Hey, good morning, everyone. Let's get started. Welcome for joining us for Jefferies London Healthcare Conference. My name is Clara Dunn, a biotech analyst here at Jefferies. So sitting next to me, we have the Chief Executive Officer of Revolution Medicines, Mark Goldsmith. Welcome, Mark. Thank you. Mark, maybe for the audience who might be less familiar with the story, can you maybe start setting the stage by giving us an introduction of an overview of Revolution Medicines, what's the current pipeline, and what have kept you busy for the past year? Yeah, thanks for having us. Revolution Medicines is a company focused essentially exclusively on the most common genetic cause of cancers, that is, RAS-driven cancer. We have developed a very rich pipeline of inhibitors of various RAS cancer drivers. In fact, we have compounds that cover essentially all the variants of RAS that cause human cancer. Our mechanism of action involves inhibiting the active or on state of RAS cancers. We have three compounds in the clinic prior to today, and they're all making good progress across RAS-driven cancers, most highly RAS-driven cancers, pancreatic cancer, which is essentially entirely driven by RAS, 50% of colorectal cancers, and 30% of non-small cell lung cancers are driven by RAS. This is a very important cause of these devastating diseases, and our strategy is to develop RAS inhibitors and various combination approaches to try to maximize impact on behalf of patients. There are some RASs. We definitely want to spend a lot of time talking about this a little bit later, but you recently also received a Commissioner's National Priority Voucher and Orphan Drug Designation for DARA in pancreatic cancer. Maybe just talk about what kind of engagement you've had with the FDA about this voucher, and how do you foresee this voucher being really implemented in your clinical development? Yeah, so you're talking about a compound known as daraxonrasib, or sometimes called daraxon, previously called RMC-6236. This is an inhibitor of essentially all forms of RAS that cause human cancer. We've made significant progress in pancreatic cancer, which I'm sure you're going to want to talk about, and the regulatory agencies, investigators, and patients have been very enthusiastic about it. This compound has the distinction of having received a Breakthrough Designation, an Orphan Drug Designation, and was one of the first nine recipients of the Commissioner's National Priority Voucher about a month ago. That voucher is intended to signal that the FDA plans to move in an accelerated way in its review once it receives a submission from us for an NDA based on a global phase III randomized trial that's currently underway with daraxonrasib in pancreatic cancer and second-line pancreatic cancer. Exactly how that will work is something we're still learning about. I think the FDA is still, frankly, developing the approach for that, but we've had deep engagement with the FDA for many years now across our programs, across indications. We are very familiar with the channels there, and now that conversation has turned to what steps we need to take in order to prepare them for a potential NDA submission so that they could review it. Their timeframe, their stated timeframe, is to be able to review that NDA over a one to two-month period. We will see how that all plays out, but it certainly signals enthusiasm by the regulatory body for daraxonrasib, and we'll do everything we can to help them in that ambition. It's certainly very encouraging for us to see daraxonrasib being one of the first to receive the voucher, and as you alluded, there might be an accelerated timeline for the review. What might be the other implications for this voucher in terms of the timeline of commercialization, maybe following your pivotal readout in second-line pancreatic cancer in 2026 as well? The review time at the FDA is certainly part of the timeline, and to the extent that that can be compressed, that'll be favorable for ultimately launching the product. We have planned for a wide range of scenarios, both for timing of an NDA submission as well as for timing of a launch, and we'll be prepared for the most accelerated conceivable timeline. If the FDA can help us get there even faster, we'll be able to deliver it to patients even faster. Great. Maybe let's take a step back, actually, talking about the pivotal phase III trial you're running in pancreatic cancer. Maybe just talk about what are the specific endpoints, what constitutes success for RASolute 302, which is the pivotal phase III for daraxonrasib in second-line pancreatic cancer, and what are the evidence so far giving you this confidence in the trial's outcome? Yeah, it's an important area. Pancreatic cancer today is treated essentially exclusively by cytotoxic chemotherapy for first-line, second-line, later-line adjuvant treatment. Essentially, all patients receive chemotherapy. There are some patients who receive surgery for resectable disease, but even those patients also receive chemotherapy. The two most common cytotoxic chemotherapies are Gem-Abraxane and FOLFIRINOX or some form of a 5FU-based regimen. These regimens are not very effective, very disappointing for patients. In second-line pancreatic cancer, cytotoxic chemotherapy delivers a median PFS, progression-free survival, of on the order of three months and a median overall survival of about six months. That's about as good as it gets in pancreatic cancer. It's pretty dismal. We have been studying daraxonrasib. We've now studied it in roughly 1,000 pancreatic cancer patients, so we have extensive experience with it across different lines of therapy and in various strategies, both monotherapy and in combinations. Based on a monotherapy cohort in second-line pancreatic cancer, we reported a median progression-free survival of over eight months as compared to the standard of care three months and a median overall survival of 13-15 months. Really a substantial difference. If you're willing to make a cross-trial comparison, we understand that that's difficult to do with these single-arm trials, but nonetheless, we all do it. We understand from investigators, patients and their families, and advocacy groups that their experience of being treated with daraxonrasib qualitatively very much matches the numbers that we've reported. We feel quite optimistic that these data are very encouraging and increase the probability that a phase III trial would be successful. That trial is running globally. It's a randomized two-arm trial. Patients get randomized either to standard of care chemotherapy, and I've mentioned what those cytotoxic chemotherapy regimens are, or to receive daraxonrasib as monotherapy and reflecting the data that I just alluded to earlier. I'm actually really pleased today to report that there has been great enthusiasm and receptivity to this trial, both in the U.S. and internationally. We have had rapid enrollment in it, and as of now, we have fully enrolled that trial. We've completed enrollment, and now we're monitoring patients, and we expect a readout in 2026. We are very excited to have reached that important milestone. In terms of the patient you're enrolling for the pivotal trial, should we expect any patient characteristic difference versus the previous phase, early phase trial in the context of enrollment eligibility? We really don't expect any difference. We carefully constructed that cohort that we reported out to reflect what we expect to receive in terms of enrollment in the phase III trial. The eligibility criteria are very, very similar. We've also matched those eligibility criteria and even the patient profiles from that single-arm cohort that we've reported against all of the phase III trials that we had access to in terms of patient demographic and other characteristics. We feel encouraged that what we saw in the phase I-II trial will be reflected in some form in the phase III trial. Of course, we can't be certain. There can be differences that we just don't know about, but structurally, we'd expect those patients to be quite similar. Next year, before the pivotal readout, should we expect any interim analysis as well? The trial has in place the opportunity for interim analysis. That interim analysis is driven by overall survival, which sort of gets to one of the earlier questions you raised, which is what are the endpoints. Overall survival is really the critical primary endpoint. It actually has a dual primary endpoint, overall survival and progression-free survival, but it's powered for overall survival, which means it's actually overpowered for progression-free survival. Patients, physicians, and the regulatory bodies in pancreatic cancer really want to see changes in overall survival, and so that's what we're focused on. It is an event-driven trial, meaning there's not a date upon which it stops simply because of the Gregorian calendar, but rather it is driven by the number of overall survival events, that is, deaths that we've statistically projected to indicate whether or not there would be a difference between the groups. We're just awaiting the accumulation of those events, and when we read it out and sort of open the envelope, we'll know whether that's an interim read or whether that's the final read. It's possible that we hit on neither of those endpoints. That's conceivable, not very high probability, but conceivable. It's possible that we will have hit on both of those endpoints at that time, at that first read, in which case it's the final read and the trial's over. It's also possible that we hit on PFS but have not yet reached statistical significance in OS, in which case it would become an interim read and there would be a follow-up read subsequently. Beyond second-line pancreatic cancer, you also have a phase III in front-line pancreatic cancer. You also recently announced a trial design for that trial. Maybe just talk to us about the rationale for the three-arm design and the choice of chemo in the trial as well. We're very committed to patients with pancreatic cancer. We believe, based on feedback from leading authorities in pancreatic cancer, that daraxonrasib has delivered so far really unprecedented benefit for patients in the single-arm trials. We are interested in all the indications for pancreatic cancer. They're all driven by RAS, and therefore the treatment with an effective RAS inhibitor should be similar across all of these. We announced two additional pivotal trials beyond the RASolute 302 trial. One of them is for patients with adjuvant disease or for adjuvant treatment of resectable disease. That trial we announced a few weeks ago has initiated. Those patients received surgery and perioperative chemotherapy according to standards of care and get randomized either to observation or daraxonrasib monotherapy for a period of two years and will follow disease-free survival for those patients. That study has been initiated. The study you just alluded to, which is called RASolute 303, is the first of our first-line studies in pancreatic cancer, our global phase III first-line studies. It is a study with a three-arm trial design, as you mentioned, that is comparing standard of care cytotoxic chemotherapy versus daraxonrasib monotherapy versus a combination of daraxonrasib plus chemotherapy. Those are the three arms. It's a very attractive trial design for patients. It means everybody has a two out of three chance of receiving daraxonrasib. They have a two out of three chance of receiving chemotherapy as well. We had indicated we expected to initiate that trial in the fourth quarter of this year, and I'm also pleased to announce today that we have, in fact, initiated that trial as well. We're now running three global phase III trials in pancreatic cancer. We're looking to cover every possible indication in pancreatic cancer, and we'll continue to build on that with additional trials. Maybe just a little bit more on the front-line pancreatic cancer trial. You do have this monotherapy arm and also a genotoxic chemo combo arm. When we look at your early phase monotherapy data, it's in fact already very highly encouraging as a monotherapy, even in the context of front-line. How should we think about in the front-line monotherapy versus chemo combo, under what scenario you think monotherapy might have a shot as well? Pancreatic cancer is a RAS-driven disease, and it turns out if you treat it with a really good RAS inhibitor, you can modulate that disease. The data you just alluded to were that in the second-line monotherapy trial that we had performed previously, the PFS and OS outcomes were not only superior with daraxonrasib to standard of care in second-line, they were also superior to standard of care in first-line pancreatic cancer. I think that's the point you were just making. We also reported a cohort of first-line patients treated with daraxonrasib monotherapy, and those patients also showed very good outcomes. From a response rate perspective, we've not yet reported durability from those, but we expect that to be durable also. I think the evidence supports the biology that pancreatic cancer is a RAS-driven disease and daraxonrasib is very active against that disease. Why bother with cytotoxic chemotherapy? The question has been changed. It used to be, why are we running monotherapy? That was before we reported the monotherapy data. Now the question is, why bother with cytotoxic chemotherapy? It really comes down to just our philosophy that we are trying to find the most effective regimens for patients with RAS-driven diseases. It is conceivable that cytotoxic chemotherapy combined with a targeted RAS agent will simply deliver the greatest effect. We do not really know that. In the cohort I mentioned of first-line patients, we actually compared monotherapy with cytotoxic chemotherapy as a combination. We compared mono versus the doublet. The response rate for the monotherapy patients was 47%, and the response rate for those with gemcitabine plus daraxonrasib was 55%. Are those different? We do not really know. This is not a randomized controlled trial of the size that would answer that question, but it certainly is a trend towards a possible difference. In preclinical work, we've seen that a cytotoxic agent combined with daraxonrasib does deliver greater, at least initial, efficacy. It makes sense for us to evaluate that in the clinic, and the best way to answer the question is simply do the experiment. It may turn out that different patients will prefer monotherapy versus the combination with cytotoxic chemotherapy. A 45-year-old robust patient might say, "Doc, I want to receive the most aggressive therapy you have available. Give me the strongest chemotherapy and give me daraxonrasib." A less robust 85-year-old might say, "I don't think I can handle chemotherapy, but I can certainly take a daily, once-a-day pill, and so I'd rather have monotherapy." I think in this world today, especially with such a devastating disease, creating options for patients and their physicians is really the best way to go. That's fair. In terms of the front-line response rate you just alluded to, should we expect an update on that data in the near term? We do expect at some point to report out durability data from the treatment arms that I just mentioned, the monotherapy and the combination with cytotoxic chemotherapy. Those data are maturing. We tend not to report durability until we have stable numbers that we think can hold up for the long term. We prefer that instead of getting out ahead of ourselves. We will report it when we have stable enough information to share. Great. I also want to quickly touch on the adjuvant opportunity as well. I mean, in this setting, maybe people are less familiar in terms of how large exactly is the opportunity. How should we think about if we use daraxonrasib in adjuvant setting? How does that change maybe how physicians will sequence the drug in the front-line setting and the second-line as well? Right. So roughly 25% of patients are radiologically identified in the first diagnosis as being resectable, meaning the surgeon looks at a CT scan and says, "I think I can remove this." Of those 25%, about two-thirds of them prove to have truly resectable, localized and resectable disease, which is a surgical pathologic diagnosis. So 15% versus the 25% who radiologically look like they might be. That is the numbers. About 15% end up being have a formal pathologic diagnosis of resected disease. Those patients will have received cytotoxic chemotherapy either before surgery or after surgery or some doses before surgery and some doses after surgery. It varies from practitioner to practitioner and from country to country. Generally, almost everybody who receives surgery will also receive cytotoxic chemotherapy. It is not an insignificant population. There are 56,000 new pancreatic cancer diagnoses in the U.S. each year. If we say 15% of those, so roughly, let's say 7,500 patients each year in the U.S. alone, and you can globalize that number, really deserve to have the chance for a potential cure. Now, of those patients who receive surgery and cytotoxic chemotherapy, maybe 20% of them will have long-term durable benefit from the surgery and chemotherapy. That means 80% do not. Adding an agent that biologically targets the pathway that's causing the disease seems like it gives a chance to actually increase that overall survival rate and potential cure rate. At a minimum, it may extend people's lives. We're excited to do it. We think that trial will enroll very readily, and it's compelling to do. Got it. And then also for your G12D inhibitor, zoldonrasib, you also have very strong data in pancreatic cancer. So how should we think about the position of this asset in kind of your clinical development strategy in terms of the pancreatic cancer franchise? Yeah, thanks for mentioning zoldonrasib. Sometimes called the Zoldon at Revolution Medicines, zoldonrasib. And it is a G12D- selective inhibitor. It's an interesting agent. It's orally bioavailable. It's once a day, and it is a covalent modifier of the aspartate-containing variant or the G12D variant. It's the only compound actually in history to go into the clinic to do that. It carries with it a remarkable tolerability and safety profile, as reported by investigators. Many patients can't distinguish it from taking no drug at all, which is quite amazing for a targeted agent. It also carried with it significant anti-tumor activity in patients with pancreatic cancer and a G12D mutation. Back to our philosophy, we're very deeply committed to patients with pancreatic cancer and other RAS-driven diseases. We want to bring forward any compound that looks compelling and try to find its place in the armamentarium for treating pancreatic cancer patients. Zoldonrasib is clearly a compelling compound and deserves that. Whether it should be studied as monotherapy or in combination is something to be determined. We expect that it'll be more of a combination agent than a monotherapy agent, particularly because of its high tolerability profile. We expect that it could be combined with cytotoxic chemotherapy of any form, but we also think it could be combined with daraxonrasib. If daraxonrasib emerges as really the backbone of treatment for patients with pancreatic cancer, then it might make sense to combine with a mutant selective inhibitor. We've shown strong preclinical data supporting the thesis that the combination of a mutant selective inhibitor, zoldonrasib plus daraxonrasib, actually delivers greater anti-tumor punch as measured by deeper responses, more frequent responses, and more durable responses. We believe that combination can counter some of the major forms of resistance that can occur to a RAS inhibitor. We're excited about all of those. We've announced that we expect in the first half of 2026 to initiate a zoldonrasib phase III pancreatic cancer trial that would likely be in earlier disease, a first-line trial. We're just developing the strategy now, and we'll lay out the details of it around the time that we initiate that trial. That will be our fourth pancreatic cancer phase III pivotal trial. We have definitely spent a lot of time on pancreatic cancer, but I also want to make sure we also talk about non-small cell lung cancer development as well. You do have a pivotal trial with daraxonrasib monotherapy in non-small cell lung cancer. Maybe talk about the timeline for that trial and then what is your overall vision and strategy in lung cancer? Yeah, that trial is known as the RASolve 301 trial. It is also a global phase III randomized trial. This is of daraxonrasib versus standard of care in second and third-line non-small cell lung cancer containing a RAS mutation, which, as I mentioned before, is 30% of all non-small cell lung cancer patients. That trial is also enrolling well. I do not have any particular update on it, quantitative update, but it is meeting our targets for enrollment, and we will continue to enroll those patients. We are very excited about that, and that is our first foothold into non-small cell lung cancer, and there is more to come. We have indicated that we expect to initiate a first-line non-small cell lung cancer regimen in a global phase III trial, and that would be a combination of daraxonrasib with pembrolizumab and chemotherapy. The details of that trial we haven't laid out, but that's the basic design comparing that to the KEYNOTE-189 regimen alone and more to follow after that trial as well. For maybe the last 30 seconds, let's talk about your balance sheet, your cash position, and your recent deal with Royalty Pharma, your AI collaborations. We're fortunate that we have a strong balance sheet. We're in a strong financial position. We just reported an update to that. Our cash balance was on the order of $1.9 billion. We had developed in June of this year and announced a really groundbreaking partnership with Royalty Pharma that put $2 billion at our disposal. We've drawn down $250 million of that, but we still have another $1.75 billion available, and we'll draw that down on a selective basis as needed to support our program. We think we have the capital to pursue a very aggressive clinical trial strategy across RAS-driven indications. Great. Really looking forward to the next updates. Thank you so much for your time, Mark, and thank you everyone for joining us in person and online. Enjoy the rest of the conference. Thank you.