Good afternoon, everyone. Welcome to the next session with Revolution Medicines. I'm Ami Fadia, Biotech Analyst here at Needham & Company. I have the pleasure to be hosting Mark Goldsmith, who is the Chairman and CEO of the company. Mark, thank you for being here. If you could just kick us off with some opening remarks, and we can dive straight into Q&A. Thanks, Ami. Really appreciate the opportunity to be here. This year is a very important one for RevMed, and we hope for patients as well. We have ambitious plans to advance this mission to bring revolutionary new medicines to patients living with RAS-addicted cancers. Okay, great. I wanted to just maybe open us up, open the conversation with sort of a question that we've been getting just with, you know, all the changes that have been going on in the HHS and the FDA. Just from your vantage point, based on what we know so far, how should, you know, the industry be thinking about any changes that we should anticipate in terms of just the regulatory environment? How are you guys thinking about that? Right. We don't have any control over that. The environment will evolve. You know, we have a very good relationship with the FDA and have been engaged with them across multiple assets and multiple programs, and we'll continue to do so. So far, we've continued to have appropriate response times and good engagement, and we hope that that will continue. Okay. Just maybe more broadly with regards to the tariffs that, you know, are also kind of front and center. Obviously, RevMed is not kind of there yet, but just very high-level initial thoughts on, does this change how you think about supply chain down the line? I think the biggest impact right now, of course, is in the marketplace. That's pretty obvious to everybody. We're relatively insulated right now because of our stable financial position, our strong financial position. From a supply point of view, we do have part of our supply chain that comes from outside the United States, and so that could be affected. I don't think at the moment we are experiencing any significant impact. We are, of course, scaling for commercial supply, and at some point that could come into play. At the moment, I think it's the least of concerns. Yes, absolutely. Okay, let's start with RMC-6236 and the RASolute 302 study in second line PDAC monotherapy trial. Maybe if you can talk about how the study is enrolling and if it's on track to complete by the end of the year, as you've indicated. Yes, we've seen, we've continued to see strong interest among patients and investigators. Enrollment at the centers that have been activated has been highly encouraging. We continue to expand the number of U.S. sites, and we now have a significant number of U.S. sites and are also activating ex-U.S. sites, including in the EU and in Japan. We feel optimistic about the timelines we laid out early in the year. We suggested that we should be able to complete enrollment by the end of this year and to read out the trial in 2026. As you've been sort of making progress on the enrollment, what are you seeing or what should we expect in terms of just, you know, representation across mutations relative to what we had in the phase I/II study and also relative to what you're kind of, you know, what we would expect in the real-world setting? As you're alluding to, RAS-addicted cancers come in a variety of different genetic contexts, and so it's important that our trial encompass all of those possibilities. There is a natural distribution in pancreatic cancer. Roughly 85% of pancreatic cancer is associated with a mutation at position 12. We call those G12X mutations. About 15% are non-G12X. That's across the broad population. That's roughly what we saw in our trial, except when we actually focused on a particular subset for exploratory reasons. We would expect that enrollment in the RASolute 302 trial will roughly fall along these natural distribution lines in terms of representation by mutation type. Can you talk about kind of how you have powered or what assumptions have been made in terms of powering the study just based on some of the data that we've seen around PFS and OS from the phase I/II study? Right. That study, as you know, showed a very encouraging estimate of the median PFS and OS when studied across the range of doses of 160 milligrams to 300 milligrams. We observed a median PFS of in the, you know, eight-plus month range and a median OS of in the 14-plus month range for that broad group. The OS had not matured sufficiently at the 300 milligram dose, which is the final dose for the study, in the top dose in that range for us to have an estimate of the OS, but the median PFS was also in the eight-plus month range. I don't have anything new to offer for that. In terms of how we design the trial, we use our target product profile as the foundation for designing trials, including the powering. In this particular case, it's also further informed by the PFS and OS estimates that we have from that 160 milligram-300 milligram group. With these encouraging phase I results from the single-arm trial, we do believe that our phase III RASolute trial is designed with robust power and the ability to demonstrate clinically meaningful PFS and OS benefits. Does the RASolute trial have any interim looks along the way? You know, is it just safety, or is there any other efficacy-related interim looks as well? Yes, it is designed with the possibility of planned interim analyses. Of course, whether or not we end up having multiple analyses will just simply be determined by the results at the first analysis. These analyses, one or more, will be event-driven. It is based on the number of OS events that occur. When a certain threshold number of OS events occurs, we are then able to look at the data and make a judgment about where we are. Is there sort of a predefined plan where the trial may be stopped early for efficacy? The trial will be stopped when efficacy is reached. Whether that's early or late might be in the eyes of the beholder, but that's what will determine it. Since it is OS-driven, that is, the decision to look and have an interim analysis is driven by a defined minimum number of OS events, we can expect that we'll learn something from that interim analysis. If it's sufficient to declare the study complete, then it'll be declared complete. Okay. I guess, you know, you've talked about kind of when you expect the trial to be completed, which is sort of by your end of this year. I think investors are, you know, trying to figure out when might we potentially get kind of the efficacy readout, particularly, you know, PFS or OS, actually. Maybe kind of talk about when we might be able to get those readouts. Would it end up being only in 2026? We believe the readout will be in 2026. I can't really give you any timing within that 2026 timeframe, of course, at this stage. Enrollment is going well, but we have to see how the event rates actually, you know, show up. That's what the interim analysis will help us do. You know, there are a few things that have to go on mechanically. Once we declare that we've crossed an endpoint, there still has to be additional work done before one is able to conclude that conclusively. There are some mechanics built into that. I do expect we'll have a readout in 2026. Got it. You would read out through OS endpoint? The readout is PFS and OS. The FDA has made it publicly clear that they prefer to see OS as a decision, you know, in pancreatic cancer, and that does make sense. And we are looking for both PFS and OS. As I said, again, the interim analyses are actually driven by OS events, not PFS events. Essentially, it is overpowered for PFS because the powering is driven off of OS. Got it. Okay. Understood. Let's talk about kind of the first line trial that you're planning to initiate sometime by the end of this year. Can you talk about the rationale for still studying RMC-6236 plus chemo regimen when the monotherapy has already demonstrated efficacy that's superior to chemo in first line? And, you know, could there be, you know, added toxicity of, you know, combining the two? And, you know, and do you believe that there's synergistic benefit? It is true that the daraxonrasib monotherapy demonstrated encouraging initial efficacy in the phase I/II single-arm study. Of course, that's not a comparative study. Event-driven single-arm studies aren't considered sufficiently rigorous. You really have to have the second arm to have something to compare to. On the other hand, the median PFS and median OS, as we talked about earlier, were so substantially beyond what's been well established with a wide variety of chemotherapy phase III trials that we do have confidence that daraxonrasib will be effective in first line as well as in second line that we've studied previously. We do expect to initiate a first line pancreatic cancer trial comparing patients treated with chemotherapy to two investigational arms. One is daraxonrasib monotherapy, and the second is daraxonrasib plus chemotherapy, as you just indicated. Based on the monotherapy data in second line, as well as preliminary chemo combination data, we're optimistic that both treatment arms containing daraxon have the potential to become important therapeutic options. Your question is, why have a chemo arm given that level of confidence around monotherapy? I think there really are two reasons. One is there is some basis, albeit somewhat limited, but there is some basis for believing that a combination with chemotherapy may deliver increased efficacy over either agent alone. We don't know that with any high level of confidence, but there's some basis for it, particularly from preclinical data. There is even a mechanistic foundation for that potentially. Also importantly is that community oncologists, essentially all oncologists who take care of pancreatic cancer, are very familiar with chemo. They've come to rely on it. Even though it really leaves a great deal of room for improvement, it's what they're used to providing and have some level of confidence in, at least that they know what to expect when they treat with that. It is the current standard of care, and the ability to combine with something that physicians are familiar with is something that makes sense to provide. You could imagine the possibility that if both arms of that trial are successful, that could create two paths, two options for treating patients who enter a physician's office. What are the gating factors for really finalizing this trial design? If you can share some initial thoughts around what chemo regimen you will end up using, you know, in sort of in the combination arm. Would these be sort of at the same dose as what's currently being used in terms of the standard of care today? Right. As I mentioned, we are optimistic that we have a path forward, both as monotherapy and in a chemo combination. We have been doing some studies evaluating chemotherapy in combination with daraxonrasib, and we're looking at both FOLFIRINOX and gem/Abraxane based combinations, but we haven't made a determination yet whether we'll have both types of regimens available or only a single regimen. We really need further follow-up on safety and tolerability from the patients who have been enrolled with daraxonrasib plus chemotherapy. Now, within each of these chemotherapy types, there is a well-known, well-understood range of doses and schedules that are considered acceptable. Most patients, even if they begin on the highest dose and the most aggressive schedule, most patients undergo some modification of that fairly early in the course of their treatment or at some point in the course of their treatment, such that very few patients actually get what you might call sort of simplistically full-dose chemo simply because it's difficult for patients to tolerate. There are many side effects. There are often hospitalizations, and there often are dose reductions or decreases in the frequency of dosing. That's just very common with pancreatic cancer chemotherapy. It's a harsh set of regimens. Within the range of dose reductions, modifications that are widely accepted, I think we're optimistic that we can find a combination that carries with it typical chemotherapy-induced side effect profile, but not so profoundly that it drives patients into the hospital with life-threatening side effects that require discontinuations of their anti-cancer treatment. That's really the fundamental issue for us, is to make sure that patients who should be on a daraxonrasib-containing regimen in a trial, that they are able to stay on daraxonrasib for as much of that trial and for as continuously as possible because we believe it's the biologically active agent that really is affecting and inhibiting the cancer driver. Therefore, it would not be helpful to a patient to have unintended discontinuations or breaks in treatment with daraxonrasib. That's what we're working with in this range of accepted doses and schedules. We will make a determination and then incorporate one or both of those regimens into our trial. Just going back to a comment that you made that, you know, a lot of the physicians in the community are sort of used to, or kind of as a general practice, do use a lot of chemotherapy. Given the efficacy that was seen for daraxonrasib in second line, as well as sort of the safety profile and the quality of life benefits, wouldn't it just be difficult to enroll or justify a chemo alone arm? No, I don't think so. You know, we have not yet in a randomized controlled trial proven by head-to-head comparison that daraxonrasib is superior to chemotherapy. I think the data that we have shown from a single arm, very traditional first-in-human study are highly encouraging. I think everybody recognizes that from patients to investigators and even to regulators. Ultimately, in our regime, where we have a formal process by which a regulatory body makes a decision, it's actually mandatory that we provide a head-to-head comparison versus standard of care. It's scientifically sound, and it's the ethical thing to do until that's been proven. We will conduct the head-to-head comparison, and we hope to generate the data that will then answer that question definitively and allow for regulatory action accordingly. Okay. That makes sense. You also announced earlier in the year that you intend to initiate a study in the adjuvant resectable PDAC cancer patients. The standard of care chemo in this setting, I believe, you know, varies a lot by physicians. How different are these patients from first-line patients? How different is the standard of care chemo regimen that's used in this setting versus the first-line setting? I think the main difference with patients in the adjuvant setting is that they have no visible disease by CT scan. While the likelihood is low for any given patients, there is curative potential by combining adjuvant therapy, by providing adjuvant therapy for these patients who have been surgically resected, as opposed to first-line pancreatic patients who, even with chemotherapy under any of the observed and historical regimens that we use for pancreatic cancer, patients will unfortunately succumb to their disease eventually. There is a difference between those. As to standard of care chemotherapy, there really is less of a standard of care when it comes to the adjuvant setting. The compounds that are used, the drugs that are used, are essentially the same drugs that are used in metastatic setting. FOLFIRINOX is the same. gem/Abraxane is modified a bit typically in the adjuvant setting. It's usually gemcitabine + capecitabine + nab-paclitaxel. That's the preferred regimen because that was a regimen that was first used and approved in the adjuvant setting. In Japan, there is a 5-FU-based regimen called S-1. It's an oral 5-FU-based regimen that's used for adjuvant chemotherapy based on a positive Japanese trial, but it's still 5-FU-based. These regimens are pretty similar to the treatments that are used in the metastatic setting. As a matter of just general principle, proof of concept, clinical proof of concept that's achieved in the metastatic setting is widely accepted as proof of concept for the adjuvant setting. That means that it is possible to proceed right away with the experimental treatment into the adjuvant setting. In fact, both the historical FOLFIRINOX and gemcitabine adjuvant trials that I mentioned were initiated after proof of concept was achieved in the metastatic setting. It's a very conventional approach. I guess from a trial design perspective, what all do you need to determine sort of internally to really figure out how, you know, what are patients going to get in the various arms? Right. We believe we have the data needed. There really is nothing that we need to generate at this point to help inform that planning. We are currently actively designing a registrational adjuvant trial with daraxonrasib in these resectable patients, and we expect to move quickly on developing this program. It does take some time to develop a protocol, even though one might think that once you know what you want to do, you can just move forward. It takes time to do this thoroughly and properly, and we use advisory boards. Ultimately, we have to engage with the regulatory agency. We expect to initiate the adjuvant study sometime in 2025. We also expect to initiate the first line metastatic study as well. Just to follow up there, would the standard of care or sort of the competitor arm be physician choice chemo, or would you need to pick? Stay tuned. That is something that we will be able to just talk about when we have the design. It is not constructive for me to get out in front of that design. Let us get through our work of designing that trial, and then we can describe what the design is. Okay. All right. Sounds good. Maybe we can shift gears through zoldonrasib, which is RMC-9805, which is your RAS(ON) G12D. I guess you're going to be presenting some data that's coming up at a meeting soon. Maybe if you can just step back and maybe, you know, what is sort of the potential role of this drug which targets G12D in PDAC as you think about kind of a paradigm shift from daraxonrasib monotherapy or combo therapy with chemo? How does sort of this drug kind of play a role with this changing paradigm that you're developing in? Things are moving rapidly, and I think zoldonrasib is going to play an important role. It is a compelling compound based on the initial tolerability profile, which we reported just a few months ago in pancreatic cancer. It's also clearly very active against G12D tumors, which gives us a range of strategic options. We're still in the early stages of understanding exactly its clinical profile and its potential. As you pointed out, we'll share some new clinical data in non-small cell lung cancer at AACR coming up. We believe an important part of the strategy for our mutant selective inhibitors may be in combination strategies, including a RAS(ON) inhibitor doublet combination with daraxonrasib, combinations with existing standard of care such as pembrolizumab and chemotherapy, combinations with other targeted and/or novel agents such as EGFR antibodies and PRMT5 inhibitors. I think the fundamental point I'd want to make here is that we haven't cured a lot of pancreatic cancers yet. We have an exciting set of compounds pipeline in the clinic and additional things coming behind it that will make a difference, we believe, for patients, but we haven't cured pancreatic cancers yet. I think it's just too early for us to declare victory. I like to say we're maybe in the second inning of this baseball game, and we have some momentum, but we're going to continue going until we've made a real difference. Just as you sort of talked about the kind of a RAS(ON) doublet as a concept, now, would you consider, especially in the PDAC setting, given some earlier comments around kind of how entrenched the use of chemo is in this space, would you consider a RAS(ON) doublet with chemo, or would that be the time point to explore a RAS(ON) doublet without chemo? Right. There are a variety of possibilities. We certainly believe that a RAS(ON) inhibitor doublet, by which we mean a mutant selective RAS(ON) inhibitor combined with a RAS multi-inhibitor like daraxonrasib, that those are among the most exciting combination options. We have seen in preclinical models that we have shown now in several settings that combining a multiselective and a mutant selective inhibitor, it increases the target occupancy of the mutant form of RAS, and it drives significant anti-tumor activity that can exceed that seen with either agent alone in a particular model. We have also demonstrated that daraxonrasib suppresses many of the known RAS pathway resistance mechanisms that have been shown to emerge in patients who are treated with a mutant selective RAS inhibitor, particularly the G12C inhibitors, for which we now have a lot of publicly known, you know, experience. Early evidence of translation of this preclinical data into the clinic had been observed, as we reported in December, with the combination of daraxonrasib plus elironrasib, our G12C selective inhibitor, where we observed highly encouraging combinatorial activity, which increases our confidence in the concept of the innovative RAS(ON) inhibitor doublet more broadly. That is really the context for our enthusiasm for this two RAS(ON) inhibitor approach or the doublet approach. With respect to the combination of daraxonrasib plus zoldonrasib in particular, since that is what we are talking about here, we have completed dose escalation in patients at the anticipated single agent recommended phase II dose for each drug. We plan to study these RAS(ON) inhibitor doublets further in patients, and we will continue to observe anti-tumor effects and safety, particularly as we move towards earlier lines of treatment. Would we combine a doublet of RAS(ON) inhibitors with chemotherapy? That seems unlikely. I think the goal there would be to use the RAS(ON) inhibitor doublet to spare patients of chemotherapy and to push the chemotherapy option down to the next treatment arm. You can imagine if we're introducing a doublet of RAS inhibitors in a front-line setting, now we've saved patients from having to take chemotherapy, preserve that chemotherapy to be available for second or third-line use. That's really where we could start to stack up potentially a stack-up OS benefit. Okay. That's helpful. You've indicated that you're studying zoldonrasib in several combinations for which you're going to share additional data, perhaps in second and third quarter of this year. How do you think about how much synergistic benefit you need to see to pick a particular combination and move that forward? What is sort of that bar without, you know, having to see enough durability of effect as well, right? Or would you need to wait to get the durability data? Okay. Now I understand your question. Yeah. I do not think we typically would be able to use durability as the indicator for moving to a combination in the clinic because that really can add a year or two to these studies. It is just too urgent that we get these into patients and move things towards registration. With something like daraxonrasib, we have already established significant durability with the caveat I mentioned that that is from single-arm studies in lung and pancreatic cancer. Those are not formally sufficient, you know, to declare proof. It is quite encouraging. If we are adding a mutant selective inhibitor on top of that, and if we see an objective response rate benefit, I think it is very likely from there that that would translate into greater long-term benefit. That's certainly what we've seen in the preclinical models where combining two RAS(ON) inhibitors can result in really highly durable anti-tumor benefit in animals. In fact, in many cases, no recurrences. I think the concept is well established, and we can use faster markers of anti-tumor activity like response rates in the right context, just as we did with the colorectal cancer study where we took two agents, daraxonrasib and elironrasib, either of which alone was going to have a single-digit response rate. When we combine them, we saw a 25% response rate in patients with very advanced colorectal cancer. I think that's sufficient to encourage us to move forward. Yeah. Okay. Why don't we shift gears to your RAS(ON) G12C inhibitor, which is elironrasib or RMC-6291. These are all tongue twisters still for me. You showed that the combination of 6291 and 6236 with pembro was well tolerated. What is the next step here in terms of exploring the clinical development path forward in first line lung? Yeah. We are very excited about elironrasib. It's sort of been, you know, a little bit behind the scenes since it was first disclosed back in, you know, in 2023. We think it's a very exciting compound, and we're pursuing a variety of combination approaches for first line lung cancer, particularly for, you know, for G12C positive lung cancer. As you mentioned, the dominant standard of care in first line lung cancer includes pembrolizumab. Combining with pembro and the ability to do that safely is important. As you indicated, both daraxonrasib and elironrasib so far, we've seen very encouraging signs and very little evidence of additive toxicity. We also, as you indicated, have seen encouraging signs in the colorectal context that putting two RAS(ON) inhibitors together can achieve something that neither alone can achieve, which leads us to the concept of combining two RAS(ON) inhibitors with pembro. We think we've essentially already demonstrated the safety and tolerability of that, at least with a limited data set. We don't really have much of a concern, but it is a good idea. I think the regulators and investigators would expect to see some evidence that the triplet does not, you know, incur or carry with it some significant adverse event liability. We certainly are studying, you know, that triplet combination. I think we're moving, though, towards our first line strategy, both for G12C lung cancer, which is really a subset of the total of lung cancer, of RAS lung cancer. It's about 12% of the 30% of lung cancer that is a RAS-driven tumor. The other 18% would not benefit from eliron, but could benefit from daraxonrasib. We are moving forward in thinking that all through. As the data mature, but more importantly, as our trial design work proceeds, we will be able to share information about that. Maybe just stepping back, and you obviously have a very deep pipeline and kind of just the things that we've talked about. But, you know, kind of stepping back, as we think about the RAS on platform, how do you think about potentially combining that with other mechanisms beyond just RAS on? Other mechanisms directed towards RAS or other drugs like pembrolizumab and PRMT5 inhibitors and EGFR antagonists, all of the above? All of the above. Yeah. I think all of the above could be interesting. I think we have a lot of dialogue, a lot of conversations underway with parties that have other compounds that they're evaluating or that have already been proven and are part of standard of care. We don't really need to have a big conversation about cetuximab combining with a RAS(ON) inhibitor in colorectal cancer. That's just something we're now, you know, testing. We've announced that we're testing through a collaboration with Tango Therapeutics. We're providing them daraxonrasib, and they're going to test it in combination with their PRMT5 inhibitor. Our own RAS(ON) inhibitors combining with pembrolizumab. These are all options. To the extent that the preclinical data or known clinical data provide good justification for moving something into the clinic as a combination strategy, we'll do so. My allusion to being only in the second inning of this baseball game means that there's a lot that we don't know yet as to which of these are the highest priority from an end game perspective. We make judgments and we'll move a lot of things in parallel into the clinic and then make judgments based on what we see. Okay. All right. Those are the questions I had. Thank you so much. I really appreciate you taking the time to be with us today and to all our listeners for joining. Thank you, Ami. I appreciate it. Thank you. Have a good day.