Okay, I guess we can get started. Good morning. I'm Eric Joseph, Senior Biotech Analyst with JP Morgan. Our next presenting company is Revolution Medicines. Presenting on behalf of the company is CEO Mark Goldsmith. There'll be a Q&A session after the presentation. Just raise your hand, and we'll get a mic to you. For those tuning in via the webcast, feel free to submit questions via the digital conference book. We can work them in where appropriate. With that, Mark. Good morning, and thank you, Eric, and JP Morgan for the opportunity to provide an update on the momentum at Revolution Medicines and our conviction that we continue on target to outsmart cancer on behalf of patients with RAS-addicted cancers, and to create shareholder value. Please review our notice regarding legal disclaimers. RAS mutations are among the most common genetic causes of human cancers. Despite accelerated approvals of two KRAS G12C inhibitors, large unmet medical needs remain, including among patients with tumors harboring KRAS G12C and other more common RAS mutations for which no targeted therapeutics have been available. Clinical experience, nonetheless, has validated the KRAS G12C mutation as a therapeutic cancer target, and extensive scientific work shows that other oncogenic mutations in the RAS family are likely to follow a similar paradigm. Our clinical and preclinical pipeline of targeted therapeutics is designed to address unmet needs across a broad range of RAS mutant cancers, and we are now a poise for important clinical milestones. Today, I'm excited to be able to share with you something new about each of six development stage drug candidates across our portfolio of groundbreaking RAS on inhibitors and RAS Companion Inhibitors. RAS proteins are central to maintaining cell growth, cell growth signaling, and numerous genetic mutations in RAS cause excessive signaling by activated RAS, or what we call RAS-ON, leading to uncontrolled cell growth and cancer. These mutations are the main drivers of nearly a quarter million new cancers in the US each year, including major epithelial cancers in the lung, pancreas, and GI tract. Our unique pipeline of targeted therapeutics is designed to extinguish excessive RAS on signaling at the heart of these cancers. The core of our pipeline is a first-in-class collection of RAS(ON) Inhibitors, orally administered compounds designed to robustly suppress RAS(ON) signaling. Today, I'll review our first two RAS(ON) Inhibitor drug candidates that began clinical testing recently, a third candidate that should enter clinical development later this year, and complete the first wave from our RAS(ON) Inhibitor collection, and an exciting new drug candidate that is part of a second wave of assets planned for a clinical evaluation after 2023. It's also well known that patients with RAS-addicted cancers frequently develop clinical drug resistance when treated with inhibitors of the RAS pathway, which is typically due to other cellular proteins and pathways that cooperate with RAS to sustain these cancers. The second part of our pipeline is a set of RAS Companion Inhibitors designed specifically to counter clinical drug resistance by suppressing some of the most important RAS cooperating proteins. In many instances, we expect that RAS On inhibitors and RAS Companion Inhibitors will be combined to deliver the greatest clinical benefit. Let's begin with our RAS On inhibitors, a groundbreaking collection of design-based small molecules that engage RAS On proteins exclusively. Unlike other approaches, these compounds bind to the RAS On protein surface at a site immediately adjacent to all three major mutation hotspots, positions 12, 13, and 61, which provides unique chemical access to the differentiated structural features of nearly all cancer-causing RAS variants. These compounds link the RAS target to cyclophilin A, a protein chaperone that is widely expressed in human cells, essentially burying RAS in a Tri-Complex and extinguishing its actions. These potent selective and oral inhibitors cause deep and sustained suppression of RAS cancer signaling. Today, RevMed has development stage RAS(ON) Inhibitors, including both covalent and non-covalent compounds that target all three cancer hotspots. Mutations at position 12 are by far the most common in RAS cancers and are targeted by our first three drug candidates in development. We also have a G13 targeted drug candidate, and today I'll introduce you to our first Q61 targeted drug candidate. Let's run through these individually. RMC-6236 is a bold drug candidate, a first in class RAS(ON) multi-selective inhibitor with potential utility for more than 130,000 new pancreatic, colorectal, or lung cancer patients in the US each year with tumors harboring one of various mutations at amino acid 12 in KRAS, which we refer to collectively as G12X mutations. Over the last year, we showed that RMC-6236 has an attractive preclinical profile. It's highly potent and selective for the RAS family of proteins and is orally bioavailable in animal models, promoting effective target coverage in cancer cells. In many preclinical models of human lung, pancreatic, and colorectal cancers bearing a range of G12X mutations, substitutions of cysteine, aspartic acid, arginine, serine, or valine for glycine 12, RMC-6236 induces tumor stasis, regressions, and often complete or near complete responses in these waterfall plots of tumor size at the end of treatment across 51 in vivo cancer models. The impact tends to be strongest in lung and pancreatic cancer models, but even roughly half of colorectal models show regressions or at least disease control. Further, the Kaplan-Meier plot on the right shows that the impact of RMC-6236 typically is quite durable. The profound antitumor effects seen in these experiments are mediated by direct inhibition of the excessive RAS(ON) signaling that drives these RAS-addicted cancer cells. Overall, RMC-6236 exhibits a compelling preclinical profile. Oral dosing, either daily or on an intermittent schedule, is well-tolerated long term in an active dose range, and at higher doses, the side effects are on target, measurable, and reversible. RMC-6236 is currently being evaluated in a phase I/IB clinical study that began in mid-2022 with patients carrying tumors bearing KRAS G12X mutations. I'm gratified to report today that the compound is behaving well so far and exhibiting a profile consistent with our predictions. The dose escalation portion of the study is proceeding according to plan, and our clinical investigators have treated patients with multiple tumor types and KRAS G12X genotypes, as anticipated. Early results have confirmed that RMC-6236 is orally bioavailable in patients. It's exhibiting pharmacokinetics consistent with our expectations from preclinical data and is showing dose-dependent increases in plasma exposure on once-daily dosing, and the option of intermittent dosing is also enabled. Further, we've cleared several dose levels and observed good tolerability with no dose-limiting toxicities reported so far. We have not yet reached a recommended phase II dose and schedule. Based on quite high patient interest and current pace, we expect to be able to provide additional information from the ongoing study, including initial activity data around mid-2023. The basic profile we've seen so far is clearly encouraging regarding RMC-6236 itself, and we believe it has favorable implications across our RAS(ON) Inhibitor collection and the Tri-Complex drug discovery platform more generally. The next compound, RMC-6291, is our first mutant-selective inhibitor and is focused exclusively on the KRAS G12C target. Based on preclinical studies, we believe RMC-6291 has best-in-class potential for treating KRAS G12C cancers, primarily lung or colorectal cancers. It is highly potent and selective for KRAS G12C. It is also orally bioavailable preclinically, promoting effective target coverage in cancer cells. Shown here is a mature dataset from a large in vivo mouse clinical trial we've conducted with RMC-6291 in human KRAS G12C lung cancer xenografts, as seen in the waterfall plot of end of study tumor size on the left. We observed a particularly high response rate, shown in blue, often with deep regressions, as shown in this favorable head-to-head comparison with Mirati's adagrasib, shown in gray, that recently received accelerated approval. Likewise, these antitumor responses showed good durability when followed long term, as indicated in the Kaplan-Meier plot on the right, and this preclinical profile supports its best-in-class potential. Based on its strong performance preclinically, RMC-6291 is being evaluated in a phase I/IB clinical study that began a few months ago with patients carrying tumors that harbor KRAS G12C mutations. In the dose escalation portion of the study, our clinical investigators have treated patients with several tumor types, all bearing G12C mutations and mainly patients who have previously received a RAS(OFF) inhibitor. Dose escalation is proceeding according to plan in the crowded G12C space, and this compound is somewhat earlier in its stage of development than is RMC-6236. Nonetheless, early results have confirmed that like RMC-6236, RMC-6291 is orally bioavailable in patients exhibiting pharmacokinetics consistent with our expectations based on preclinical data. We've also here observed good tolerability with no dose-limiting toxicities reported so far. It's a well-behaved second drug candidate from a RAS(ON) Inhibitor collection, the first of our mutant-selective inhibitors into the clinic and provides further encouragement regarding potential read-through to other RAS(ON) Inhibitors and the Tri-Complex platform broadly. Given the earlier stage and constrained access to eligible patients, we expect to provide additional information from this study late in 2023. The third drug candidate is RMC-9805, a very exciting inhibitor of the KRAS G12 cancer variant that is on path to enter the clinic this year and round out the first wave of clinical compounds from our collection. G12D mutations are the most common among RAS-addicted cancers, thought to serve as a primary driver of 55,000 new colorectal, pancreatic, or lung cancer patients each year in the US. RMC-9805 is a highly differentiated drug candidate. It is both potent and mutant-selective, benefiting from what we believe to be the first ever covalent engagement of the oncogenic aspartic acid in this clinically important variant. Like our other development stage acids, it is also orally bioavailable preclinically. RMC-9805 breaks new ground in medicinal chemistry. It uniquely engages the G12D variant covalently on the oncogenic aspartic acid residue. We believe it is the first known drug candidate to target any aspartic acid residue covalently. Like others in our collection, RMC-9805 is orally bioavailable in preclinical species, providing for active drug exposures that drive robust and sustained suppression of RAS pathway signaling. Suppression of the RAS pathway biomarker phospho-ERK in a tumor xenograft is evident in the top immunohistochemistry panels comparing samples from untreated and treated xenografts and is accompanied by induction of tumor apoptosis, as shown in the bottom panels. Here we're showing two interesting new experiments with a G12D bearing pancreatic cancer line and grafted into mice. Unlike typical subcutaneous grafts that can be followed by manual palpation, here tumor cells were implanted directly into the pancreas on the left as a representation of a tumor primary, or intracranially on the right as a representation of a CNS metastasis. In each study, the tumor cells have been marked with a luciferase gene that allows real-time monitoring, by non-invasive imaging. In the pancreas xenograft on the left, RMC-9805 administered orally suppressed tumor growth and induced regressions, as indicated in the curves, above left, or the images below it. Likewise, in the brain xenograft on the right, RMC-9805 administered orally suppressed tumor growth and induced regressions, as indicated in the curves above and the images below. These experiments demonstrate that RMC-9805 given orally distributes effectively, both systemically and across the blood-brain barrier, which may be important for treating metastatic CNS disease. We've also performed traditional subcutaneous tumor xenograft studies with 25 different lung, pancreatic, and colorectal cancer models carrying the G12D mutation. RMC-9805 administered orally again was broadly and highly active, as shown in these waterfall plots at end of study. Lung and pancreatic cancers were particularly responsive. Even colorectal cancer models showed high rates of disease control. Overall, RMC-9805 is a remarkable inhibitor of KRAS G12D. It is delivered orally, shows high potency and selectivity via covalent binding to the G12D ON state. It drives sustained tumor regressions and distributes into tumors both systemically and in the CNS. Our RMC-9805 development team is on track to begin clinical development mid-year. We've also tested RMC-9805 in immunocompetent syngeneic tumor models to determine its potential impact on antitumor immunity. As a single agent, RMC-9805, like RMC-6236 and RMC-6291 shown here, causes an increase in antigen presentation by tumor cells while also increasing T-cell infiltration and decreasing myeloid suppressive cells in the tumor, all of which are favorable effects on the tumor immune microenvironment. In many tumor-bearing animals, each of these agents alone induced durable tumor responses, as shown in these Kaplan-Meier plots. Moreover, a combination of any of the three RAS(ON) Inhibitors with an anti-PD-1 antibody prevented progression in 100% of animals over a 100-day observation period, accompanied by induction of immune memory in nearly all animals. We believe these findings are quite encouraging for combination opportunities with checkpoint inhibitors in the clinic. The first three RAS(ON) Inhibitors directed to mutations at RAS residue G12 represent our first wave of inhibitors for clinical development, and I've today provided an initial report on early clinical experience with RMC-6236 and RMC-6291 and progress of RMC-9805 toward the clinic. These compounds are our top priority, development programs for the near term. In addition, our second wave of RAS(ON) Inhibitors is in preparation for post-2023 clinical development. Today, I'll introduce you to our newest development candidate as part of this second group, RMC-0708, an exciting mutant selective inhibitor of the KRAS Q61H cancer variant. KRAS Q61H is less well-known but is found in approximately 10,000 new cancer cases in the US each year, divided evenly across lung cancers, colorectal and pancreatic cancers, and multiple myeloma. It is the fourth most common RAS variant in pancreatic cancer ahead of the better-known G12C mutation. RMC-0708 is highly potent and selective against KRAS Q61H, and it breaks new ground as our first mutant selective RAS(ON) inhibitor drug candidate to engage its RAS target non-covalently. Like other compounds we've described, oral administration of RMC-0708 pre-clinically achieves drug exposures and prolonged tumor residence that provide for effective and sustained target suppression. In lung and pancreatic cancer models carrying Q61H, daily oral treatment drove significant regressions and achieved sustained partial and complete responses. This compound now enters IND-enabling development. With this latest drug candidate, the fifth development-stage RAS(ON) inhibitor that we've described publicly, our portfolio contains assets directed to every RAS mutational hotspot. With the innovative RAS on inhibitors described today, we've updated the portfolio view of our targeted RAS drug candidates against human disease with a particular focus on pancreatic cancer, a devastating disease that is almost entirely attributable to mutations in the RAS family and for which treatment still depends on largely bleak and ineffective chemotherapy and surgery without targeted drugs. Current development-stage RAS on inhibitor drug candidates designed by our scientists cover virtually all of the RAS variants that cause human pancreatic cancers. In many instances, by both our RAS multi-inhibitor and a RAS mutant-selective inhibitor. We are interested in filling in this picture even further. With two compounds in the clinic, a third on its way, and a second wave in preparation for future clinical development, the prospect of converting pancreatic cancer broadly into a treatable disease is now a realistic possibility. Beyond RAS(ON) inhibitors that are core to our treatment visions, I mentioned that our strategy also includes developing specific RAS Companion Inhibitors, targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers and confer drug resistance. I'd like to update you briefly on two RAS Companion Inhibitors that are in clinical development. RMC-4630 is our potent selective and oral inhibitor of SHP2, a convergent signaling node that is believed to mediate some types of resistance to RAS inhibitors. Earlier, we showed that RMC-4630 is clinically active as a single agent. We developed an innovative intermittent dosing regimen that is the basis of ongoing clinical evaluation of combination treatment with a RAS inhibitor. In the second half of 2022, Amgen reported an initial evaluation of dosing RMC-4630 in combination with sotorasib in second-line treatment of patients with various G12C tumors in the US CodeBreaK 101 trial, showing that the combination of sotorasib and RMC- 4630 was safe and tolerable, and at the top two doses induced objective responses in three of four lung cancer patients not previously treated with a KRAS G12C inhibitor. RevMed continues conducting its global phase II RMC-4630-03 study of the combination in G12C lung cancer patients, and Amgen is supporting this trial with clinical supply of sotorasib globally. I'm pleased to report that this study is now greater than 80% enrolled, and we expect to complete enrollment shortly to enable a top-line readout later this year. Sanofi has been our global partner and main financial sponsor for the development of RMC-4630 since 2018. After conducting an internal review of its own pipeline priorities, recently indicated plans to withdraw from the collaboration and RevMed will regain all rights to the compound later this year. Finally, I'm able to provide a brief update on our phase I/IB study of RMC-5552, our innovative potent selective inhibitor of mTORC1 designed to reactivate the tumor suppressor 4E-BP1 that is downstream of mTORC1 and often inactivated in tumors with high levels of mTORC1 signaling. Our vision is to use RMC-5552 in combination with RAS(ON) Inhibitors in patients with tumors carrying both RAS and mTOR pathway mutations, representing some 30,000 new US cases per year. In the dose escalation and optimization phase so far, 28 patients with a range of different tumors and genotypes and treated with 6 mg or 8 mg IV weekly were efficacy evaluable. 20 achieved stable disease or better for a disease control rate of 71%. 13 showed tumor shrinkage, and one had a deep and sustained partial response. Multiple patients had favorable changes in surrogate disease markers. In particular, three of six patients with stable disease and oncogenic mTOR pathway mutations showed molecular responses indicated by a 50% or greater reduction in mean variant allele frequency in ctDNA on treatment. The patient with a PR was not formally evaluable for a molecular response by mean variant allele frequency but nonetheless showed a complete loss of the pathogenic PTEN allele. These radiologic and molecular data further indicate that RMC-5552 is clinically active and suggests a compelling profile as a RAS Companion Inhibitor. We're making good progress determining the optimal way to dose RMC-5552. We have growing evidence of antitumor activity and tolerability as a single agent and continue planning to deploy RMC-5552 as a RAS Companion Inhibitor in combination with RAS(ON) Inhibitors in patients with activating mutations in both pathways. Let's return briefly to the distinction I made earlier regarding RAS(ON) Inhibitors versus RAS Companion Inhibitors. These classes of compounds may not always be mutually exclusive. Recall that RMC-6236 inhibits essentially all RAS(ON) proteins, including normal RAS proteins that may help augment oncogenic signaling in tumors that have a mutant form of RAS as a primary driver. Shown here is an example of a lung cancer model containing KRAS G12C that shows only modest growth inhibition to either RMC-6291 or RMC-6236 as single agents, suggesting that this cancer line contains multiple underlying oncogenic drivers. Upon co-administration of RMC-6236 and RMC-6291, however, engrafted tumors showed significant regression, suggesting that there is at least additive or potentially even synergistic benefit for combining the two in some contexts. We intend to continue our clinical evaluation of RMC-6236 as a single agent, since in many tumor models, it showed sensitivity preclinically, but also as a RAS Companion Inhibitor in combination with RAS mutant-selective inhibitors. This completes today's review of our rich development stage pipeline of clinical and preclinical RAS(ON) Inhibitors and clinical RAS Companion Inhibitors. We believe that in aggregate, this collection of exciting assets, singly or in combinations, may be applicable to the majority of RAS-addicted cancers and initial clinical evaluation is proceeding. Further, our research organization continues its work toward producing new mutant-selective drug candidates to enhance this very strong pipeline. This year, we anticipate providing significant updates regarding five clinical programs as shown here. Financially, we ended third quarter with a strong balance sheet and project that our cash and investments can support company operations through 2024 under our current plan. As of today, drug candidates in formal stages of development at Revolution Medicines inhibit the drivers of all major RAS-addicted forms of human lung, colorectal, and pancreatic cancer, two drug candidates of which are now in clinical studies, with a third expected to begin clinical evaluation this year. We are highly encouraged that the era of targeted treatment for patients with RAS cancers broadly is within reach. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors and shareholders, and of course, the tireless efforts of RevMed employees in pursuit of our mission to outsmart cancer. Thank you very much. Thanks, Mark. As a reminder, just raise your hand if you wanna ask a question, we'll get a mic to you. I think I might ask a couple coming in from the portal here. I guess the first is really just picking up on your comments around dose escalation with RMC-6236, not having reached an MTD or yet defined the phase II dose level. Can you just sort of recap for us the dose escalation scheme and how many additional dose cohorts do you think you'll need in order to kinda be at a to be in range for, you know, arrive at a phase II efficacious dose? I think we're not gonna be able to give you much information on the second question, but we can certainly address the first question. I think Stephen Kelsey can come on up and talk about the design of that study. As I mentioned, we do now expect to be able to provide an update that would include initial clinical activity mid-2023. Maybe Steve can talk about the design of that study and dose escalation. Sure. There's nothing terribly unique about the dose escalation schema for the RMC-6236 program. It follows the ones that we've used previously for the SHP2 program and the mTOR program. As we dose escalate on a fairly conventional sort of paradigm, we tend to backfill the dose levels that are being cleared with patients who we think might be, you know, uniquely amenable to treatment with that agent. As we're grinding up through the dose levels towards the recommended phase II dose and schedule, we tend to enroll more patients in the study than we might have previously done sort of a decade or two decades ago. The other thing that Mark did mention, which is something that I think is inevitable, but not necessarily necessary, if you know what I mean. It's probably something that will have to be explored is alternate schedules. Because, I think that, you know, the preclinical data suggesting that the intermittency of hitting a RAS mutation is hard, particularly with a non-covalent inhibitor, has certain advantages with regards to the therapeutic index. That will definitely be explored. Whether or not it's necessary to do that or not, we clearly, we don't know at the moment. It was something that will be explored. That just adds a little bit of complexity to the ultimate, determination of recommended phase II dose and schedule. Any comment around the balance of histologies and RAS genotypes that you're enrolling into the RMC-6236 phase I trial? It's exactly as expected. You know, G12D mutations are very common. G12V mutations are the sort of second most common, and then there's a smattering of others. In terms of the histotypes, it's exactly what you would expect. I mean, the unmet medical need is enormous, and the sort of distribution of patients coming into the program is similar to the pie chart that we showed. Sort of reasonably equitably distributed across non-small cell lung cancer, colorectal cancer and pancreatic cancer. There are, you know, there's inevitably gonna be a couple of patients who fall outside of that bucket as the program gets bigger. Really, it just represents the need. The need is enormous. It is absolutely huge. Which also addresses, in part why the backfill strategy that Steve described is so important, is that we really wanna make sure we get enough sampling of within a given histotype and/or genotype to really be able to interpret that. That's not easy to do when you've got multiple histotypes and multiple genotypes coming in. The backfill helps that. It helps build a dataset. As you backfill, what kind of numbers, per genotype, per histotype make you comfortable that any signal that is generated is real? Yeah. No... [crosstalk] Realer. I think that's... [crosstalk] That's getting... [crosstalk] T hat's a difficult question for us to answer. I don't think we'll be able to give you an answer to that today. Yeah. I think the Supreme Court wants to find that. You'll know it when you see it. There's a question here. Hi, Mark. That's a great presentation. Apparently Revolution has the best RAS portfolio. Thank you. That's my personal opinion. I have a quick question on RMC-5552. That's mTORC1 inhibitor. I notice you're going to do the IV weekly, 6 mg, 8 mg. I'm just wondering, what's the case? You know, that's your preferred administration route, or would you consider oral dosing if you can? I mean, is there solubility issue with that compound? Yeah. Well, I think it's hard to argue that IV is the preferred route. You know, this is a very complex molecule. We just published a paper that describes that the medicinal chemistry behind it in great detail and, you know, it's an enormous molecule. I don't think oral bioavailability is very practical, realistically. Whether or not there might be some other parenteral form of administration, I think is sort of a TBD. Okay. Congratulations. Congratulations, Mark... [crosstalk] Thank you. T he team as well. It's very impressive. You know, I'm very intrigued by your data you're showing, the lack of, I guess, great activity in colorectal setting for different mutant or inhibitors of the different mutants. I'm curious whether, you know, now you have the multi as well, you show the interesting data combining the multi and the G12C. I wonder, you have done studies, you know, combining multi with the G12D and others in the colorectal setting. We do have some of those studies. The question, I guess I should be repeating the question is whether or not we've combined the RAS multi-inhibitor RMC-6236 with other mutant selective inhibitors in colorectal cancer, where clearly there's less monotherapy activity across essentially all RAS inhibitors. We have done some of those studies. We might have even put one of those experiments out at some point, but clearly that's something that's very much on our mind. You know, the colorectal cancers tend to be quite diverse in terms of mutations. Right. that can be present, it may be extremely important. In fact, I think it will be important to do combination strategies, as we've already seen so far in the G12C field. we're excited about RMC-6236 as a combination agent and was the point I was trying to make at the end there, that while we are pursuing it as this monotherapy, you know, single agent, and may well be useful in that regard, it may also be useful as a combination agent. Right. If you don't mind, another question on the G12C inhibitor. It's very exciting to see, right, you're trying to tackle the resistant patients from the off inhibitor. It looks like your initial strategy was going so after the treatment naive. Is that from the ongoing data, or is the priority of your study? Well, maybe Steve can comment on this. We remain very interested in the treatment-naive because generally we feel like if you can get in early with the most effective treatment, you might actually delay progression and have more benefit than if you wait until after somebody has an established resistant tumor. It's not our preference to start with those, but maybe Steve can elaborate on it. Yeah. As Mark said, the G12C space right now is extremely competitive. However, we are relatively fortunate at the moment in that the uptake of KRAS G12C off inhibitors outside the United States is relatively low. Opening sites outside the United States usually allows access to a very large number of patients with KRAS G12C mutant tumors that have not previously seen a KRAS inhibitor. I think that that's where the, you know, operationally, where we will be going. I think also the emerging genomic data from circulating tumor DNA studies does illustrate the huge number of mutations that arise in response to pressure on G12C from a G12C inhibitor. Interestingly, a large number of those mutations are actually either in signal through RAS, like receptor tyrosine kinase, other mutations in KRAS themselves. Those you would imagine could be amenable to inhibition with RMC-6236. Getting in early and doing those combination studies is high priority for us. Agreed. Yeah. Yeah, because the resistance is very diverse after the fact. Yeah. With that said, we should acknowledge though that in the early dose escalation with RMC-6291, which has been primarily here in the US, most of those patients have seen a RAS inhibitor before. That, as Steve was pointing out, will shift, over time as we get to... [crosstalk] Sorry, walking directions to find 24 patients. I think you said we could find 24 patients. I suppose. One last question. Sorry for putting us, you know, putting up other ones. Because I worked on like covalent inhibitors before, I'm really, you know, impressed with the G12D work. Can you comment on how much, you know, activity and selectivity is coming from covalently targeting G12D? Well, it's highly selective. We don't see it covalently binding to anything else. You know, the history of the field, it's probably a conversation to have offline, but the history of the field of covalency trying to go after something like an aspartic acid took everybody in the wrong direction by going to hotter, more reactive warheads, which then just blew out everything. We've been able to go just the opposite direction, which is really. Right. Because the ingenuity of our team and the Tri-Complex allows us to place the warhead in the optimal three-dimensional position relative to that aspartic acid in order to gain selectivity for that particular aspartic acid versus others. There's a lot going on in the compound, and it's really an exciting compound. Right. I was referring to the selectivity from the non-covalent interactions, because you still need very potent non-covalent interactions, right, with the... Yeah. Yeah. The initial binding is not selective. That's true. Although that binding is relatively transient and doesn't really end up being... [crosstalk] Okay. Particularly important. Great. Thank you. Congratulations again. Thank you. Mark, your most recent commentary on phase I accrual of the phase I study with RMC-6291 is sounds very encouraging. Has there been sort of a change in the level of interest in among investigators, potential investigators in that study? Have you seen a change in the pace of enrollment? You're talking about RMC-4630, the SHP2 inhibitor? RMC- 6291 G12C. Yeah. It's enrolling. I mean, a lot of investigators are quite interested in it, and patients are interested in it. I don't know if we've seen a change. That's a little bit hard to measure. You know, we have a good base of U.S. sites. We're opening up ex-US sites. I don't think we're having tremendous difficulty, even though we acknowledge it's a crowded space. One question that comes up fairly frequently when it comes to RMC-6236 is really just this question of treatment window, treatment index... [crosstalk] Mm-hmm. As a result of having some activity against wild type RAS. I guess how does one get comfortable that the treatment window is wide enough to support, you know, single agent activity in a manner that might be, you know, different from what we've come to know with SHP2 inhibition or MEK inhibition or other sort of non-mutation specific directed modes of inhibiting the RAS signaling pathway? Yeah. You know, I think of it more as a, as more like a, an EGF receptor antagonist that's not mutant selective, but in EGFR-driven tumors than I would a MEK or an ERK inhibitor. That's just been what the biology looks like, that inhibiting the direct driver of the cancer is materially different than inhibiting something that's a upstream or downstream regulator or effector. Exactly why that is a little bit hard to explain, but it does seem to be the pattern. Pre-clinically, when we compared RMC-6236 to any other pathway inhibitor in mutant driven tumors, it just is not comparative at all. I mean, they're just like black and white in terms of differences. Now how will we know that that is gonna happen in people? By testing it and developing the data, and that's what we're doing now, and so far, so good. We're seeing, good tolerability and no dose-limiting toxicities so far. Okay. A quick question on the combo of the RAS Companion Inhibitors. You mentioned about mTOR and the SHP2 and also SOS1 on that too. Just curious about your any comments on the other Companion Inhibitors on your slides. Right. specifically regarding SOS1. For example. Well, yeah. SOS1, we have a really good compound. We've essentially deferred development of it while we're getting our arms around some of these other assets. A SHP2 inhibitor is pretty active. We've got a lot of experience with it and before diving into something that's going to be quite similar in its behavior, we wanna figure out whether SHP2 inhibition actually delivers the clinical value in combination. We're prepared to do it, but we need to understand more about where we are with the other assets. You know, I think the trickier question is, with all these different combinations, how are we gonna decide which patients should get which combination? You know, we do have a strategy and if one sort of unpacks some of my comments and things Steve has said at various meetings, there are markers that would suggest why one should use one or another in a particular patient. It also has to do with line of therapy. If you're gonna be in front line lung cancer, you're gonna have to be able to combine it with a PD-1 inhibitor. If you're in a patient who has pathway mutations in both mTOR pathway and RAS pathway, that seems like the right place to be combining those two agents. If you're in colorectal cancer, it might make more sense to combine with RMC-6336 that can take out all of the other, the range of other mutations. There's gonna be some art to this, sort of figuring out the pattern to do it, but we think the biomarkers, will guide that. Okay, great. I think we'll have to leave it there for time. Thanks again, Mark and the Revolution team for presenting this morning.