Thanks, everyone, for continuing to join us here at the Stifel two-day virtual oncology event. My name is Brad Canino, Senior Analyst here at Stifel. Very happy to be joined for the next fireside chat with Revolution Medicines. We have CEO Mark Goldsmith. Mark, thank you so much for joining us. Pleasure to be here. Thanks for having me. Can you just kick off with an introduction to RevMed and an overview of the state of the portfolio today? Sure. Revolution Medicines is a company focused essentially exclusively on the most common genetic driver of human cancers, which are mutations in RAS proteins. We have developed a novel set of approaches to inhibiting the RAS pathway and specifically targeting the RAS cancer drivers. We've introduced the concept of inhibiting the on or activated form of RAS, and today have three clinical stage assets, each of which has shown essentially clinical proof of concept, one of which has moved into two late-stage pivotal trials with two additional pivotal trials expected to initiate later this year. The other two assets are moving along very well as well. We have a very comprehensive approach to targeting the wide range of mutations that do drive RAS-addicted cancers. We're excited about the progress we've made so far and the promise of things going forward. Now, the lead asset, daraxonrasib, it's in a phase III trial for second-line pancreatic cancer. Can you just discuss some of the key design elements of that study and the data that support the trial? Sure. There are actually two pivotal trials underway, two phase III pivotal trials, one in pancreatic cancer and one in non-small cell lung cancer with daraxonrasib. Let me just remind everybody that daraxonrasib is a RAS multi-inhibitor. It's specifically designed to inhibit all forms of RAS. It certainly has proven to do so in every experiment we've ever done. It is an orally available drug. It's once a day. It clearly has shown significant activity against both of these tumor types. In pancreatic cancer in particular, we've shown a substantial data set in second line, as well as in later lines beyond second line, but particularly focused on second-line pancreatic cancer treatment. We've reported from a single-arm trial, PFS and OS and ORR values that are all quite exciting and significantly differentiated from the well-established standards of care in pancreatic cancer, which is exclusively a chemotherapy-treated disease today, but it is also nearly exclusively a RAS-driven disease. It's the cancer for which there is most likely to be a RAS driver. More than 90% of all pancreatic cancers have a RAS mutation. The ORR typically has been for these patients with chemotherapy in the range of less than 10%. Median PFS has been in the range of three to three and a half months and median OS in the range of six to seven months. With daraxonrasib, we've established an overall response rate that's greater than 30%, a very high rate of disease control, a median PFS value in the eight-month range, and a median OS value in the 14-plus month range. Again, it depends on exactly what dose and so on, but without getting into that level of detail. Very compelling numbers, of course. They are based on a single-arm trial, and there are limitations to comparing that to standards of care in the absence of a head-to-head comparison. We are now moving into and enrolling patients and treating patients in a second-line pancreatic cancer trial. It is a global trial. Enrollment is benefiting from extremely high interest. This is an area of very deep unmet need across the globe, and it is currently enrolling quite well. Okay. On that last part there, for second-line pancreatic, to deliver value to those patients, how important is it to match the phase I PFS of 8.8 months for the daraxonrasib arm in the phase III trial? Oh, I think there's a lot of room for improvement above standard of care, three to three and a half months of median PFS and six to seven months of median OS. Really, I think we can achieve clinical impact regardless of whether our PFS and OS values exactly match. In fact, I'm quite sure they won't exactly match what we've reported so far just by going to a larger study and a global study. I think there's quite a lot of room for improvement here within the window between what we've shown so far and what's been reported over the years for chemotherapy. Okay. In pancreatic cancer, there does seem to be a little bit of a disconnect between ORR and PFS values. Maybe we think about the pan-RAS mechanism specifically in this cancer type. Why might it produce a longer PFS than historically would be associated with a mid-30% response rate? Yes. I think it probably has most to do with pancreatic cancer per se rather than the genotype that's driving the cancer. Pancreatic cancer biology has only been studied in the context of chemotherapy for all these years. With limited response rates and limited PFS and limited OS, there really hasn't been the possibility of establishing any good biological or pharmacologic understanding of the relationship among those. I think daraxonrasib is really the first to do so. It inhibits all forms of RAS, and we believe in many RAS cancers, not only the initial defined genetic driver of the cancer is a RAS mutation, but also tumors may be sustained by other forms of RAS, including wild-type forms of RAS and potentially other mutant forms that are lurking inside a heterogeneous tumor. Therefore, our thesis has been that daraxonrasib as a multi-RAS inhibitor will have the greatest chance of suppressing all of these different ways in which a RAS-addicted tumor can get its fix for RAS signaling. That is essentially exactly what happens biologically. As to why that does not lead to much higher objective response rates, I think that that seems to come from the criteria that are used for defining response rates. We have a set of RECIST criteria that are established by consensus. They are fairly simplistic. A 29% reduction in tumor volume, which could have huge clinical benefit for a patient, does not count as a response. A 30.1% reduction does. It does not really make any sense. Also, keep in mind that pancreatic cancers really are a combination. The tumor itself is a combination of actual cancer cells, but also a significant inflammatory and stromal response, which is a natural response within the pancreas to the various factors that are elaborated by the tumor cells. Shrinking a tumor may require much more than just killing the tumor cells, but may take time for the overall bulk of the tumor to shrink as the inflammatory or sclerotic response gets resolved much more slowly. Indeed, with daraxonrasib, we've seen that the longer a patient stays on the medicine, on the investigational drug, the more likely that their tumor will shrink. In many cases, it continues shrinking over multiple cycles of treatment and multiple scans. I think at this point, we've come to believe that durability is the most important measure of the clinical benefit, and that is indicated by both PFS and OS. We are quite encouraged by what we have seen so far. Right. As I think about the potential registration of this drug, how important in second-line PDAC is it to deliver a statistical OS benefit versus a trend of benefit/no detriment? That's a review question, of course. That's a question best addressed to the FDA. They have made it clear publicly that they view OS as the right measure for pancreatic cancer. I think that's largely due to the fact that the gap between progressing with your disease and succumbing to it is pretty narrow. I think the FDA has taken the position, why should they rush to make a decision on the basis of progression-free survival when just a few months later, in principle, they would have an OS result? That again is based on the historical standards with chemotherapy. We're seeing a widening of that relationship with the targeted therapy directed against RAS, particularly from daraxonrasib. That relationship may not hold. I think that might be partly where the, excuse me, partly where the FDA is coming from it. Also, there have been historical examples of early signals of response rates or PFS in single-arm trials that then did not pan out over time as they moved into more definitive studies. I think for all those reasons, the FDA has made it clear they prefer to see an OS. What would happen if they saw a strong PFS value and an encouraging OS value, but it was not statistically significant? I have no idea. That would be a review issue for the FDA to decide at that point in time. We feel very confident about daraxonrasib and feel like the most appropriate thing for us to do is to test PFS and OS, to do it rigorously. We have powered the study around OS. I mean, we are optimistic. Of course, we will have to see what the results actually show, but we are optimistic that we will be able to demonstrate that. If we do, that would establish a major paradigm shift in thinking about pancreatic cancer and converting it from a near-term sentence to something that might be managed on a more longer-term basis. Yeah. Can you talk about the patient experience on daraxonrasib when it's received in that second-line PDAC setting, especially relative to the available standard chemotherapies? The only thing worse than chemotherapy in pancreatic cancer is the pancreatic cancer itself. It's a terrible disease. Patients really suffer from it. The treatment is considered to offer some benefit, which is why it's provided by oncologists, but it's quite minimal. You replace the symptoms of pancreatic cancer with the symptoms of the treatment of pancreatic cancer. Most patients experience significant side effects from the chemotherapy itself and often require dose reductions, dose holds, and often do not make it even through the full planned cycle of treatment with chemotherapy. That's not what we've seen with daraxonrasib. It has shown so far an encouraging tolerability profile. Patients have often reported to their physicians who have shared with us the news that patients are often feeling much better on daraxonrasib, that their disease-induced manifestations become much more manageable. Patients we've heard can come in anorectic, weight loss, limited mobility, and really sort of down and out and are turning around on drug and starting to eat again, becoming active and resuming some important aspects of their lives. That's what we've heard. We don't have a quantitation of that. That's a qualitative description, but we have heard that from many investigators and frankly, even from some patients who have communicated that. I think there's the possibility that patients might see a significant change in their outlook on life, the quality of life. We think that's extremely important. We also hope to provide more lifetime as well. Now, beyond your own programs, there is a wave of emerging competitive pan-RAS, pan-KRAS, G12D selective inhibitors. Yeah. We'll likely get some emerging results from them on how they shrink tumors, especially in pancreatic cancer. What is your view on whether or not another molecule could reach a higher ORR threshold at a cancer specifically compared to daraxonrasib? Yeah, I don't know the answer to that. We don't have any clinical data yet. It is certainly possible that the pan-K, which let's just define what that really means. I think it's a confusing term. It's not really pan. It's K. It's K-selective. Maybe we should have called those KRAS spectrum selective compounds. They can be very potent. They typically are directed largely to the off-state, not to the on-state, although there may be some exceptions to that among the various compounds that have come forward. We do know that the off-state inhibitors have had some significant limitations. They've not generally lived up to at least initial expectations in the field. The KRAS inhibitors may show initial response rates that are encouraging. Whether they're lower than, equivalent to, or higher than what we've seen, I have no idea. We'll have to find out. The most important thing, though, is going to be what do we see in terms of durability. That's the really important measure. We've said that. We didn't come up with this recently as a response to pan-KRAS inhibitors. We've been saying this for years that that's really the important measure. The FDA says it's the important measure. We don't really have much confidence that they will deliver superior PFS or OS, and it will take some time to establish that. In the meantime, we're moving forward to pursue full registrations based on significant robust randomized control trials. I think it's also worthwhile to consider that RAS is a very wily driver of human cancers. Once a cell is addicted to RAS, it will do everything in its power, anthropomorphizing a little bit, but everything in its power to get access to RAS signaling. There's strong selection for those few cells that can upregulate RAS signaling and work around the inhibitor. The way they do it is they can increase the signal through the original mutation and try to overcome the inhibitor. That clearly happens. They can engage wild-type RAS. That clearly happens. They can engage new mutations that emerge in the setting of a mutation selective or even a KRAS selective inhibitor potentially. Therefore, we have a long way to go before we're curing patients who have RAS cancers. It is really one of the most challenging biologic mechanisms behind cancer. Therefore, combination strategies will ultimately be the most useful way to prolong people's lives and give them the lifestyle that they'd like to have. Exactly what those combinations are are yet to be determined. We have a number of very good ideas about it and are exploring many of these combinations. One of them might ultimately be a combination of a so-called pan-KRAS inhibitor with a daraxonrasib or even with our mutant selective inhibitors and so on. There is a wide variety of things. The field is wide open at this point. I like to say we're in the second inning of this baseball game. We have much more to play out over the coming years. Okay. Mark, in your 4Q earnings, you mentioned the plan to build out commercial in the U.S. and are exploring ex-U.S. strategies that could include partnership opportunities. Yes. On that ex-U.S. element, I'd like to give you the chance to elaborate and describe your thinking around this potential strategy. Sure. Let me start with the U.S., since that is the starting point, both in time and as the core value driver for the company. We all recognize that. We are very committed to retaining the full U.S. rights, value, responsibilities, and control of the portfolio in the U.S. for building the clinical impact and the long-term value for shareholders. We're resourcing our U.S. effort quite substantially and making fantastic progress to really making sure that we have the best strategies, commercialization strategies, the best tactics, the best capabilities, and the best people so that we can bring daraxonrasib with urgency to patients in the U.S., of course, subject to regulatory approvals. The other half of the world, from a market perspective, is outside the U.S. We are very committed to providing global access to our drugs. The question at hand is, what's the best way for us to deliver that? I think we're continuing to study that question. It could include a partner or multiple partnerships outside the U.S. It's a more complex environment to operate in because of the number of different regulatory authorities, the pricing factors that go into it, and so on. There is kind of a set of special skills needed and a platform to operate outside the U.S. We, of course, are considering whether or not a partnership should be part of our plan. We don't feel any urgency to rush these decisions. We are in a very strong place with our pipeline. It's getting stronger by the day. Our confidence about it gets stronger by the day. Our organization's getting stronger by the day. We're growing quite dramatically to serve the goals of the company. We have a very strong financial position that gives us the flexibility to make those decisions. We have not done so yet. There is widespread interest in our pipeline, as you can imagine. We feel that interest. We have seen very interesting ideas from a variety of parties, any one of which could be interesting and useful to us. We have just not made any decisions yet, and we will not make it until we feel we have enough understanding of the diverse set of possibilities, and that will maximize both our global impact and, of course, our commercial value, the commercialization and the value for our shareholders. Beyond second-line PDAC, could you talk about the goals of the ongoing daraxonrasib chemo combination work that you're doing and how you believe that will position it for a successful front-line PDAC trial and a compelling combination for physicians? Going beyond daraxonrasib or beyond monotherapy? Make sure I understand. Beyond monotherapy, yeah. For front-line PDAC, the chemo combo work that you're doing now, what's the goal for that? Got it. Okay. Again, returning to the data we've reported so far in pancreatic cancer, although it was all in second-line or even later lines, it clearly gave us the confidence that daraxonrasib could make a real difference as monotherapy. In fact, numerically, the numbers that we reported are superior, if you're willing to make that cross-study comparison, are superior to the numbers delivered by chemotherapy in first line. That is both for PFS and for OS. We believe, based on the underlying biology, the substantial body of data that we have so far, and the mechanistic rationale, that daraxonrasib as monotherapy is likely to outperform or has a good chance of outperforming chemotherapy even in first line as well. Why bother with anything else? As I mentioned, we haven't cured many RAS cancers yet. There is some mechanistic reason to believe, and even some preclinical evidence, that combining chemotherapy with a targeted RAS agent, specifically daraxonrasib, could increase the impact on tumors. That is one justification for evaluating it. We'd hate to not answer that question if that actually could deliver something that's more impactful than monotherapy. We'd like to know that in patients. A second reason for considering a chemotherapy combination is that it is the standard of care in this very threatening disease. Patients often progress while they're on chemotherapy and sometimes even die during chemotherapy, which is quite a miserable thing to think about, starting a very difficult chemotherapy and having your cancer progress while you're still being treated. It does have some impact compared to no treatment at all. Doctors are used to using that, particularly in the U.S., but even globally. They're used to using chemotherapy. There is some logic for those physicians who are most comfortable with chemotherapy to provide an option in which chemotherapy plus daraxonrasib is available. Maybe ultimately, if that succeeds as well as monotherapy, that then leaves physicians the choice based on the performance status of a patient, based on a patient's wishes. Do they want to undergo the challenges of chemotherapy, or should they not? To tailor treatment regimens to the individual patient. We see no real downside to evaluating that realm and maybe even some upside on behalf of patients. Therefore, we're going to make a decision about whether to include a chemotherapy combination arm in the trial. We're certainly leaning in that direction. The initial evidence suggests that that's a reasonable thing to do. We've not made a final design for our first-line trial. It's currently underway. Once we make that decision, we'll declare exactly how we're proceeding. Now, in the interest of time, your next data event is for a second asset, zoldonrasib, in lung cancer at AACR. Could you quickly introduce this asset and talk about where you think it could have the most utility as a therapy, both as monotherapy and potential combinations? Big question. I'll try to answer very briefly, but zoldonrasib is a RAS G12D selective covalent inhibitor oral. It has been shown to be quite well tolerated in the initial study in pancreatic cancer and showed a significant response rate in pancreatic cancer that was sort of competitive with daraxonrasib. We will report on lung cancer in the G12D population, which represents about 4% of non-small cell lung cancer, about the same size as the ALK mutant population. It is a significant subgroup. Similarly, we're proceeding with, by the way, our mutant selective G12C inhibitor as well and continuing to evaluate that. The overall idea that we have is having a robust set of inhibitors, both the multi and mutant selective, will give us the greatest range of possibilities, including potentially combining any two of those in an individual patient. We have now reported the first-ever data from treating patients with two RAS inhibitors in advanced colorectal cancer back in December. It was compelling and exciting. I think it forms the foundation of a longer-term strategy. Maybe last for me is, as investors think about the AACR data that's coming up, I think a lot of us are anchored to the experience of G12C inhibitors, where there has been a spectrum of response rates and profiles, with kind of sotorasib being at the low end, adagrasib, and some of these newer drugs being at the high end. How applicable is that spectrum of activity likely for G12D tumors? Is there any biology difference that we should think about? One difference to note, and it will require that folks think about this carefully, but G12D lung cancer often occurs in patients who are nonsmokers. That has some impact on the overall genetic diversity of their tumors. I can't really give you any predictions as to what we'll be able to present. It's coming up soon, and we're looking forward to it. All right. Mark, thank you so much for spending some time with us to overview the portfolio. A lot of interesting things going on. I look forward to tracking it for the rest of the year. Thanks very much. Thanks again for having us. All right. Thanks, everyone, for joining in. Bye now. Bye now.