Hello, everyone. Thanks for joining us for the last session of the day. My name is Jonathan Chang. I'm part of the Leerink Partners Equity Research Team. It's my pleasure to host the management team of Revolution Medicines. We have with us today President and CEO Mark Goldsmith. Thanks, Mark, for joining us. Thanks for having us. Glad to be here. Would you like to briefly introduce the company? Sure. Revolution Medicines is a company focused exclusively on RAS-driven, or RAS-addicted cancers. We have a deep pipeline of targeted agents that bind to one or multiple forms of RAS that drive human cancers. The most common human cancers driven by RAS are pancreatic cancer, which is almost 100% driven by RAS variants; colorectal cancer, 50% driven; and lung cancer, 30% driven. We have three late-stage development compounds that are moving along nicely, and I'm looking forward to talking with everybody about them today. Great. Let's start with the phase III RAS-Loot 302 study evaluating Daraxonrasib. This is your multi-RAS inhibitor. Right. Previously treated pancreatic cancer patients. Can you discuss how that study has progressed and how we should be thinking about the timelines? Right. As you mentioned, Daraxonrasib, which was previously known as RMC-6236, is a RAS multi-inhibitor. It binds to and inhibits essentially all forms of RAS, both mutant forms and wild-type RAS. We've evaluated it in second-line and later lines of pancreatic cancer and shown very significant anti-tumor activity in a single-agent study. Based on those results, both PFS and OS results, we've initiated a phase III trial, a randomized global phase III trial comparing Daraxonrasib at 300 milligrams to standard-of-care chemotherapy and looking for a PFS and OS endpoint. We initiated that study towards the end of 2024. It's enrolling very well. It's meeting our expectations. There's a lot of enthusiasm by investigators and patients. All of our U.S. sites are just sort of enrolling as fast as they can enroll. We are adding additional sites in the U.S. As part of our original plan to create a broad platform across different kinds of investigators, community-based and academic-based. We are also now adding European Union and Japan sites in order to create the platform needed for a global registration study. We expect to complete enrollment in 2025, so this year, and to have a clinical readout in 2026. Got it. Understood. Can you discuss your pancreatic cancer strategy for earlier lines of treatment? Yeah. About half of the patients who are treated for first-line metastatic disease go on to receive second-line treatment. That tells you that there are a lot of patients who present with pancreatic cancer who simply do not make it to second-line treatment. Getting into first-line is very important. We have now announced our intention to launch a first-line pivotal randomized global trial by the end of this year in first-line pancreatic cancer. We also have interest in the other major form of early-stage disease, which is resectable disease. We expect to initiate as well later this year a trial, a pivotal trial for adjuvant treatment of resectable pancreatic cancer. With those three trials, the 302 trial, the first-line trial, and the adjuvant trial, we will have covered virtually all or most of pancreatic cancer from early to late-stage disease. Got it. What are the considerations around the different potential combinations for Daraxonrasib in pancreatic cancer? Right. In the second-line study, we're studying monotherapy and have seen encouraging progression-free survival and overall survival. In first-line, we also expect to have an arm of monotherapy compared to standard of care. There is a good likelihood that we would include a third arm, which would be a combination of Daraxonrasib plus some form of standard-of-care chemotherapy. The arguments for including that arm are simply that there could be additive benefit from combining chemo with a targeted agent and that physicians who take care of pancreas cancer patients are used to using chemotherapy. Most of them don't recognize RAS as the primary oncogenic driver. Introducing a third arm where patients can be randomized to something they're familiar with, which is a chemotherapy plus Daraxonrasib, makes some sense. The main concern we have and are navigating now through a study of a number of different cohorts is that for pancreatic cancer, chemotherapy is a very harsh treatment. Either modified FOLFIRINOX or gemabraxine, a large number of patients, a high percentage of patients experience adverse events, grade III or greater adverse events with chemotherapy. A large proportion of patients end up having dose holds and dose reductions, and many patients even progress on chemotherapy. We are really fighting an uphill battle if we are adding Daraxonrasib on top of chemotherapy. Because Daraxonrasib is a targeted agent that really is modifying the biologic driver of the disease, it is most important that we maintain high dose intensity, meaning high continuous coverage of the target during the course of their disease in order to keep the foot on the brakes of the tumor growth. We'd like to have as few and as short interruptions as possible of that treatment. We are looking within the realm of FOLFIRINOX and gemabraxine for a dosing regimen that is most likely to permit continuous dosing of Daraxonrasib. We are currently studying that. There are well-accepted step-downs from what is called full-dose initial chemotherapy to lower doses or less frequent dosing. Very standard, very well-understood in the pancreas cancer field. Within that range, we are evaluating now combinations with Daraxonrasib in order to choose one or more regimen to go forward with. Understood. How are you thinking about the commercial opportunity for Daraxonrasib across these different settings of pancreatic cancer? I think I've come at this from a medical point of view. The unmet needs across all forms of pancreatic cancer are very deep. Almost nobody gets cured of pancreatic cancer today. Some patients with resectable disease may not have a recurrence of their disease, but it's infrequent. Most patients do progress. Moving from first-line to second-line simply means moving from chemotherapy to more chemotherapy. It is not a very promising prospect for patients. Second-line, as I alluded to earlier, is a pretty aggressive disease, and median progression-free survival is three months, and median overall survival is six months. If you're treated for second-line pancreatic cancer, you're likely to progress during the course of your treatment, if not shortly thereafter, and you're likely to die shortly thereafter. It is a pretty dismal situation, and the unmet needs are quite deep. I think there's a commercial opportunity anytime you can really have an impact for patients, particularly on survival. We also hope that Daraxonrasib can have an impact on the quality of life. We don't yet have any quantitative measures of quality of life, but quality of life on chemotherapy for pancreas cancer is marginally better than quality of life just having pancreas cancer. I mean, it's a really terrible, terrible kind of condition. We think we can improve on that. The feedback we get from patients and frequently from investigators is that there really can be a sea change in how a patient is experiencing life, and that's really meaningful and very important. I think with quality and quantity of life, there for sure will be a commercial opportunity to be rewarding. Understood. How does Zoldonrasib, this is your G12D, previously known RMC-9805, how does that fit into your pancreatic cancer strategy? Since you're mentioning the name, I can take the opportunity to point out that all of the names of our compounds, Daraxonrasib, Eleronrasib, and Zoldonrasib, all have the suffix of onrasib. That alludes to the fact that all of our compounds bind to the active or on state of RAS, unlike the first generation of RAS inhibitors that are known as simply RASibs. Zoldonrasib, it's kind of a fun name for a not-so-fun disease or target, KRAS G12D, is a highly active, orally bioavailable targeted agent for the G12D genotype. We have demonstrated in an initial cohort of pancreas cancer patients an encouraging objective response rate. That has been coupled to a very encouraging tolerability profile. The presenter at the triple meeting made the comment that this was the least, the best tolerated targeted agent he had ever experienced in his practice. That is quite encouraging because it implies that not only could it be a monotherapy, but it could be combined with other things, which we are currently evaluating. I have forgotten exactly what the question was, but I was just waxing eloquent about Zoldonrasib. I just wanted to know, how does Zoldonrasib fit within your pancreatic cancer strategy? Right. G12D is the most common mutant form of RAS that drives human cancer, and it deserves extra attention. Daraxonrasib is already a pretty good G12D inhibitor. It's the most active G12D inhibitor described to date. That doesn't mean we want to leave it alone. I think we are very compelled to bring forward additional RAS inhibitors that can add to Daraxonrasib and improve the depth of inhibition, improve the durability, improve the overall outcome. Zoldonrasib could be that agent for the G12D-driven tumors. We're currently evaluating it both as monotherapy in various indications, but also in combinations, combinations with Daraxonrasib, combinations with pembrolizumab, combinations with cetuximab, and combinations with chemotherapy. We have a lot more to learn about this investigational drug, but it's an exciting compound, and we're looking forward to moving it forward. Got it. Can you discuss the reasons for confidence in the potential RAS doublets combinations, whether that's Daraxonrasib plus Zoldonrasib, Daraxonrasib plus Eleronrasib, your G12C, or some other permutation and combination? I appreciate you using the names of the compounds. That's fantastic. I have a cheat sheet for this. Yeah, that's all right. The question was, remind me now. I lost my train of thought again. Just the reasons for confidence for the potential of the RAS doublet combinations. Yeah. A number of years ago, some of our scientists had the idea of combining two RAS inhibitors in the same xenograft model. It was a fairly bold idea. Nobody had ever done that before in humans. It was not entirely clear to us what might come of it. From the very first experiment combining Daraxonrasib with Eleronrasib, we found tumor models that were insensitive to either agent alone, but suddenly showed responses and even durable responses when the two compounds were put together, which suggested that there was some complementarity between the two, one having a RAS multi-profile covering all forms of RAS and one being very selective for deep inhibition of the mutant initial driver. We know that tumors that are addicted to RAS truly have a phenotype of addiction, meaning that if you withdraw RAS by applying a mutant selective inhibitor, the response of the tumor is to find another way to activate RAS. That is what creates resistance to RAS inhibitors, is RAS activation. Therefore, having two different agents that can both inhibit RAS creates a real opportunity to get better outcomes. We have seen that now across multiple tumor models. We have seen it with both Eleronrasib and Daraxonrasib, as well as Zoldonrasib plus Daraxonrasib in preclinical models. Now we are testing it in humans. The first experiment we reported in December was a combination of Daraxonrasib with Eleronrasib in G12C colorectal cancer. To make the experiment as difficult as possible, we chose patients who were late-stage colorectal cancer patients who had previously been treated and had previously seen a G12C inhibitor but progressed on both chemotherapy and on a G12C inhibitor. These are very late-stage patients. They've developed lots of resistance. If we applied one of our RAS inhibitors, we would expect to see and would see single-digit% responses. When we put the two together in those patients, though, we saw a 25% response, including a CR. While the dataset is not a large dataset, I think we showed 12 patients, it nonetheless convinced us that the combination in humans could be more active, just like it's more active in preclinical models. That's really a breakthrough to study two RAS inhibitors in the same patient and get that kind of response. It is really compelling and very exciting. Now we're moving Eleronrasib plus Daraxonrasib forward in other indications to evaluate it there. We've begun evaluating Daraxonrasib in combination with, I'm sorry, Zoldonrasib in combination with Daraxonrasib as well. Got it. How are you thinking about the potential development strategy for the mutant selective inhibitors, Zoldonrasib and Eleronrasib, either monotherapy or combination treatment? One thing we couldn't have really anticipated three-plus years ago was that Daraxonrasib would become so big a player in the RAS field. It now is leading the field. It was supposed to be dead on arrival when we first started dosing patients, but it turned out to turn the entire paradigm on its head. It's a RAS multi-inhibitor that was supposed to be too toxic to be effective, and it turns out to be one of the most effective inhibitors with a generally good tolerability profile. Because of the dataset we have, we've now treated, I think, over 500 patients with Daraxonrasib. We've reported some good number of those patients. We really have a good feel that this is a compound, an investigational drug with legs. It has legs in at least two indications and probably many more than that. We're leaning heavily into it. If it's successful in these pivotal trials, it is likely to become standard of care upon approval by regulatory agencies. That's going to happen no matter what we do behind it. Nonetheless, it's probably not going to cure many patients of their RAS cancers. Because RAS addiction is such a real phenomenon, we're going to have to hit them very hard and hit them in multiple ways. We have a multi-year journey before we really can say that we're defeating RAS cancers. I think that will involve adding a second RAS agent where possible. That's where the mutant selective inhibitors are most likely to have the greatest impact, to be adding them on top of Daraxonrasib and to be able to have that dual action in trying to defeat RAS cancers. That's where I expect the most value will come. There may be some settings in which one of the mutant selective inhibitors should be combined with a different agent. It could be another targeted agent. It could be chemotherapy. It could be pembrolizumab. I think it creates a lot of optionality for us, both in the monotherapy and combination realm. I think the biggest win today looks to us to be likely to come from combination strategies. Understood. Let me check to see if there are any questions from the audience. Go ahead. Yeah. Yeah. The question was, what causes resistance to RAS inhibitors in pancreatic cancer, and more specifically to our compounds, I guess you're asking about? We haven't reported on that yet, so I don't have any news to disclose today. We will at some point report CT DNA data as we continue to analyze it. I think a general rule of thumb that so far has not really been broken is that the way a RAS-driven tumor defeats a RAS inhibitor is to find out some other way to activate RAS. The other way to activate RAS can be by elevating simply the level of those proteins. It can be by mutating an upstream regulator of the protein, or it can be by spinning out new mutant forms that may have been secondary in a tumor but become primary with a mutant selective inhibitor added on top. That's generally what we've seen across previously reported tumor types. I think that's still going to be the dominant feature. Upregulation of RAS signaling is the way that a tumor that is addicted to RAS somehow overcomes an inhibitor. Got it. Any other questions before we switch over and move to lung cancer? All right. Maybe switching over to the opportunities in lung cancer. Can you discuss the status and progress of the phase III Resolve 301 study evaluating Daraxonrasib in previously treated non-small cell lung cancer patients? Sure. Here again, we have reported data in second-line and third-line non-small cell lung cancer for patients carrying a RAS mutation treated with Daraxonrasib. As in pancreatic cancer, we saw encouraging response rates, encouraging progression-free survival, and encouraging overall survival that gave us the confidence to move forward with a phase III pivotal trial. We have just initiated that trial. As you indicated, it is called the Resolve 301 trial. It will also be a global randomized trial comparing Daraxonrasib monotherapy versus standard of care, which is docetaxel for second-line and later disease. We have just initiated that study, so I do not really have an update to report yet. We are actively activating sites in the U.S. and in the European Union, or we will in the European Union when we have that clearance, and expect that the European Union and Japan will contribute significantly to that enrollment as well. Understood. What do you see as the potential for combining Daraxonrasib with anti-PD-1 for lung cancer? Yeah. We have studied this now reasonably extensively. Early on in the Daraxonrasib dose escalation, we did have patients who had previously come off of pembrolizumab. Because of the long half-life for pembrolizumab, any toxicity that occurs with the combination is likely to be seen even if your compound is given as monotherapy shortly after pembrolizumab. We saw no evidence of hepatotoxicity combination effect in those patients. That was something like 20 patients with Daraxonrasib at the time. We followed all of those patients much longer than that. None of them developed a significant hepatotoxicity. We enrolled new patients into the direct combination, the concurrent administration of full-strength pembrolizumab with Daraxonrasib. We reported in December really no evidence of additive or synergistic toxicity. I think at this point, we believe that we have cleared that hurdle. This is very important because all of the early-generation RAS G12C inhibitors had difficulty combining with pembrolizumab, hepatotoxicity being the most significant side effect. We do not see that. We do not really know the mechanism behind the hepatotoxicity, but for whatever reason, presumably different chemistry, our compound Daraxonrasib and Eleronrasib have not shown any hepatotoxicity. We believe that it can be combined. I do not have any efficacy data to report today, but we are sure that if you can combine them, there should be complementary benefits from the immune-based as well as the targeted RAS therapy. Understood. We've talked about pancreatic cancer and lung cancer opportunities for your pipeline and platform. What about opportunities in other tumor types? Yeah. The third tumor on that list, of course, would be colorectal cancer. As I mentioned, 50% of colorectal cancers have a RAS mutation in them. They probably also have multiple other genetic lesions because colorectal cancer has a very heterogeneous genomic background, which makes it quite difficult to treat because even if you target one of the pathways involved, you've left open other pathways that are contributing to oncogenesis. That implies that colorectal cancer treatment will almost inevitably be a combination treatment strategy. That's our going-in belief. Frankly, based on the monotherapy data we've seen before, I think that that holds up, that theory is supported. We're focused entirely on combination strategies. Again, we have really three categories of combination strategies. One is to put two RAS inhibitors together. We've now shown, as I mentioned, in the December update, we reported combination data for Eleronrasib plus Daraxonrasib in those advanced colorectal cancer patients. Quite encouraging. That suggests a paradigm we could try to replicate. G12C is not very common in colorectal cancer. G12D is the most common form there. In that context, Zoldonrasib plus Daraxonrasib would be a more logical way to play the combination. A second combination strategy is to combine the targeted agent with chemotherapy. That makes a lot of sense. There could be some combinatorial benefit from doing that. We certainly are evaluating that combination just as we're evaluating the doublet I alluded to a moment ago. The third category would be a RAS(ON) inhibitor with a targeted agent directed against some other genetic lesion that's driving the cancer. An example of that, of course, is EGF receptor antibodies, cetuximab and panitumumab, agents like that that are commonly used in RAS wild-type cancers. Could they now be used in combination with a RAS inhibitor in RAS cancers? That paradigm has already been established with the G12C inhibitors that can combine with cetuximab in late-line colorectal cancer. That is one area we are currently evaluating. There are other genetic lesions such as MTAP deletion. Actually, our colleague who is in the room next door is now talking about their PRMT5 inhibitor, which is synthetic lethal with MTAP deletion. That occurs at about 20% of colorectal cancers. Maybe combining with a PRMT5 inhibitor makes sense. In fact, we have a collaboration with Tango Therapeutics where they will explore that combination with clinical supply from us. There are other genetic drivers of colorectal cancer. Ultimately, there is the possibility that the immune system can be brought to play by combining with an immune checkpoint inhibitor like pembrolizumab. There is some modest amount of data that suggests that in the right context, pembrolizumab can be active in the GI tract, particularly if you have a very active targeted agent. I think that is an area to keep an eye on. We might see pembrolizumab or other similar compounds move into GI tumors like colorectal cancer. All of those are possible. We have no real way of distinguishing between them today. We are evaluating some example of all of those possibilities. We will see what the data tell us. That will help drive forward to pivotal trials. Understood. How are you guys thinking about potential business development opportunities for your programs and platform? Yeah. There are two kinds of business development. There's where we acquire assets through relationships. And there's where we share assets through relationships. We've already done that some through clinical collaborations like the one that I just mentioned. In terms of business partnerships, we have a lot of inbound interest for purveyors of their assets looking for combinations with ours or asking us to take over development of their compounds. We look at those all the time. We're very systematic about it. For example, when Tango contacted us, we looked at it. The clinical data, the preclinical data were compelling. We said we'd be happy to do this together. In terms of licensing our assets or allowing somebody else to help us develop those assets, we do have an active effort exploring ex-US partnership opportunities. We declared a couple of years ago that we were confident we'd be able to commercialize in the U.S. itself. I'd say today, a couple of years later, the evidence is pretty strong that that would be the case. We've built a rather small but very high-quality commercial organization. It's rapidly growing along with a medical affairs organization. I think we feel confident we can market in the U.S. without a partner. Outside the U.S. felt much more daunting to us a couple of years ago. We declared that we would be open for business to talk to partners. We have active partnership discussions with many potential partners. There's quite a lot of interest. Now we're at a stage of maturity where we have to see things through the lens of where we are today and evaluate whether our partnership brings the most value to our patients, to Revolution Medicines, and to our investors, or doesn't. We don't know the answer to that. We haven't made that final decision. I think we're in a position where if we choose to sign such a partnership, we could do so. We'll just make a decision about what the net benefits, pros, and cons are. Understood. Did you have a question? Yeah. Yeah. The question is, what kind of threat does sourcing new compounds from China pose to us? Clearly, they've made a huge investment as a country in creating the capability to discover compounds. Many of those compounds are variants of compounds that are innovated first in the U.S. We've seen that happen. We've seen our compounds get knocked off by teams that are very good at looking at the patent literature and trying to identify opportunities to create a new compound. At least one of those compounds has been licensed to a small U.S. company. We don't consider that to be a particularly large threat because most of that work ends up creating compounds that are pretty similar to ones that are already in development. In our case, I think we're multiple years ahead of any of that work. We're very committed to aggressively creating as close to a Keytruda-like franchise as possible with our RAS inhibitors. We're making the investment to do so. We have a very bold plan to create high bars for entry to others from regulatory bars that are set by full approvals. To the extent that a new compound comes out that is clearly not only differentiated from but has superiority to offer, those could be threats ultimately to the life cycle of our compounds, just as happens in the entire pharmaceutical industry. We are deeply committed to continuing to innovate in this space. We have a very productive and I think the best innovation engine in the RAS space. We'll continue challenging our own team to create new compounds that will be superior to the compounds that are already leading the field. Got it. I think I know we're over a lot of time, but maybe just the last 20 seconds. What is your cash balance and runway? We closed 2024 with a $2.3 billion cash balance. It puts us in a very strong position to make the investments I was just alluding to. We've indicated that based on our current operating plan projecting out runway to the second half of 2027. Of course, that can be modified depending on the scope of the work that we choose to do in 2026 and 2027. Under our current plan, second half of 2027. Got it. That is all the time we had. Thank you very much for joining us. Thank you. Thanks for having us.