My name is Peter Lawson. I'm one of the SMID Cap Biotech Analysts at Barclays, and it gives me great pleasure. I've got up on stage with me the management team from Revolution Medicines. We have Mark Goldsmith, the CEO and President. I guess the first question, just topical, considering the current administration and the impact. Have you seen any impact from tariffs or any disruption in supply chain that you're kind of concerned about? Thanks, Peter, and thanks to Barclays for the chance to participate in this meeting. Have tariffs impacted us at all? I guess you mean other than the bloodbath in the market and the loss of $1 billion of market cap that's occurred as a result of those. We haven't really experienced any direct impact of tariffs or on supply chain so far. We're, of course, monitoring it very closely and will react to it if we see that. Gotcha. The communication with the FDA, has that changed in any way? Do you anticipate any changes just with staffing cuts or worry about staffing cuts? Sure. I mean, we've had some concern about that, but in practice, we have had ongoing, I'd say, business as usual exchange with the FDA, clearance of our IND for the 301 study and so on, that have all been essentially on time. So far, we have not experienced anything. Of course, we're keeping an eye out for it. Okay. Kind of the other concerns we should be thinking about, is it like NIH budgets, cuts that have anything in the near to midterm that could impact the industry or your company? We fund all of the work for our trials ourselves, so none of it is supported by the NIH or any federal agency. As a result, we haven't had any direct impact from those cuts or proposed cuts. I think it's conceivable that some of the institutions where clinical trials are conducted might find their financial support affected by any proposed changes. We have not had any manifestation of that in our clinical trials. We've been able to activate sites. We've been able to proceed to enroll and have not seen impact yet. Perfect. Thank you. Just kind of, I guess, back to your business or the trials. As we think about your pan-RAS inhibitor in second-line pancreatic, how's enrollment tracking, and is that likely to be completed by year-end? I guess that's a topical question. Yeah, this is a very exciting trial. It's called the RASolute 302 trial. It's a trial comparing patients with second-line pancreatic cancer that has previously treated pancreatic cancer, receiving either standard of care chemotherapy or randomized to the compound called daraxonrasib or RMC-6236, our RAS multi-inhibitor. We expect to enroll about 420 patients in that trial. It is now actively enrolling. We have a number of U.S. sites that are really doing very well. There's very high interest in this trial, both by investigators and by patients. There's really a scramble to get into the trial. We're expanding the number of sites in the U.S. according to our original operating plan for the trial, so that's going well. We're also now activating sites in the EU and in Japan since we received regulatory clearance to do so back in December. We expect enrollment to continue to be very strong, and we do anticipate completing enrollment this year for a clinical readout in 2026. Okay, perfect. As we think about the phase I/ll population and the phase III, how do we kind of bridge that? Will there be any differences as we think about those patients? Yeah, I think you're asking about the common trend that phase III trials tend to take some sort of discount to the phase I and II trials. We're not really anticipating that. Of course, we can't predict with any certainty, but we have gone to great lengths to make sure that the eligibility criteria for the patient population that we studied and reported on in terms of response rates, median progression-free survival, median overall survival, that those patients have the same clinical profiles or matching range of clinical profiles as the ones we expect to enrol in the phase III trials. The eligibility criteria are very similar, and we don't predict a decrement, but of course, that could happen just with the stochastic probabilities. Perfect. Thank you. And then kind of the mix of second-line versus second-line plus? This is strictly a second-line study, so this is patients who have only received one prior treatment for metastatic disease. It's really the same population as I indicated that we studied in the phase I to trial and reported on. We did also study third-line and third-line plus patients and reported on those as well, but those are not included in this particular trial. Gotcha. Thank you. And then just the expectations that we should have for the median OS for the chemo? It's hard for me to convey expectations. Everybody has to triangulate on that themselves. In the phase I and II trial that we've reported in the G12X population, that's patients with a KRAS G12 mutation, the median progression-free survival at 300 mg, which is the dose we're using in the phase III trial, the median progression-free survival was 8.8 months, and the median OS was not determined. However, in a larger group of patients which had received doses below 300, up to and including 300 mg, the median OS was 14.5 months. These numbers of 14.5 months and 8.8 months, I think, compare favorably, albeit with a cross-trial comparison and albeit with a single-arm trial, compare favorably to what the literature has reported for randomized phase III trials for median PFS and OS of around three months and six months in a similar population. We are quite excited about that result. I think patients are enthusiastic about participating, and now we just have to let it run its course, and we'll see what happens. Gotcha. It has come up before on calls, just the sense that the patients are doing really well, like you've got great quality of life impact. Just if you could walk through that. I know it's kind of not the normal numbers we kind of think about, but it's becoming increasing. Thank you, Peter. It's a really important topic that we aren't just trying to extend people's progression-free survival and their overall survival. We're also trying to improve their lives. Today, the standard of care for really any form of pancreatic cancer other than highly localized resectable cancer is chemotherapy. Chemotherapy for pancreatic cancer is very harsh. Nearly all patients who receive treatment for pancreatic cancer, chemotherapy treatment, experience grade three adverse events during the course of their treatment, and most of those are treatment-related. It's a very unpleasant experience, and for patients whose lives may be as short as three to six months, to spend the last few months of your life on chemotherapy seems like a really dismal prospect. The experience with RMC-6236 or daraxonrasib, as reported to us, has been very favorable. Many patients, we've been told, when they first show up at the doctor's office, are experiencing pain, anorexia, weight loss, and really their lives have been markedly affected. Some number of those patients have been reporting back to their physicians on their six-week visit. They're walking in the door, having less pain, no anorexia or less anorexia, and have gained weight, and their lives have been improved. We haven't quantitated that yet, so those are all really qualitative and anecdotal experiences, but it is commonly described to us by investigators who take care of these patients that this is what they see, and it gives them great hope that this is really having a biologically important effect for patients and that we might be able to improve their quality of life as well as their quantity of life. Gotcha. I know there are any qualitative comments, but how do physicians kind of talk about your drug versus other KRAS inhibitors for improvement around quality of life? We don't have any information. Really, historically, the only other RAS inhibitors that have been tested in pancreatic cancer have been the G12C selective inhibitors, and the results they've reported have been modest so far, but we haven't had any qualitative input from investigators other than that once they see patients on the compound, while some do experience side effects, there are adverse events associated with daraxonrasib, but nonetheless, their overall report is that patients are doing much better on daraxonrasib. Again, I can't quantitate it, and I'm just giving you anecdotal experience. Thank you. Given the rapid progression of the disease, how quickly would we expect to see the initial results after enrollment? I can't give you specificity on that. We do expect to be able to report out the clinical findings in 2026. The way the trial is designed, it is the number of events in the OS readout that drives disclosure or opening up of the envelope. It is an OS-driven trial, and when a certain number of deaths are reached in the trial, that will trigger the data monitoring committee to review the data and to determine whether the trial should proceed, whether it should stop, et cetera. That is all we can say today. I don't have a timeline specifically associated with that. Gotcha. As you move into the first line, kind of, I wonder if you could talk to the trial design and how you're kind of thinking about the combination used with chemotherapy. Yeah, there has been so much excitement about the impact of daraxonrasib monotherapy in previously treated pancreatic cancer patients that the presumption is that if we move to earlier lines of treatment, we would be able to preserve that benefit either in absolute terms or at least in relative terms, or in fact, might even be able to improve further upon that in absolute terms because the baseline outcomes are better in first- line and then second- line. We have seen that trend in moving from third- line to second- line in the study we have reported so far, so we will have to see what happens in first line, but we are encouraged by that. Based on the results of the second-line trial that I just described earlier, those numbers do numerically exceed the reports in first-line chemotherapy randomized controlled trials. Now, I know we really shouldn't formally make comparisons cross-study like that, so there are real limitations to the statement I just made. But just on paper, numerically, the median PFS and OS from the second-line trial are superior to the literature in first-line pancreatic cancer with chemotherapy. That gives us a lot of reason to believe that we should go study this compound in first-line patients, and we have committed to initiating a first-line metastatic pancreatic cancer trial in 2025. We're currently doing the work to help guide the design of that phase III trial, and we're quite excited about it, and we've heard from investigators that they can't wait to start it as well. We also announced just a couple of weeks ago that we expect to initiate a trial in resectable disease, patients who have resectable early-stage pancreatic cancer as adjuvant treatment. We are also excited about that. We know the investigators have been asking us to do it, and we have now held hands and agreed that this is an important thing for us to do, and we expect to initiate that trial also in this year. That would give us coverage for almost all of pancreatic cancer. How should we think about how your pan-RAS behaves with different chemotherapies because the chemotherapy regimen is not as standardized as you probably want for a controlled experiment? Yeah, I think the challenge with combining with chemotherapy is that the chemotherapy itself is harsh. As I mentioned, almost all patients on chemotherapy experience one or more grade three or greater adverse events. That is sort of a remarkable statement. That means if you start any of those chemotherapy regimens, you are very likely to have a grade three event during the course of treatment, and most of those grade three events are caused by the treatment, which results in very high rates of dose holds, dose reductions, and even discontinuation. Many patients do not complete their chemotherapy cycles because of intolerance, and it is a cumulative effect. After the first cycle, it is much harder in the second cycle and much harder in the third cycle and so on. That is the baseline that is occurring in these patients. Their median dose intensity for really either FOLFIRINOX, modified FOLFIRINOX regimen, or for Gem/Abraxane, those are the two most common standards in first-line metastatic pancreatic cancer. The dose intensity is around 70% for both of those, meaning that a lot of doses are being missed or doses reduced drastically. Because chemotherapy has such a steep dose response curve, that really does have impact on the overall benefit. If we're adding daraxonrasib on top of that, we're just starting with a very difficult set of patients' experiences. That's tough for them to get through it even without daraxonrasib, and daraxonrasib will bring its own generally moderate side effects, but nonetheless some side effects. I think the main goal for us right now and active work that's underway is to establish a regimen, hopefully one for 5-FU-based chemotherapy and one for gemcitabine-based chemotherapy that is tolerated enough that we can provide daraxonrasib on top of that or in conjunction with that and not have the chemotherapy drive significant dose reductions or dose holds or dose continuations. That's really the issue is that the chemotherapy itself often results in the medicine being withheld, and we wouldn't want daraxonrasib to be withheld during that time unless absolutely necessary. It's important to keep in mind that daraxonrasib is a targeted therapy. It's inhibiting the very biologic driver of cancer. If you withhold a dose or a week's worth of doses or two weeks' worth of doses, you're taking the foot off the brakes of the tumor and allowing it to regrow, and that can't be good for patients. That is what we're trying to determine now is what's the right regimen or regimens to proceed with. Gotcha. Okay. In the community setting, presumably there's no real standard of care for the chemotherapy. There is both for modified FOLFIRINOX and Abraxane. There is a well-accepted range of doses and schedules that are commonly used, that are standards of practice, and different physicians may start at different points in those regimens, but because they tend to step down during the course of treatment anyway, pretty much everybody ends up getting ultimately the same exposure to chemotherapy across different physicians, even though they might go about it slightly differently. They are all working within the same range. Any protocol that we proceed with will also be within that same range, and I think it will be perfectly adequate for answering the question of whether daraxonrasib with chemotherapy is superior to chemotherapy. Now, we also will have a monotherapy arm in this trial, daraxonrasib alone, and that's really a direct outcome of the comment I made earlier that daraxonrasib 300 mg in second-line pancreatic cancer already delivers numerically superior outcomes, at least in the single-arm trial that we've reported, to first-line chemotherapy. I think it certainly is justified to evaluate that, and hence I think we'll have a three-arm trial. That would be the most likely plan. Gotcha. Thank you. Is there any, what's the level of confidence that there's no cross-reactivity for your pan-RAS with other chemotherapies? You mean additive toxicity? Yeah, additive toxicity and any drug-drug interactions. Oh, drug-drug interactions. I do not think we have high concerns about a drug-drug interaction. I think the main question really is going to be tolerability. Given that the chemotherapy itself is poorly tolerated, adding daraxonrasib could be taken down with it, but I am not aware of any particular drug-drug interactions that we need to be concerned about. Are there good examples where you can kind of maintain a backbone therapy despite dosing down the chemotherapy? There aren't good examples because there really are almost no targeted therapies for pancreatic cancer. Pancreatic cancer is treated with chemotherapy except in rare exceptions for BRAF mutations or, in fact, an EGF receptor antagonist was approved years ago, or erlotinib was, but they're very rarely used because most patients have a RAS driver for their cancer, and therefore, in the absence of RAS treatments, it's been chemotherapy, chemotherapy, chemotherapy. Gotcha. What are your expectations going into the study for the OS around the chemotherapies? I can't really predict what the outcomes would be, but I certainly would expect or hope, maybe it would be a better way to put it, that we would be able to exceed the OS for first-line chemotherapy, which has been reported to be roughly 11 months for first-line metastatic pancreatic cancer patients, 6 months for previously treated second-line patients, and 11 months for first-line patients. That certainly would be our ambition is for daraxonrasib either alone or in combination with chemotherapy to be superior to that number. Gotcha. Thank you. We have a really interesting combination with Tango's MTA cooperative PRMT5 inhibitors. Just your thoughts around kind of our expectations, what did the preclinical data look like, and kind of what are you expecting to see? Yeah, so pancreatic cancer, like other RAS-driven cancers, does often have other co-mutations as part of the genetic or genomic landscape within the tumor, and among those is deletion of the MTAP gene, which we now know from preclinical work is synthetically lethal with a PRMT5 inhibitor, and that has driven Tango and several other companies to develop PRMT5 inhibitors. Because of that, there is the possibility that a patient may have both a RAS mutation and an MTAP deletion, and if that's the case, maybe they would benefit from combining a RAS inhibitor with a PRMT5 inhibitor. We have conducted, in collaboration with Tango, experiments preclinically in which we've combined those two agents in in vivo models of cell lines that carry both of those mutations, and we have seen additive anti-tumor effects. That, in our minds, justifies biologically evaluating that combination in patients. Tango, in this case, Tango is taking the lead. They're sponsoring a clinical trial, and we're providing daraxonrasib for that trial, and we're looking forward to seeing what the results might be. Okay. Will there be further preclinical data disclosures around that, or is that a Tango question? You know, we haven't really discussed that. It is certainly possible. I think the results are going to be just what I described, that in these in vivo models, anti-tumor effect is increased in combination, increased over either of the two agents alone, and I'm sure at some point that will be reported. I just don't know of a timeline for it. Gotcha. Perfect. Your G12D kind of monotherapy additional data this year, what we should expect to see? Yes. Our compound that is selective for the G12D mutation is called zoldonrasib. It's been historically known as RMC-9805. Just comment that both zoldonrasib and daraxonrasib have the onrasib core to their names, onrasib, which alludes to the fact that these compounds all inhibit the active or on state of RAS. Our third compound, which is our G12C selective inhibitor, is called elironrasib, also with the onrasib as part of the name. Zoldonrasib is a really exciting compound. It's, again, an oral agent. It is highly selective covalently for the G12D mutation. Our scientists were able to do something with chemistry that's not been done previously, and that is to engineer a warhead and to design the compound in a way that it can covalently bind to the aspartic acid, which is the D in the G12D mutation. G12D is the most common mutation among RAS-driven solid tumors, so it's a very important mutation to target, and zoldonrasib is designed to do so. We reported preclinical data showing very strong activity of zoldonrasib in xenograft mice, and we reported monotherapy, initial monotherapy data in pancreatic cancer at the Triple Meeting just this fall, which were quite encouraging from a response rate perspective. Now, to your question, that's the background. To your question, we expect to report additional monotherapy zoldonrasib data sometime in the second or third, in the second quarter of this year, and we also expect to report additional combination data involving zoldonrasib or elironrasib in combination with daraxonrasib. We call this a RAS-on inhibitor doublet, taking two RAS inhibitors and combining them in the same patient. We saw encouraging results when we combined the G12C selective inhibitor with daraxonrasib, and we hope to report additional data in second or third quarter of this year. Okay. How much data should we expect for that? Like I said, there's two updates. Is that a handful of patients or? Don't know how to quantitate it. We'll be able to quantitate it when we report it, but we've generally reported data when we have enough information that we think it directionally tells us where things should go and when it helps guide future studies. Gotcha. Is that going to be conference or? I can't answer that today. We typically try to submit data for medical meetings. That's our preferred venue, but of course those meetings are very locked in, and if our data happen to come out at a time when it's not possible to submit an abstract, then we'll present it through an investor forum. I think almost all of our data have been presented at medical meetings either before an investor conference or after we've presented it publicly. Gotcha. In the final few seconds, what are the expectations around safety for making these doublets and potentially triplets? Yeah, so far we've seen pretty good safety in combining elironrasib with daraxonrasib. Zoldonrasib is extremely well tolerated, so I expect it would be able to combine very well. Perfect. Thank you so much. Pleasure to speak to you as always. Thank you. Thank you.