care for pancreatic cancer treatment, plus daraxonrasib. Those patients also did well. They tolerated the regimen. They had a good dose intensity, and we reported a response rate in the ballpark of 55%. Both of those data sets really complement the much larger data set that we have had and longer follow-up we have had in second line that all suggest that pancreatic cancers are RAS-driven cancers. They're RAS-addicted cancers, whether they're first line, whether they're second line, whether they're third line. It is the underlying biology of pancreatic cancer. Treating with a very effective RAS inhibitor, and particularly a RAS(ON) inhibitor from Revolution Medicines, is a compelling thing to do. That led us to design the first line trial. We think there are two opportunities to win in this trial with three arms. Patients will be randomized one to one to one, so equally across three different treatment regimens. One is standard of care chemotherapy. The second is daraxonrasib monotherapy, and the third is daraxonrasib plus chemotherapy. Mimicking the data that we have from the first phase I trial. From a patient perspective, that means they have a two out of three chance of being randomized into a daraxonrasib-containing arm. That is a highly attractive clinical trial for patients. That also means they have a two out of three chance of receiving standard of care cytotoxic chemotherapy. That is encouraging. And only a one out of three chance of receiving only cytotoxic chemotherapy, which is the standard of care. We are excited about that trial and look forward to getting that off the ground. Question on the study. If both treatment arms succeed, which is plausible or even likely over chemotherapy alone, how would physicians weigh whether to use daraxonrasib monotherapy or the combination? Yeah, it's an interesting point. From our point of view, the best thing we can do is create as many options as possible for patients and their caregivers. This is a very devastating disease. It doesn't make sense for us to sort of pre-guess what's the one thing that ought to be made available for patients. If we have multiple regimens that we think could offer patients better quality of life and longer life, we ought to make those available. Let each patient and their doctor determine what approach they want to take. If somebody's a 45-year-old, robust, has no other medical problems, they might say to their doctor, "I want to do everything I can to shrink this tumor. Give me whatever chemotherapy you have. Give me whatever targeted therapy. I'm ready for it. I'm robust enough to take it." If somebody's an 82-year-old who has other medical problems, they might say, "I can take a daily pill. I don't want to go to an infusion center. I want to use every day to spend time with my grandchildren." Those are two extremes, and there might be everything in between. We absolutely believe that creating multiple options, if we can, is the best thing to do, and we don't need to pre-define for doctors what regimens they must choose. I'd say that even extends to the rest of our pipeline where we have other RAS(ON) inhibitors that are proving to be quite compelling as well. Some of the indications that are associated with those may overlap with indications for which there may be approved daraxonrasib-based therapies. That's fine. More options means more patients will have access. More patients will find the regimen that's appropriate for them. Okay. Then a question on your recently initiated study in locally advanced pancreatic cancer, which is sort of in the adjuvant setting. Perhaps just remind us of sort of what are outcomes for patients today in the adjuvant in this treatment setting and, yeah, what degree of improvement do you think would be necessary to demonstrate for folks to use daraxonrasib for the, I think, the two-year timeframe? Yeah, let me—sure. Thanks, Michael. Let me just clarify. This is for patients with resectable disease, which is distinct from locally advanced, which is considered unresectable disease. Just to differentiate those, resectable disease means that a CT scan showed a surgeon or convinced a surgeon that they think they could go in and remove enough of the tumor to give the patient a chance at a cure. Now, in reality, of those patients who go to surgery, about two-thirds of them end up actually being truly resectable, meaning fully resectable with clear margins or minimal cancer remaining in the margins. Those patients are called resectable, surgically resectable, or resected. Those patients typically do receive standard of care chemotherapy. Some physicians use FOLFIRINOX. Some use gemcitabine. Some use capecitabine. There are a few different variants of the regimen around the world, but in virtually all cases, patients will receive chemotherapy either before, after, or both before and after surgery. They tend to have a fairly long disease-free period, but almost everybody progresses. Of the truly resectable patients, 80% of patients will recur with metastatic disease. Roughly 20% will have long-term durability out of it. There is the chance to have a cure or something approaching a cure, but it's rare for those patients, even with the cytotoxic chemotherapy. The question is whether daraxonrasib might change that. We've designed a trial. I think it's a very simple and attractive trial design. It allows patients to receive standard of care, whatever their local standard of care is, with a minimum of four cycles of chemotherapy, which may be before, after, or both before and after surgery. Perioperative chemotherapy, surgical resection, and then they get randomized to receive either daraxonrasib monotherapy or no treatment at all and observation. Those patients will simply be followed. The chance of increasing cures or prolonging disease-free survival is there's a high enough chance that this is a very worthwhile study to do. It's going to be very easy for patients to enroll in, and it's an exciting approach. Great. Is there opportunity to leverage surrogate endpoints in the study, or would you have to just wait for events to occur? I think it's going to be event-driven. I wouldn't rule out that there will be some biomarkers tested here, but the real gold standard is disease-free survival, which is the equivalent of progression-free survival, but it's what's used in a post-surgical setting. Disease-free survival, and if we can lengthen that for patients or even convert some of those patients into cures, that would be a fantastic addition to the field. Okay. Okay. Then perhaps moving to non-small cell lung cancer, where you have the RASolute 301 study up and running in second line patients. Maybe just remind us how the study's been enrolling relative to expectations, given that lung cancer can be a little bit more competitive for clinical studies. Yeah, that trial is doing fine. Daraxonrasib potentially serves all RAS mutants, all RAS mutations that drive non-small cell lung cancers. So that's about 30% of non-small cell lung cancers. It's not an insignificant population. Right now, the only subset of patients who are served by a RAS-targeted agent are those that have the G12C mutation, which represents about 12 out of the 30%. It's a little bit more than 1/3 of those. The other, let's say, 2/3 are non-G12C, for which there are no targeted agents at all. In this trial with daraxonrasib, a patient with any RAS mutation can enroll. That means potentially daraxonrasib might serve across the entire 30% of non-small cell lung cancers that are RAS-driven. We are enrolling that patient now, patients into that trial in both the U.S. and outside the U.S. in the EU and Japan. It is on track to our projections. We're doing well with it. Great. In first line non-small cell lung cancer, the market is a bit more fragmented with different patient subsets. You did recently announce or confirm plans to initiate a registration study there as well of daraxonrasib in combination with chemo and pembrolizumab, right? Yeah. Just help us how you made the decision to include chemo versus pursuing a chemo-free regimen. Yes. About 1/3 of patients with first line non-small cell lung cancer have a PD-L1 high phenotype, and those patients can receive just pembrolizumab alone. Any regimen in first line lung cancer right now is going to include pembrolizumab. That's pretty much standard of care, except in maybe some parts of the world. I think in China, they use a different PD-1 antibody from Beijing, B1. Generally, KEYTRUDA is the standard of care around the world. That's the first thing you have to be able to do with any RAS inhibitor is to combine with pembrolizumab. Daraxonrasib, from all of our studies so far, is readily combinable with pembrolizumab. We've not seen any evidence of particular toxicities that are created by combining the two, which already differentiates it from many other RAS inhibitors in the field. We know we can combine with pembrolizumab. We also know we can combine with chemotherapy, first line chemotherapy, platinum-based doublets. It makes sense for us in going into first line to really try to differentiate by combining all three of those agents: chemotherapy, platinum doublet chemotherapy, pembrolizumab, and daraxonrasib. We think that gives patients the greatest chance of having an outcome that is differentiated from what they might have with either pembro or pembro plus chemo alone. Right now, in the U.S., patients are free to take chemo plus pembro regardless of their PD-L1 status. That makes it a universal treatment as opposed to pembro alone, which is just for that small subset. We are taking the approach of going with the broad-based strategy. Everybody would receive the KEYNOTE- 189 or chemo plus pembro plus daraxonrasib. Great. Thanks. Yeah, help us understand on your latest thinking on how to incorporate your mutation selective inhibitors into the lung cancer treatment paradigm longer term. We have two mutant selective inhibitors that are in the clinic now, both of which are, I think, quite distinguished molecules. We have a KRAS, a RAS G12C ON inhibitor. It's the first of those to enter the clinic. It's an exciting compound. It's very well tolerated. It has really a de minimis safety profile. Investigators are excited by it, and it's done very well as monotherapy. It also appears to be combinable with pembrolizumab and to be part of really whatever regimen can make sense. Its most distinguishing feature right now from a profile perspective is that we've shown that patients who have been on a RAS off inhibitor, one of the first-generation RAS G12C inhibitors, and then progressed, if they go on to take elironrasib, that's our G12C(ON) inhibitor, as monotherapy, we've reported a response rate that's above 40% and a PFS that's above six months, which is quite remarkable for these third line patients. These data were first reported, or a subset of these data were first reported two years ago when we first announced elironrasib's initial results. Now, with longer follow-up at a larger sample, it has continued to show essentially the same results plus the durability that I alluded to. I think the field's quite excited about that, and that is a place where we think we can make a real difference right off the bat. That patient population, that is, patients who have progressed on a RAS(OFF) inhibitor, a G12C(OFF) inhibitor, will continue to grow. That population will be a growing unmet need that can be served by elironrasib. Stay tuned for our plans. We've not yet announced any plans, but we're excited about that opportunity. We also think there's going to be room for elironrasib in other lines of therapy. We're evaluating that. We know that we're entering a crowded space. We don't do that lightly, so we would want to go into that competition with the greatest possibility of moving the needle for patients, and we're working to make the determination about what's the best way to do that. Okay. On zoldonrasib, your 12D inhibitor, you did recently announce plans to initiate a registration study in first-line pancreatic cancer. Yes. Just maybe talk a bit more about the thought process in terms of how a study could potentially look like and how this could be positioned relative to daraxonrasib. Zoldonrasib is a RAS G12D-selective (ON) inhibitor, so it follows the same paradigm as our other RAS (ON) inhibitors. It is also a covalent inhibitor. It is the only covalent inhibitor of any target that is aspartic acid containing. It is the only covalent inhibitor that targets that D or aspartic acid. It has never been done before in the pharmaceutical industry. It is the only protein of any disease that is targeted by a covalent agent. The advantage of that is that it permanently disables the molecule, the target. Once it binds, it is irreversibly bound. It takes it out of commission. That is a dead molecule at that point. It is orally bioavailable, and it has a safety AE profile that is very attractive. It has often been described by patients and investigators as being indistinguishable from placebo, which again moves it into really a rarity among RAS inhibitors. That gives us the potential to apply it in a variety of different ways. It could be used as monotherapy, but it could also be applied with the most aggressive chemotherapies that are out there because it won't add, it's not expected to add toxicity on top of those chemotherapies. We have a range of possibilities. One of the things we're excited about with zoldonrasib is combining it with chemotherapy. Another thing we're excited about is combining it with daraxonrasib. We have found in a variety of preclinical studies and now reported in two different clinical studies, one in lung cancer and one in colorectal cancer, that combining a RAS mutant selective RAS(ON) inhibitor with the RAS multi-selective daraxonrasib leads to greater activity than either agent alone in many instances. That creates a unique opportunity for us to really try to hit the mutant very hard with the mutant selective inhibitor while also suppressing all the other forms of RAS in a tumor cell that might be contributing to oncogenesis. Those are two very prominent options we have in a first line pancreatic treatment strategy. We've not yet announced that strategy, although it will be a combination regimen, and we will clarify that as we approach initiation of that trial. I wouldn't necessarily assume that we'll only pursue one approach. We think that there are two, three, four, five potential approaches. We'll pick the regimen or regimens that we think have the most promise. Sounds good. With that, I think we need to wrap up. Thank you so much, Mark. Really appreciate it. Thank you. All right.