Good afternoon. My name is Peter Lawson. I'm one of the Biotech Analysts at Barclays. Welcome to Lawson's Lunchtime Deep Dive With Revolution Medicines. The goal of these calls is to help preview upcoming data. We've been doing it for the last three years at Barclays, and Revolution Medicines is our 10th in our series, and I think we've got another four left this year for this series. I hope you find them useful. It's, of course, II season, so we very much appreciate any, all votes of support. Thanks so much for that. Just as a way of orientation, this is a 30-minute call. If you have questions, do email me directly. It's peter.lawson@barclays.com. You can get me on Bloomberg. I'm on Bloomberg, you can pester me that way. It gives me great pleasure here to introduce Revolution Medicines. We don't cover the company, non-covered. Thank you so much, Mark Goldsmith, CEO, thanks for your time today. Time permitting, we'd love to cover the multi-RAS inhibitor, updated data in the second half, and then your G12C, and then, of course, the SHP2 inhibitors. We cover Relay, there's a clear distinct read-through for us. With that, maybe the first question would be, there's multiple KRAS players. You've got a kind of unique approach with this kind of multi or pan-RAS inhibitor. Just curious on how your approach differentiates from other KRAS players within the space. Well, thanks, Peter. We really appreciate the chance to talk with you today. O ur approach as a company is differentiated in that essentially the entire company is focused on RAS-addicted cancers, and that creates a great deal of internal know-how and crosstalk, leverage that we think will ultimately help us defeat RAS-addicted cancers. The core of our pipeline is a very large collection of RAS inhibitors that bind selectively to the activated or ON form of RAS, which is in fact the oncogenic state for RAS. When we began doing this, work several years ago, we acquired a company called Warp Drive Bio, that had made some early breakthroughs in, with regard to drugging the activated or ON form of RAS. We incorporated their technology into our platform, and since then have created really a vast collection of highly selective inhibitors of the RAS on state. Some of those inhibitors are uniquely active against a particular oncogenic variant of RAS, and some of those are active against multiple forms of RAS. The compound that you just spoke to, RMC-6236, is something we call a RAS multi-on inhibitor. Multi because it inhibits virtually all forms of K, N, and H RAS that we've tested to date, which is essentially all forms of RAS. It has activity against essentially all mutant variants of those isoforms of RAS. That's why we call it RAS multi, and we call it ON, because it is active only against the ON state of the RAS proteins. Got it. thank you. The data you showed at early this year, so safety looks really encouraging. Well, I think you're at 220 mg now, and 80 mg was a theoretically active dose, and it seems to be, well tolerated. W hen do you think you hit DLTs and, could talk about the rash and if you think that could become a dose-limiting toxicity, and if that could even preclude the use of the drug in any way? Right. RMC-6236, the RAS multi ON inhibitor, has been presumed to be one that would be difficult to use in humans under the theory that inhibiting wild-type RAS would cause intolerabilities. Our approach to it assumed that inhibiting wild-type RAS would actually contribute to anti-tumor benefit, since RAS-addicted tumors will recruit any form of RAS in the cell that they can find in order to stay alive, and therefore inhibiting all forms of RAS could be more active as an anti-tumor agent. Preclinically, RMC-6236 was highly active at dose levels that were also well tolerated. We put out very extensive data sets across many different tumor models that showed how active RMC-6236 is with animals able to tolerate it for many months on end. We've had mice treated for, 100 days, without any difficulty. The question really was: Would that translate into humans? That's always a question in moving from mouse models into human. What we reported, back in February, about six months into the study, is that the very first dose level, which was 10 mg in human, was already pharmacologically active, and we had been dose escalating from there. The data we showed on tolerability included patients up to 120 mg. As you point out, it actually was quite well tolerated. No patient had come off of drug for intolerability, and really the most common side effect was and remains today, rash. A rash that both investigators and patients have reported is manageable, is not really a cause of intolerability. In fact, as far as I'm aware, maybe only one patient has ever even had a dose reduction associated with the rash. Now, since that early report, we've disclosed that we continued to dose escalate above 120 mg. We went to 160 mg per day. Then we cleared that dose level, and we went to 220 mg per day. I can now share with you that since then, we have cleared the 220 mg dose level from the DLT window and have moved on to 300 mg per day. It's moving along quite well in terms of antitumor activity. We began to see really objective antitumor evidence at 40 mg and above, but even much more so at 80 mg. 80 mg is roughly the equivalent of in the ballpark of 10 mg per kilogram in the mouse, which is the dose level at which we began to see significant numbers of tumor regressions. Really, I think 80 mg, we kind of hone in on as a threshold for shrinking tumors, and now we're already, three times that dose level. We've seen continued increases in exposures associated with the increases in dose levels. Got it. How far do you think you'll be able to go up? I know it's difficult triangulating between the mouse studies and the human studies based upon the dynamics of the interaction and the molecule. It's hard to say. W e sort of we'll know it when we, when we get there, to be honest. If we don't clear a dose level, then we know that that dose was above the tolerated dose level. We just don't know it until we're there. We have all sorts of betting pools internally and so on, but I just don't really know the answer to it. Clearly, we did clear the DLT window for 220 mg, and we'll see how 300 mg plays out. Got it. thank you. As we think about efficacy, you saw a number of encouraging responses and in the original release. Just, do you expect the patients that are on drug to stay on drug? If any come off, it sounded like one had a dose reduction. Just anything you can kind of help us frame, kind of, the second half expectations around response rates and what you want to see. Generally with RAS inhibitors, more is better from the point of view of antitumor response. I think that's true for virtually every RAS inhibitor that's been tested, and it is true for RMC-6236 as well. We'd like to be able to deliver to patients as much drug as they can tolerate and still stay on drug. I t's not a very effective drug if patients have to stop taking it, so it is important that there be, continuity in taking the drug. We just don't know what that dose level will be, but the higher, the better from an antitumor perspective. What we've disclosed is that we've continued accumulating evidence of antitumor activity, and we haven't given any more detail than that yet. We'd not like to do that sort of piecemeal. We'll do it, this starting in Q3, we'll introduce a series of presentations, both corporate and scientific meeting presentations, that will put together the whole package for people to see rather than just bits and pieces. We're very encouraged by what we're seeing. A feedback from investigators is very positive, very encouraging. There tends to be a waiting list to enter this study at our clinical sites, which is both a sad indicator of how much a need there is for it, but also a very encouraging indicator that amongst patients and investigators, it's viewed as a high priority, drug candidate. We're excited about that. We have no trouble getting patients into the dose escalation cohorts, and we will present as much data as we can when we start that series of presentations. Got it. thank you. Then I know you saw kind of a dose-response relationship in the earlier doses. Are you seeing a similar kind of thing pan out to say? Yeah, I can't really comment, of course, on clinical data subsequent to our February release. The one thing we did report in May that, although it's only a single data point, I think it is indicative of general observations. The general observation is that the longer a patient stays on drug, the more likely that they will convert to an objective response. We had already indicated back in February that that was the case for the patients who had shown responses. In particular, there was a patient we described who had metastatic pancreatic cancer, late-stage pancreatic cancer, had failed multiple other therapies, began on RMC-6236 at 80 mg, and on their first on treatment scan, which is six weeks after they started treatment, had a modest but noticeable reduction in tumor volume, and I think it was around 17%, not enough to trigger RECIST criteria for a partial response, but nonetheless, notable. Subsequently, the patient had a second scan, which was after 12 weeks of treatment, they converted to a greater than 30% response, that became a partial response, considered unconfirmed at that stage. In May, we reported that that patient, after another six weeks on the same dose, had a greater than 80% reduction in tumor volume. Really, by scans, some people look at it and say it looked like a CR, but formally, it was read as an 80% or 82% tumor volume reduction. I think that is evidence that at least at those doses, at that dose, that the longer one stays on drug, the more likely one can convert to an objective response. That's quite exciting, quite encouraging. The fact that the compound has been generally well tolerated means that there's a greater chance that one could stay on drug long enough to see an objective response. Beyond that, we're, of course, monitoring patients longer term, and as long as they're staying on drug, we're interested to know what's the durability of the response and durability of benefit. Got it. Thank you. I had an inbound question around the speed of response. How does that compare to peer molecules? Well, there is no peer molecule for RMC-6236. There's really nothing to compare it to because it is the only RAS multi-on inhibitor in the clinic that we know of to date. There really isn't a peer molecule. Some people try to compare it to Adagrasib or Sotorasib, which I'd consider the pioneering RAS inhibitors and the only two approved drugs. Of course, those are mutant selective for KRAS G12C. They're covalent inhibitors and only inhibit G12C. With regard to those, I'm familiar with Sotorasib, which showed that the mean time to an objective response was around that first scan, or median, I'm sorry, was around the first scan. What that means is, about half the patients did not show an objective response on the first scan, but showed one subsequently. I don't think it's unusual that it may take time for responses to occur, but it's also the case that not all of our patients who've shown a response required multiple cycles to show a response. It's not a fixed characteristic. It just says that if one doesn't have an objective response on the first scan, one shouldn't be discouraged. If there's some evidence of tumor volume reduction, that may well convert subsequently to a PR. Got it. thank you. Then as we think about these data releases in the second half, is that gonna be medical meetings or on earnings calls, just to have you worked out through? I think it'll be a combination of corporate and scientific meeting presentations. W e certainly understand the value of peer-reviewed settings. At the same time, sometimes peer-reviewed settings only provide a limited amount of time, and there's a lot more information. You can imagine now that this study, which has been underway now for roughly a year, we've accumulated a lot of data, a lot of different types of data, and can be hard to squeeze into even a podium presentation. We'll do some combination of corporate and scientific meeting presentations, and in our next earnings call, we ought to be able to lay out a more precise timeline of which settings and at what times people should expect these data to be shared. Got it. the approach then, how should we be thinking about potential registrational pathways and kind of which tissues you go after, which cancers? Yeah, well, it's an exciting question. I f you think about this, a year ago, a year and a half ago, when we first introduced RMC-6236, most people's immediate reaction was that it would never be tolerated enough to provide any clinical benefit. Now we're talking about what kind of registration path might be possible. I think that's honestly an appropriate question, because the early evidence that we shared in February was quite encouraging. Of course, people will have to look at the additional data later this year to decide if they feel that way. We feel very excited about this compound, and as I've indicated, feedback from investigators continues to be very strong, and I believe even patients have been reporting their own self-reporting results in various settings that is consistent with what the investigators are telling us. Let's see what the data look like, though, when we present it in the late summer and into the fall. In terms of a registration strategy, that's clearly something our development team is intensively focused on these days. We do believe that there is encouraging evidence of monotherapy activity in settings where there are significant unmet needs. Recall that all of the patients that we are treating today with RMC-6236 are patients for whom there is no targeted RAS therapy available. In other words, we're working in entirely white space. The mutations that are permitted in this study are all mutations for which there are no, not only no approved targeted therapies, but no known experimental targeted therapies that have shown activity yet. We're really at the vanguard in this field, and that creates opportunities to pursue monotherapy from a registration perspective, if the data support it, and we would obviously lean heavily into that as supported by the data. Beyond that, though, I want to be really clear, and we've said this consistently for many years now, and I want to stay on this point, that really to defeat RAS-addicted cancers in the long run, for the most patients to get the deepest and most durable responses, one's likely to require combination strategies. RAS is an essential component of, for these tumors, and any attempt to suppress them, even very effective attempts, like RMC-6236, effective biochemically, is going to elicit some form of resistance mechanism that will require a second or even a third component. We just know this from all the experience in the RAS field to date. W e would expect that there will be combination strategies that will build on the monotherapy activity in order to provide distinct patient subsets with the best therapeutic options. Do you think your multi RAS ends up being kind of earlier line versus a more targeted, say, G12C, et cetera? Well, that's a great question. I mean, t hat's a really complicated question. It's very hard to give a straightforward, simple answer. There aren't enough data, clinical data to answer that. Preclinically, 6236 is really the most active compound we've ever tested, full stop. We're very heavily invested scientifically in this idea, and it leads to the possibility that RMC-6236 could become a broad, broadly applicable drug onto which one adds additional drugs. For example, combining a G12C selective inhibitor with RMC-6236, or combining a G12D selective inhibitor with RMC-6236. We've shown a pretty good body of preclinical data that supports that idea, and we're quite excited to pursue it. As soon as we feel that we're even in the zone of a recommended phase II dose for RMC-6236, we expect to bring forward into combinations at least one of the mutant selective inhibitors with RMC-6236. That the first mutant selective inhibitor is most likely to be RMC-6291, which is our KRAS G12C inhibitor that is also in the clinic and making progress now. Got it. on your G12C, how should we be thinking about when you get the recommended Phase II dose? Is that kind of a second-half thing or early next year? We're making good progress on that. We've shared less information about it than RMC-6236, and the only reason for that is it's a crowded space, and so the bar is simply higher, and giving an early look just doesn't provide enough information for people to judge it. We indicated by the end of the year, we expect to share some data around our RMC-6291. It's going well, dose escalation is going well. It's been very well tolerated, and it, too, is an extremely active compound. We reported at AACR and in various other settings, much more detail over the last six months about that compound, including its chemical structure, and its entire profile. It's really a remarkable KRAS G12C on inhibitor. Its differentiation is that it inhibits the on or active state of KRAS G12C, unlike the other compounds, Sotorasib, Adagrasib, and the other 10 RAS off inhibitors that are out there today, which all operate by binding to the off or inactive form of KRAS G12C. It is a highly differentiated molecule, which means that it has the potential, because of its mechanism of action, to deliver a different biological impact. Of course, we're banking on that and testing that hypothesis. Do you think that the data we see year-end, we'll have enough to see whether there's a differentiation on safety or response rates, or how long do you think that takes to pan out? Yeah. Safety is much easier for us to accumulate evidence on because, of course, every single patient that comes in becomes part of a safety database. I think we will have good evidence around tolerability and safety by the end of the year. Proving that it is differentiated from an efficacy standpoint or an antitumor activity standpoint is a higher bar. What we've seen so far with the first half dozen KRAS G12C off inhibitors, the first-generation inhibitors, is that they all seem to confer a roughly 30% to 50% objective response rate in second line, non-small cell lung cancer carrying the KRAS G12C mutation. We know kind of a benchmark that we have to at least be in the ballpark of that number. That's not the number we're looking for true ultimate differentiation. What we're really looking for is progression-free survival and then ultimately overall survival, because at this stage, with two drugs having accelerated approval, the game is really all about true long-term clinical benefit. It's no longer about objective response rates. That's just not an important parameter anymore. We're not likely to focus on objective response rates. We just want to make sure the compound's behaving at least as well as others in that regard, then you're gonna see us really doubling down on how do we really smash these tumors? Combining RMC-6291 with RMC-6236 is a high priority study for us to pursue. As soon as we're in the range of recommended Phase II dose for RMC-6291 and RMC-6236, which may well be later this year, that's when we'll pull the trigger on a combination study. A lot of work going into that combination study as we speak now, so we fully expect to be able to pull that off. That would be the priority for the combination study, your RAS, multi RAS and your G12C versus the PD-1 combination? Well, that's a very important question. W e've spent a lot of time talking with investigators about what they think, because that's an important part of our own considerations, is learning from investigators who've been around all these compounds now for the last several years. We sense a very strong excitement about the RMC-6291, RMC-6236 combination, which mirrors our own preclinical data and our own assessment. With regard to PD-1, ultimately, in first line, one's likely to have to play with PD-1 and have it be part of your regimen. A single agent combined with PD-1, that is, a single G12C inhibitor combined with PD-1, just may not be sufficient to move the needle.... We're really going more for the RMC-6291, RMC-6236 combination, then, eventually bringing in a PD-1 into that combination as well. That might be, really a fantastic combination, where you take advantage of all the immune benefits of the RAS(ON) inhibitors, plus the PD-1 checkpoint inhibitor, and put all those together into a package. If patients can tolerate it, if that regimen is tolerable, it has real promise. Got it. thank you. Would that be an accelerated approach, or randomized? How should we think about that? It's hard to say that a doublet or triplet will be an accelerated strategy, even if you mean lowercase accelerated. T hat is a little bit of a slog from an operational point of view. I don't think we're that focused on accelerated approvals, and I think the field of oncology is generally needs to be much less focused on accelerated approvals, given the FDA's posture on it. Right now, the end game for us is to develop the most active, beneficial therapeutic regimen we can on behalf of patients and let the registration timeline just work itself out. Along the way, we might generate sufficient data for the FDA to consider whether something should be approved on an accelerated basis, but it's really. It's not our priority. Our priority is to get the best regimen, optimal dosing into the right patients. Got it. thank you. I'd love to move on to the SHP2 initially, how do you see the differentiation of your molecule or your combination versus, say, the Roche Relay combination and others out there? Well, we were among the earliest to bring a SHP2 inhibitor into the clinic. We invested a great deal of time in optimizing the dose regimen for RMC-4630, which is a very clean and active SHP2 inhibitor. Very well behaved, but it does carry with it the same general side effect profile of RAS MAPK pathway inhibitors, which is that normal tissues don't like to have their RAS pathway suppressed. That can lead to gastrointestinal manifestations, skin rashes, edema, a number of different things that are well described for the BRAF inhibitors, for MEK inhibitors, for ERK inhibitors. We worked very hard on the dosing regimen to try to design a strategy that would maximize antitumor effects, but minimize impact on normal tissues, and that led to an intermittent dosing regimen. We landed on a day one, day two weekly schedule. For example, Monday and Tuesday, a patient takes a dose on each of those two days, and for the rest of the week, doesn't take a dose. That leads to very high Cmax and above IC50 exposures for many days of the week, and then allows normal tissues to recover towards the end of that week cycle, when the drug concentration dips below the IC50, and then we hit the tumor again the next week with the same regimen. We think that that is the best approach for RMC-4630. No other compound has been tested with such an intermittent regimen, no other SHP2 inhibitor. There may be differences in the inhibitors themselves, but I think the dosing regimen is probably the most differentiating feature. Now we are in the throes of accumulating data from a combination study with Sotorasib, so RMC-4630 plus Sotorasib, both dosed at their optimal doses and regimens, and we expect to read that out later this year. We will see whether the tolerability benefit of our dosing regimen translates, or whether the combination with Sotorasib is tolerated sufficiently for patients to stay on drug long enough to get the benefit, and what level of benefit do they receive? We've set a reasonably high bar for that, and there's no reason for somebody to take an additional drug if it's not really moving the needle for them clinically. We're looking at both response rates, but also, more importantly, even duration of response, we'll have a good sense of that, later this year. Okay. Do you think that benefit plays out in depth of response, or is it duration? I think duration is the most important thing. I'm not sure a patient would be able to tell if they had a 32% response or a 45% response. I'm not sure that would matter much, but whether or not that response lasts for six months or 12 months or 18 months makes a real difference. I think we're most interested in durability of response. One of the limitations of sotorasib and Adagrasib has been that only a fraction of patients even show a response, and then when they do, it's not a particularly durable response. I think durability is the main thing for us to try to extend, and the data will tell us whether it does that or not. Got it. for a phase III, would you continue with Amgen? How does that work? Would you add your own, G12C in or RAS(ON)? Yeah, of course, our pipeline is designed ultimately to have intra-pipeline combinations, and now we have two RAS(ON) inhibitors in the clinic. We have our KRAS G12D selective RAS(ON) inhibitor called RMC-9805, which is about to enter the clinic. W e will be a company with three RAS inhibitors in the clinic, plus two companion, potential RAS companion inhibitors. We're clearly most focused on developing our pipeline, but we have a very good relationship with Amgen, and if the data are supportive, we'd be certainly open to talking with them about what the next steps would be. Got it. where do you think you are versus competitors for generating, whether it's phase III data or potential approval with a SHP2? The SHP2 compound? Yeah. It all comes down to what the phase two study shows. As far as we know, this is the most significant phase two study design and trial underway, so we think it will be a very important readout. It just depends on what it shows. I don't have the answer today, but once we know that, we'll be able to answer your question about where does that lead. Got it. thank you. What's the bar to continue to move that forward in the sense of duration, since that's the key aspect here? Progression-free survival by sotorasib treatment in second-line lung cancer is something like six months. I t's not yet providing the kind of benefit that, as a monotherapy, really moves people. That's what we want to improve upon and what's the number to achieve that improves upon that. I'm not gonna get into that today, but I think it will be pretty obvious whether or not there's something to continue pursuing. Got it. thank you. I've got a, final question, and it's an inbound question, is, just going back to the rash, how severe is that? I n a clinical trial setting, it's very different. In the real-world setting, could that preclude the use of your multi-RAS? We see no evidence that it would preclude the use of it. As I mentioned, with as far as I know, one patient having a dose reduction. If you look across all drugs and particularly all the KRAS G12C inhibitors, there are far more patients discontinuing drug for a dose-related side effects than the number I just mentioned to you. There's a lot of experience with RAS pathway-mediated rashes, including EGF receptors, all of which, whether it's an antibody or a small molecule, we've had decades of experience with those, and most patients do develop rashes, and for most patients it's tolerated, and for most patients, for many patients, it actually resolves on its own in the historical experience. I don't think we have any reason to expect that it will be materially impactful in terms of patient treatment. Got it. thank you so much. We're the way past the bottom of the hour, so thank you so much, Mark, for your time today. Next up for us is, of course, we've got Corcept call on ovarian cancer, which is goes to be really timely, and that's 8:00 tomorrow, and then next Tuesday, we've got Tango Therapeutics for a fireside chat. Mark, once again, thank you so much for the time today. Thank you, Peter. Appreciate it.