Good day, thank you for standing by. Welcome to the Revolution Medicines Q4 and year-end 2022 earnings conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Peg Horn, Chief Operating Officer. Please go ahead. Thank you. Welcome everyone to the fourth quarter and full year 2022 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President of Research and Development, and Jack Anders, our Chief Financial Officer. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide of our corporate presentation or the press release, as well as all of the company's filings with the SEC concerning these and other matters. During this presentation, we will be referring to a number of slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer. Mark. Good afternoon, and thank you for joining us. Today, I'll provide an update on our company progress. Steve Kelsey will provide additional information about our RMC-6236 clinical program, and Jack Anders will provide highlights of our financial results. Revolution Medicines is advancing our pipeline of groundbreaking RAS(ON) inhibitors and RAS Companion Inhibitors on behalf of patients with a wide range of RAS-addicted cancers, setting up an exciting and data-rich year. We have advanced into clinical development the first 2 drug candidates from this highly innovative RAS(ON) inhibitor portfolio. RMC-6236 is a groundbreaking RAS inhibitor with the potential to treat all or nearly all RAS cancer patients due to its highly differentiated mechanism of action, facilitating broad activity across major RAS variants. RMC-6291 is the vanguard of our mutant-selective RAS(ON) inhibitor portfolio, which also includes our oral and covalent KRAS G12D inhibitor, expected to enter the clinic mid-year, and a second wave of inhibitors designed to treat a range of RAS mutant cancers. Together, the 2 phase 1 programs will provide key insights into the potential of each exciting drug candidate and initial information to validate our tri-complex RAS(ON) inhibitor platform as a whole. RMC-6236 and 6291 have been well-behaved so far in the dose escalation portions of the RMC-6236-001 and RMC-6291-001 clinical studies respectively. Both compounds have exhibited oral bioavailability, leading to increasing exposure levels with increasing dose, consistent with our preclinical projections. They've both been generally well-tolerated. We've cleared several dose levels for each compound with a once-daily dosing schedule. We have not yet reached a maximal tolerated dose or defined a recommended phase 2 dose for either compound. Today, we'll expand further on the findings related to RMC-6236 in particular. Momentarily, Steve Kelsey will share with you additional information coming from the RMC-6236-001 trial. You'll hear about initial pharmacokinetics, molecular and radiographic findings from the early stages of this study, supporting our belief that we are dosing this compound in a pharmacologically active range and observing antitumor activity consistent with clinical benefit with acceptable safety and tolerability. Although the data Steve will describe today are early, we believe these findings are quite encouraging for RMC-6236 itself as a drug candidate. They are insufficient to define the full profile and potential of RMC-6236, including response rates or long-term durability in any tumor type, which will require more data and time. Nevertheless, we feel these data are important as they significantly de-risk key aspects of our broad portfolio of multiple clinical and preclinical RAS(ON) inhibitors that all share a number of fundamental properties. Let me offer additional context by reminding you of some key elements regarding the compound RMC-6236. Our description of RMC-6236 as a RAS(ON) multi-selective inhibitor has three components. It is designed to bind selectively to RAS proteins. It binds to and inhibits all or nearly all forms of RAS, including every known oncogenic mutant and wild-type form we've tested. It binds RAS exclusively in the on or activated state, in contrast to first generation KRAS G12C inhibitors that bind RAS in the off state. 6236 shows high potency in cellular assays, inhibiting RAS signaling, typically at low nanomolar to subnanomolar concentrations and frequently driving deep and sustained RAS pathway suppression in RAS-dependent tumor cells. We've shown extensive preclinical evidence that 6236 induces deep and sustained regressions in diverse in vivo cancer models representing multiple tumor types and multiple RAS mutant genotypes, especially KRAS G12X mutants, a RAS inhibitor profile that is, to our knowledge, unprecedented. Overall, the design of RMC-6236 as a RAS multi-on inhibitor not only chemically and pharmacologically breaks new ground in the field, but also serves the bold biological goal of leveraging its ability to inhibit all or nearly all forms of RAS, including both the primary mutant RAS driver and normal or wild-type RAS forms, to maximally suppress RAS signaling overall in cancer cells that are addicted to RAS. A fundamental question being evaluated in the RMC-6236-001 clinical trial is whether 6236, with this biological profile, can be dosed in patients at levels that deliver clinical antitumor impact without also causing unacceptable effects on normal tissues due to the compound's intentional activity against wild-type forms of RAS that would also be anticipated in normal cells. The extensive preclinical evidence of dramatic antitumor activity in multiple animal models came from studies at dose levels that did not induce concomitant intolerability. The RMC-6236-001 clinical trial study is a first test of these aspirations for this drug candidate in patients. Steve Kelsey, our President of R&D, will present our first report of clinical experience with a RAS(ON) inhibitor RMC-6236. Steve? Thank you, Mark. As we've stated previously, based on extensive preclinical studies of RMC-6236, our working assumption is that the on-target effects of inhibiting wild-type RAS in normal tissues will ultimately determine the maximum tolerated dose in people. We have consistently represented that we believe RAS-mediated toxicities will be predictable, manageable, monitorable, and reversible. We have also presented preclinical data suggesting that the slower clearance of RMC-6236 from tumors compared with normal tissues may enhance the therapeutic index for RMC-6236 and contribute to achieving meaningful antitumor activity for tolerated exposures. Meaningful clinical activity includes both reduction in tumor size and durable inhibition of tumor growth, represented most frequently as progression-free survival in clinical trials. In the clinical program to date, patients have been treated in 5 dose cohorts ranging from 10 mg daily to 120 mg daily. To calibrate you, based on measured drug exposures in these patients, the 10 and 20 mg doses fall at the lowest end of exposures we evaluated preclinically and were associated with some degree of tumor growth inhibition in xenograft models. Drug exposures seen in patients treated at 40, 80, and 120 mg daily are similar to those associated with more significant antitumor effects in preclinical studies. These included dose-dependent tumor regressions and delay in time to tumor growth in in vivo studies of several RAS mutant cancer models. With these doses in patients, we haven't yet reached exposure levels achieved at the dose we studied the most preclinically. That is 25 mg per kilogram daily. 36 patients have been evaluated for initial safety and tolerability in the clinical trial so far. As shown in the table of drug-related adverse events on slide 11, treatment across all dose cohorts has been generally well-tolerated. Some patients have exhibited predicted on-target normal tissue effects, presumably due to inhibition of wild-type RAS. These are primarily Grade 1 or 2 skin rashes similar to those observed with EGFR inhibitors and a range of mild to moderate severity gastrointestinal toxicities, usually nausea or diarrhea. The frequency and severity seem to be dose-dependent and thus far have been manageable with standard supportive care. 1 patient required a brief dose hold for skin rash and resumed dosing at a reduced dose. Skin rash and gastrointestinal toxicity are recognized consequences of suppressing RAS signaling in normal tissues based on a wide experience in the field with other drugs and drug candidates, including EGFR, MEK, ERK, and SHP-2 inhibitors. Skin rash has been historically viewed as a biomarker of pharmacologic activity by some of these drugs. The clinical findings further support our belief based on PK data that we are achieving exposures of RMC-6236 in patients that are in an active range without inducing unacceptable toxicity. Among all 36 patients evaluated so far, 1 related serious adverse event has been observed. This patient with metastatic pancreatic cancer and a KRAS G12V mutation entered the study with extensive abdominal disease, including a large and deeply invasive tumor implant in the serosal wall of the large intestine. About 1 week into treatment at 80 milligrams daily, the patient experienced an unfortunate bowel perforation that occurred at the invasive tumor site, accompanied by radiographic evidence of tumor reduction at that location and other metastatic sites. No evidence or clinical symptoms of colitis or colonic ulceration were seen preceding the event or observed on subsequent imaging. Based on abdominal CT scans and the opinions of the clinical investigators, we believe that this event is likely attributable to shrinkage of the tumor by RMC-6236 in the heavily infiltrated bowel wall, even within this short treatment period, rather than to a direct toxic effect of RMC-6236 on the normal bowel wall. Similar events attributed to tumor shrinkage in the bowel wall have been occasionally described on treatment with BRAF inhibitors and with chemotherapy. We have treated patients with RMC-6236 in a higher dose cohort, 120 milligrams, without observing additional serious adverse events so far and expect to continue dose escalating even further towards a recommended phase 2 dose. Let me provide some information on the antitumor activity we have seen in the study. Consistent with study eligibility criteria, patients with a range of tumor types in which KRAS G12X mutations are common have been enrolled, including major epithelial cancers such as non-small cell lung cancer, pancreatic, colorectal, and other tumors including ovarian cancer, appendiceal, and bile duct cancers. The KRAS mutations in those tumors cover the range of KRAS G12 mutations, G12D, V, A, S, R, with D being the most heavily represented so far. This is consistent with the epidemiology of RAS mutations in human cancers. Patients enrolled in this study have been previously treated with a standard of care and or other regimens with an overall median of 3 prior therapies, as is typical for an oncology dose escalation phase 1 study. At the 10-milligram and 20-milligram dose levels, radiographic imaging showed either stable disease with some tumor reduction or disease progression as the best responses. Interestingly, in several patients at these lower dose levels, we have measured significant reductions in tumor variant alleles in ctDNA. For instance, in 1 patient with a KRAS G12V non-small cell lung cancer, treatment at 20 milligrams daily was associated with initial stable disease and 100% clearance of all RAS mutant alleles and all other concurrent tumor variant alleles. These earliest signs were consistent with our expectations at these low dose levels and were encouraging. We'd like to show you more detail regarding early and preliminary treatment-related activity at the 40 mg, 80 mg, and 120 mg dose levels. We're focusing on non-small cell lung cancer and pancreatic cancer since those are the two histologies most likely to be sensitive to a RAS inhibitor monotherapy based on the G12C experience. We will report on other tumor types, including colorectal cancer, in future updates. The waterfall plot of tumor volumes on slide 12 shows our experience so far with the 9 pancreatic cancer patients and 3 non-small cell lung cancer patients that have been treated at 40 mg daily or higher and are efficacy evaluable. All 12 of these patients have exhibited stable disease or better as their best response and remain on study from approximately 1.5-4.5 months as of the data cutoff date. 10 of 12 patients have shown some degree of tumor volume reduction by RECIST. 1 patient with a KRAS G12V non-small cell lung cancer achieved a partial response on first restaging scan and was subsequently confirmed with a follow-up scan. 1 pancreatic cancer patient with a KRAS G12V mutation also achieved a thus far unconfirmed partial response, a case study I will describe more fully in a moment. Even at this early stage with short follow-up, small patient numbers and doses below the anticipated recommended phase 2 dose, we believe that these data compare favorably with chemotherapy regimens for advanced pancreatic cancer, where disease control rates rarely exceed 60% and the response rates are low. The durability of disease control is of high importance for conferring clinical benefit and ultimately regulatory approval, particularly in advanced pancreatic cancer. Follow-up continues on all of these patients, as we've noted. In some cases, tumors continue to reduce in size beyond the first response evaluation. Let me now describe to you a particular case that is still ongoing and requires further data collection while the patient's treatment continues, but even at this stage provides a view into the therapeutic potential of RMC-6236. As described on slide 13, this patient is a 76-year-old male with metastatic pancreatic cancer harboring the KRAS G12V allele and associated gene copy number loss in tumor suppressor genes to CDKN2A and CDKN2B, as well as the associated putative tumor suppressor MTAP. After both neoadjuvant and post-surgical adjuvant chemotherapy, he developed metastatic disease in the lungs and progressed following a third course of chemotherapy. He received RMC-Six Two Three Six at 80 milligrams daily, which as noted earlier, we project to be in the mid-range for antitumor activity and is below the anticipated recommended phase 2 dose. The patient is tolerating the drug well. At baseline, the patient had three distinct lesions, one in the right lung and two in the left lung, that are being followed radiographically. These lesions are identified on the upper row of the three CT images on slide 14. All three lesions underwent significant reduction over 12 weeks of therapy. At six weeks, all three tumor lesions were reduced in size with an overall 17% reduction in tumor size by RECIST. On the 12-week scans shown in the second row of CT scans, target lesion one has disappeared and target lesion two is considerably reduced. The single non-target lesion is barely detectable. In addition, the density of the residual tumor has changed. RECIST quantifies response by measuring only the unidimensional longest axis for each target lesion and does not consider density or three-dimensional volume. As the first target lesion has been assigned a minimum measurement of 5 millimeters, this patient has formally achieved a 70% tumor reduction and a clear partial response by RECIST even though volumetrically, the reduction in tumor burden appears greater. He continues on study and the partial response needs to be confirmed with a follow-up scan. We must emphasize that it is too early to project the frequency or durability of responses or comparative results across tumor types and genotypes. The numbers are small, the dose levels are likely to be below the recommended phase 2 dose, and follow-up is short. Nevertheless, the totality of data across these 12 patients reinforces our growing conviction about the potential for RMC-6236 to exhibit promising clinical antitumor activity in patients with advanced RAS mutant tumors at doses that are well-tolerated. Now I will turn the call back to Mark. Thank you, Steve. The collection of data just presented is, to our knowledge, the first-ever clinical data to be presented on any inhibitor designed to target the on state of RAS, any RAS-targeted therapy used to treat a patient with a tumor bearing the KRAS G12D mutation, or any oral RAS(ON) inhibitor used to treat a patient with lung or pancreatic cancer bearing KRAS G12D or various other non-G12C mutations. While initial data from the patients described today are quite encouraging overall in terms of tolerability and antitumor activity in multiple tumor types with multiple RAS genotypes, and the case report shows a dramatic effect in KRAS G12D pancreatic cancer at a tolerated dose, we will need additional data to project response rates or durability in pancreatic lung or other cancers and across different RAS mutations at the recommended phase 2 dose and schedule. We show these early data today to illustrate what may be possible with a RAS(ON) inhibitor, as represented by the boldest compound in our collection with arguably the greatest a priori therapeutic index risk profile, and we will continue to develop more clinical information. These findings are quite encouraging about the ability of a rationally designed tri-complex RAS(ON) inhibitor to be taken orally, for it to exhibit drug-like pharmacokinetics, and for the tri-complex mechanism of action to drive inhibition of RAS(ON) proteins and confer promising antitumor benefit in patients without being accompanied by extraordinary toxicities. We confirm our intention to provide a more detailed public update on RMC-6236 mid-year, including further follow-up from patients described today and information we expect to collect from additional patients in the dose escalation phase of the study. Let's briefly touch on RMC-6291, our mutant selective KRAS G12C(ON) inhibitor for which we also have some early experience that allows us to build on the earlier comments about general drug-like behavior and tolerability. Based on initial PK molecular data, that is ctDNA, and radiographic imaging data, that is serial CT scans, we believe that we are also dosing this compound in a pharmacologically active range and so far with acceptable safety tolerability. We plan to provide a more substantive update in the second half of this year. Based on the aggregate early evidence from the RMC-6236 program as updated here and initial experience with RMC-6291 I summarized briefly, we believe these findings serve as growing validation of the distinctive chemistry, pharmacology and biology and therapeutic vision for our RAS(ON) inhibitors more broadly. Much more information is needed for more definitive conclusions to be drawn about each individual drug candidate, which we expect will be forthcoming over time. We believe the information we've shared, intended to represent our experience with 2 RAS(ON) inhibitors so far, increases the probability of success for these 2 assets and may well read through to other assets we are developing. Next up in our RAS(ON) inhibitor collection is our mutant selective inhibitor of KRAS G12D, the most common RAS variant causing human cancer, RMC-9805. This compound that we introduced last year is administered orally, engages the on form of KRAS G12D, and executes a covalent attachment selectively to the oncogenic aspartic acid. IND enabling work remains on track toward our goal of beginning clinical evaluation of this exciting compound in mid-2023. Last month, we also introduced a new RAS(ON) inhibitor drug candidate. RMC-0708 is an oral mutant selective non-covalent inhibitor of KRAS Q61H. It has now entered development to prepare it for clinical evaluation after the first wave of RAS(ON) inhibitor drug candidates, that is RMC-6236, RMC-6291, and RMC-9805. It represents the fifth drug candidate we've disclosed in our portfolio of RAS(ON) inhibitors. We have now described both RAS multi and mutant selective drug candidates directed to each of the three common mutation hotspots in RAS proteins. Finally, let me provide brief updates on two clinical stage RAS Companion Inhibitors in our portfolio. RMC-4630, our SHP-2 inhibitor, continues under study in patients with KRAS G12C non-small cell lung cancer in combination with sotorasib in our global Phase 2 trial RMC-4630-03. The study is fully enrolled now, and we continue to expect to read out top-line results in the second half of 2023. RMC-5552, our mTORC1 selective inhibitor, continues under study as monotherapy in patients with tumors carrying mutations associated with hyperactivation of mTORC1 signaling. We expect to provide a more detailed update from this study later this year, and our aim is to bring it together with one or more RAS(ON) inhibitors to test as combination treatment in patients with tumors harboring both RAS mutations and mTORC1 pathway activation. Now I'll shift to our corporate progress and comment on our priorities for 2023. With a strong balance sheet, we entered this year with an explicit focus on the timely execution of the multiple development stage activities currently underway, with our highest priority being to deliver on important clinical milestones in the year. We continue deploying our development resources primarily to ensure we meet the goals of our first three most advanced RAS(ON) inhibitors, RMC-6236, 6291, and 9805, and two clinical stage RAS Companion Inhibitors, RMC-4630 and 5552. While interim in nature, we at Revolution Medicines view the information shared today as quite important and impactful on our own assessments of technical probabilities of success. With greater confidence that our innovation engine is delivering assets that deserve to be progressed and can earn the right to be deployed on behalf of patients, part of management's bandwidth is now directed toward defining the paths and steps we need to take now and over the next several years to ensure that we can maximize the value of these exciting product candidates and others in our growing portfolio. Building on this momentum, I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack? Thank you, Mark. As shown on slide 34, we ended the year with $645 million in cash and investments, which is expected to fund planned operations through 2024 based on our current operating plan. Revenue from our collaboration agreement on SHP-2 inhibitors with Sanofi was $15.3 million in the 4th quarter of 2022, compared to $9.5 million in the 4th quarter of 2021. The increase in revenue was due to a $7.6 million non-cash adjustment related to the acceleration of revenue resulting from the termination of the Sanofi agreement, which has an effective date in June 2023. As a result of the termination of the agreement, we adjusted our estimates of the accounting transaction price and estimated percentage of completion of work performed to date, which resulted in a cumulative catch-up adjustment that increased collaboration revenue in the quarter. Collaboration revenue for full year 2022 was $35.4 million. Total operating expenses for the fourth quarter of 2022 increased to $77 million, largely driven by R&D expenses, which totaled $66.1 million. Total operating expenses for full year 2022 increased to $293.7 million, with R&D expenses increasing to $253.1 million. The increase in total operating expenses in 2022 was primarily due to the advancement of RMC-6236 and RMC-6291 into clinical trials, as well as an increase in personnel-related expenses related to additional headcount, an increase in research expenses associated with the company's preclinical research portfolio, and an increase in stock-based compensation. Net loss for the fourth quarter of 2022 was $56.5 million or $0.63 per share. For full year 2022, net loss was $248.7 million or $3.08 per share. Turning to financial guidance for 2023, we expect full year GAAP net loss to be between $335 million and $365 million, which includes estimated non-cash stock-based compensation expense of $40 million-$50 million. The increase in expected GAAP net loss for 2023 is a result of increased expenses associated with the advancement of our RAS(ON) portfolio and a decrease in expected collaboration revenue. With that, I'll now turn the call back over to Mark. Thank you, Jack. We are highly encouraged with the progress of our rich development pipeline, particularly by the body of clinical evidence developed so far that provides initial validation of our RAS(ON) inhibitor platform and is described here, promising early evidence that RMC-6236 can be dosed in patients to induce significant antitumor activity without unacceptable side effects. We look forward to sharing further information on our collection of exciting clinical and preclinical assets throughout the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors and shareholders, and of course, the tireless efforts of Revolution Medicines employees in pursuit of our mission to outsmart RAS-addicted cancer. This concludes our prepared remarks for today. I'll now turn the call over to the operator for the question-and-answer session. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from Jonathan Chang with SVB Securities. Your line is now open. Hi, guys. This is Hasan Ahmed for Jonathan. Wanted to ask, you reported on those 12 patients, who were treated at 40 mgs and above with lung cancer and pancreatic cancer. What's the denominator on that number? Like, how many patients were treated there, as in, like, how many were excluded for being non-evaluable, or how many were excluded for having another tumor type? Steve, do you want to comment on it? Sure. We didn't report on the patients treated at 10 and 20, basically because there's really was no evidence from the preclinical models that we were gonna be anywhere near the exposures required to see anything worth reporting, to be honest with you. The actual data is restricted largely to reductions in ctDNA, and we haven't reported on the colorectal cancer patients at all because it's a completely different disease. There is no precedent right now for a RAS inhibitor being effective as a single agent in RAS mutant colorectal cancer. It is quite likely that we will compile information on the colorectal cancer patients as it reaches critical mass with a view to putting together a more comprehensive strategy for the treatment of patients with RAS mutant colorectal cancer, RMC-6236. Essentially, the data that we're showing you right now is the data that we're showing you, and all of the rest of the data will be in the more formal update in the middle of the year. Please stand by for our next question. Our next question comes from Michael Schmidt with Guggenheim Partners. Your line is now open. Hey, guys. Thanks for taking my questions. It sounds like the preclinical data has been pretty predictive as it relates to dosing ranges and, you know, some of the dose response, et cetera. Based on that, I guess, Mark, what is your prediction what the MTD might be in this study, and how much more room to increase dose, do you think you'll have on the phase one study here? Hi, Michael. Thanks for your question. You know, I think we just don't know how steep the curve will be in humans. I think that's the point of the experiment right now. You know, we're clearly below what's likely to be the recommended phase 2 dose. I think my sense is from all the discussions we've had internally, that it's the sort of thing that you'll know it when you see it. I don't know if Steve wants to add any more color to it, but I would just wanna confirm, I think that the preclinical data have been very predictive of what we've seen in humans, and we try to convey that sort of in a soft way, you know, back in January, but now we're providing concrete data to support that statement. Steve, anything to add? No. I mean, other than that, as you can see from the adverse event table that we've included, the tolerability profile right now, even at 120 milligrams daily, is pretty benign. I think Mark is correct in that at some point we are going to be hitting wild-type RAS in all tissues at a point which will make the compound or the dose intolerable. It's really hard to predict how high we can go there. You know, just to be clear, I mean, we dose mice at 25 milligrams per kilogram daily routinely, and that's because if we increase to 40 milligrams per kilogram daily, we saw some intolerability. Right now, you know, we're dosing way below the equivalent of mirin equivalent of 25 mgs per kilogram daily. We think that's a reasonable amount of headroom left to go, but it's very difficult to say exactly how much. It sounds like you have some additional upside on the dosing. I guess when we think about, you know, read-through of this data to your mutant selective KRAS inhibitors, where I guess one would expect less on target toxicities, you know, how should we think about that, you know, in terms of the dosing ranges? I guess, you know, how much wider would one expect the therapeutic index to be as it relates to that? Well, we fully expect the therapeutic index to be wider with the mutant-selective inhibitors, sort of by definition if it's not wider, if they're having well outside RAS effects, then they're not being selective. You know, there will be a wider therapeutic index. I think as we talked about before, meaning ultimately the issue isn't therapeutic index, it's how high can you dose and what's the absolute impact at that dose level. It will all converge around 1.0, as you and I talked about before, because that's the point of MTD, you know, dosing. I think just to go back to the big picture, we're obviously quite encouraged by a significant level of antitumor activity that we've seen at, as Steve Kelsey described, a very well-tolerated dose range. Although this is below the 25 mgs per kg that we use as our standard dosing advice, it's not below dose levels that we know should have antitumor activity. It's actually quite consistent with our collection of preclinical data. We're quite encouraged about it. But I think the mutant-selective inhibitors one would expect to be have much more flexibility around dosing. We think of RMC-6236 as sort of the highest risk molecule from that perspective. Today's information, you know, in our view, substantially lowers our calculation around that risk profile. Yeah. Great. could you, when you're looking at the waterfall chart on slide 12, could you just comment on the response kinetics? You know, did you see these, you know, responses early at the first scan? You know, did they happen later? Did they deepen over time? How should we think about that? Yeah. Well, there is a row across the bottom that says most recent scan, and that was designed to give you the information of what the bar represents. You'll see that, you know, it varies. Some of them are in cycle 3, day 1, which would be the first post-treatment scan, and others are at cycle 5, day 1. I think the case that Steve described is pretty informative there, where on the first scan, which would've been cycle 3, day 1, it was an aggregate 17% tumor volume reduction by RECIST criteria. Although the scan looks a little more impressive than that's what it was. By cycle 5, day 1, you know, it's pretty clear that the tumor is nearly obliterated across all 3 of those lesions. That score is RECIST, you know, in the 70% range, and probably in terms of tumor content is far more than a 70% reduction. You know, that's what we have. That's what we're seeing so far. As we get to higher doses, possibly it will take fewer cycles to see that, who knows? It might also just be the kinetics of the tumors. That's the sort of thing we need more information on to be able to give a more precise answer. Right. Just in terms of the study conduct going forward, do you plan to enrich for certain tumor types, perhaps lung cancer and PDAC, or are you still continuing with the all-comers approach at this point? Well, I think as we've described it, publicly, and I think we'll stay with this, is that the backfill patients really give us the greatest opportunity to put a finger on the scale, if you will. Clearly we're showing you some information that we think is exciting and the investigators think is exciting. I would imagine you'll see more of some of these patients, you know, in the backfills. There's always this tension, and I know you and I have also talked about this before. There's a tension between wanting to sample across tumor types and genotypes because that's important information too, versus wanting to get a deeper data set in a smaller number of tumor types and genotypes. I think in a sense it's sort of playing out the way the epidemiology would predict. We end up with a larger data set with G12D and in pancreatic cancer, not surprisingly. We'll continue enrolling patients across these, eventually with some enrichment by the investigators. Yeah. All right. That makes sense. All right. Well, thank you for taking my questions and congrats on the data update today. Thank you. Thank you. Please stand by for our next question. Our next question comes from Marc Frahm with Cowen. Your line is now open. Hi. Thanks for taking my questions, and congrats on the data and, you know, seeing that RMC-6236 is active in the clinic. maybe just to follow up on one of the earlier questions to start. Steve, I think there's 20 patients, dosed at 40 milligrams and above in the AE table, and then there's 12 in the waterfall plot. Can you just explain those incremental AE patients? It sounds like maybe a few of them are colorectal cancer patients that, you know, you just don't have enough to talk about monotherapy with. Then, you know, are there more patients who are just on study but haven't been scanned yet versus people who may have dropped out before the first scan? Yeah. There's far more patients on study that have not yet been evaluated for efficacy than there are patients with colorectal cancer. You know, I was deliberately vague about these, the other histopaths, but that's because we will, you know, provide an update later in the year which addresses that. The reality is that the discrepancy is due to the speed at which this study is enrolling and the fact that patients have to be on study for 6 weeks before they get their first scan. If you enroll a whole bunch of patients within the last 6 weeks, they are evaluable for safety, but not for efficacy. Yeah. Well, that's the key point there, Marc, is that they're on the table for adverse events, or they're considered as part of that calculation once they start dosing. They need to be on study for 6 weeks before you get a scan. Okay. Thanks. That's helpful. Maybe just to the point of the preclinical modeling being pretty predictive. I guess, one, you know, given the exposures you're seeing so far, I guess, what dose level do you think might be equivalent to that 25 milligrams you tested mostly? Also kind of related to that, is there any sign preclinically that G12D alterations might be, you know, maybe modestly more sensitive than the other alterations and make sense that they would start responding first? Or do you think this is just kind of the noise in the system of seeing a lot of different tumor types and a lot of different mutations? On the second question, not so much. I mean, when we I think we shared data on the G12X versus non-G12X in various presentations, not necessarily corporate, but at some of the scientific meetings, we've given a further breakdown. Without any doubt, the G12X as a group showed enrichment for higher sensitivity on average. You start to get into fairly small numbers trying to compare D to B to A to S. You know, in some cases, we only have a couple models of one particular genotype or another. I don't think we can say that today. I don't think we would conclude that D is more sensitive in the waterfall. It's just not enough. You know, 9 out of or 8... 8 out of 12 are D in the waterfall plot, 3 are B and 1 is A. It's just really no way to determine sensitivity from that yet. We need to collect more information. Your first question was? What dose will we get to? What dose will we get to? Yeah. How does it match up? What dose, you know, Given the exposures you've, you know, you've got a fair amount of clinical exposure data now, to start building the human model, not just the extrapolation from animals. You know, based on that kind of, where does that 25 milligram animal dose fall on the pyra-- Is that, you know, 240? Is it 400 milligrams? Higher than 120, I think is what we should, is what we can share today. We'll give you that information. It's not, you know, it's not 10 miles away. I think we'd rather give that to you in the context of showing PK curves and by then we'll have more information. It just seems, you know, potentially misleading to sort of give you a projection that's not showing you the data to go with it. I think we'll stay with where we are. Okay. That's very helpful. Completely understand your points in your prepared remarks about, you know, it's pretty early to. It's too early to be talking about, you know, specific response rates and efficacy and, you know, individual tumor types or genotypes. Do you think you'll be in a position to start saying that for some tumor types and genotypes in the middle of the year at that update? We hope so. You know, I mean, that's an ambition, that's a hope. Okay. You know, of course, it's a matter of opinion, but just seeing, you know, 10 out of 12 patients at 40 milligrams above showing some degree of tumor volume reduction with some clear evidence that more time on drug, you know, gives you a greater chance at actually hitting a PR threshold, is quite encouraging. I just... It's hard to say, and I feel like anything we say here probably will not be rewarded with- Yes. with anything positive. In the spirit of not to break into jail, I think we'll just stay with where we are. Okay. Fair enough. Thank you and congrats again. Thank you. Please stand by for our next question. Our next question comes from Eric Joseph with J.P. Morgan. Your line is now open. Hi. Good evening. Thanks for taking the questions. On the 20-milligram cohort, with it being larger than the others, I just want to confirm that that's a result of backfilling and that there wasn't necessarily some kind of a safety event that triggered a further expansion of that cohort. Then maybe just secondly, can you sort of state where you are right now in terms of further enrollment of the 120 milligram cohort? If you do in fact proceed through further dose exploration, would you kind of move through, you know, 40 milligram increments as well? Steve, I guess you have the first question. Eric, it's a combination of two things. One is, there were a few patients that were backfilled after the escalation to 40 milligrams, but we also built in a food effect study at that dose level. Six of the patients were in a food effect study. We don't have the results yet from the food effect study, but the patients have been enrolled at that dose level and have been evaluated for safety, which is why the denominator for that dose level is somewhat larger. The 120 milligram dose level is fully enrolled and it'll read out, we'll know shortly whether or not we can dose escalate to the next dose level. That dose level, by the way, is determined by a conversation between us as the sponsor and the investigators. I'm not really in a position at the moment to tell you what that dose level will be. It will be some sort of similar increment, 160 or 180, something in that range. Okay, got it. I guess if we're just trying to prepare ourselves for the scope of the readout that you're planning for mid-year, I guess any sort of rough guidance in terms of additional patients you would expect to have accrued to the trial and, I guess additional follow-up that you'd want to have for the evaluable patients that you're describing here today? Well, there's clearly gonna be additional follow-up on all these patients. I mean, you'll get more information on whether or not. Well, firstly, there's a bunch, as I said, there's a bunch of patients that have been enrolled that haven't yet been evaluated for efficacy. We'll have that. There'll be more durability data, hopefully, for the patients that are currently on study. You know, as Mark said, the investigators are beginning to lean into the selection of patients for this study. It's heavily biased towards non-small cell lung cancer and pancreatic cancer. The epidemiology of that means that around half of them are gonna have a G12D mutation. Probably a third of them are gonna have a G12E mutation. The rest will be a scattering of other things. I would expect there to be a substantially larger database predominantly focused on pancreatic cancer and lung cancer, with G12D and G12E being the major mutational forms that we report on. Yeah. I would just say, Eric, we have discretion about when we do this mid-year update. You know, mid-year isn't a date or a time, it's just kind of a time of year. It's a, it's a season. You know, obviously we're giving you some information now, which wasn't necessarily contemplated previously. We're gonna collect some more information. We're gonna try to make the next update, you know, a meaningful update incremental to this. There's no sort of prescribed formula, which is why asking us, you know, more about what we'll have, you know, we'll have more patients and we'll have more follow-up, that's for sure. Mark, with that comment, I take it that you're not necessarily targeting presentation at one of the, at a major scientific meeting. Perhaps there's some expectation that you guys would look to present at ASCO. Well, as I pointed out previously, we did not link this specifically to a scientific meeting or not. We've left that unspoken. If we do a scientific meeting, we may still have a corporate session. If we don't do it at a scientific meeting, we'll probably sell the corporate session and then do a scientific meeting after that. It's sort of all of the above are in play here. Okay, great. understood. Thanks for taking the question, guys, and congrats here. Please stand by for our next question. Sure. Thank you. Our next question comes from Chris Shibutani with Goldman Sachs. Your line is now open. Hi, everyone. This is Charlie on for Chris. Thank you so much for taking our questions and congratulations on the data thus far. Just real quick from us regarding the 120 mg dose cohort. Just wondering if you can give us a sense of how long these patients have been at this dose level and being dosed at this level. I understand that it's probably at a lower, on the lower end of the range of duration of therapy that you guys gave us some color on there. Just trying to get a sense of how long they've been on drug. Also if you can give us some, a sense of the kinetics with the appearance of adverse events such as rash, like how long does it typically take for the rash to show up? Is there the potential for the severity of rash to increase over time in subsequent cycles? Thank you very much. Let me address the second question first, because it's a more concrete question for which we actually have data. The time to onset of rash is between 1 week and 2 weeks into dosing, depending on the dose being used. The higher doses, it tends to start sooner, but not usually before 1 week of dosing has been completed. The severity does not increase over time. In fact, if anything, it either stays the same or improves. We have had reports of patients whose rash has got better with just persistent dosing. We have reports of patients whose rash remains unchanged and is easily manageable with cream and, you know, just like putting up with local treatment. It, you know, these rashes are very much like EGFR associated rashes in that they occur in different parts of the body in different people. Sometimes it's just the face, sometimes it's just the arms or the trunk. Nobody seems to think that it's terribly, you know, terribly debilitating. We've actually only had one patient who had to stop for a couple of days and then restart. That wasn't actually because of rash, it turns out. It was because of an associated urticarial itch that was associated with, that seemed to accompany the rash. I think, you know, That's pretty much all I can tell you at the moment. Then in terms of the duration on 120 milligrams, I think the only thing we can fully tell you is that the 3 patients who are on that waterfall plot, you can see that the bar that's shown there is associated with the first scan. Got it. Thank you so much. If I could just sneak one more- Yeah. Yeah. Understood. That makes sense. Thank you. If I could just sneak in one more. Just based on the safety profile that you're seeing thus far, are you still considering the potential for intermittent dosing in the future, or has this given you more confidence for the potential for just the once daily? Thank you so much for taking our questions. Yeah. Thank you, Charlie. Appreciate it. I think we're very much where we were, you know, in January when we commented on this, that we're feeling quite encouraged by the once daily dosing. All of the data we're showing you here is based on once daily dosing. We've gotten away with it quite well, with very good tolerability and safety profile and clear evidence of antitumor activity. It's not looking to us as if intermittent dosing is on a critical path to defining our first recommended phase 2 dosing schedule for monotherapy. With that said, we also indicated in January, and I think we'll stand by this, we're likely to test an intermittent dosing schedule. It's not our highest priority at the moment. To the extent that we can move forward with monotherapy on a daily basis, we want to do that. We would want to determine at some point whether we're leaving anything on the table in terms of potential clinical benefit. So far it doesn't appear to be so. Please stand by for our next question. Our next question comes from Benjamin Burnett with Stifel. Your line is now open. Hey, thank you very much. I wanted to ask about the patient that you just mentioned. The one patient that stopped treatment due to an itch, but then was restarted. Can you comment if were they restarted at the original dose? Also, how long did they pause dosing? I think I'm just going from memory with them, so forgive me if what I say subsequently turns out to be slightly inaccurate. My recollection is it was only for a couple of days that they actually stopped dosing, and then when they restarted, they started at a dose level below the one that they had originally been on. That patient remains on study. Okay. Okay, that's helpful. Thank you. Then just going back to, can you comment on what the median follow-up time is in the adverse event table overall? It's really short. I mean, the median is really short. I would have thought, right. It's, we haven't actually formally calculated it, but I would be surprised if it was in excess of a couple of months. Okay. Okay. Just straight off, for the record, since we haven't calculated it. Yes, we haven't. No, we haven't. No, we really haven't calculated it, but it's really short. I think the, you know, the data that we're showing you is deliberately a very preliminary snapshot of what we're seeing and not something that we can necessarily claim will persist over time. That's helpful. Okay. You know. It's also fair to say that in the 40 mg-120 mg group with pancreatic or lung cancer, they're all still on study. Oh, yeah. No, they're all the patients that have been evaluated for efficacy are all on study. The lung and pancreatic cancer patients that we evaluated are still all on study. Okay, that's great. I also wanted to ask, going back to that intermittent dosing conversation, you know, is there Can you frame the level of toxicity that's tolerable and is it likely to be different in different indications? Like could there be a scenario wherein you may have intermittent dosing for CRC or for, you know, certain tumor types but not others? Not so much because of differences in tolerability, but there could be differences in sensitivity across tumor types. I think that was really the point about not wanting to leave activity on the table. I just realized the metaphor is you wanna leave it all out on the field, but you don't wanna leave anything on the table. It makes those two metaphors. You know, one can imagine that there may be some benefit in some settings to if you can achieve a higher dose intensity for particular tumor types, or if there's a particular combination in which that's particularly logical to do. I mean, we're out really over our skis for my third metaphor, just to say anything like that at the moment because it's just not what we're experiencing. By the way, pre-clinically, as you know, the vast majority of what we showed was on, was daily dosing, admittedly in a mouse with different pharmacokinetics. Nonetheless, we had target coverage for 24 hours a day and we were able to do it. What's happening in humans seems to reflect that at least, you know, within the limits of what we can detect so far. Interesting. Okay. Okay. Thank you. I think it does contrast with, you know. I think it does contrast. Maybe I have one other bit of color here since we're amongst the groups that have spent years studying a SH2 inhibitor. It does contrast significantly with the SH2 inhibitor experience, where in humans really to get the kinds of overall dose intensity that we felt would be needed, it was mandatory in our view to go to intermittent dosing. Pre-clinically, the antitumor activity, even at the best optimized SH2 inhibitor schedule and dose just didn't wasn't in the same league as for RMC-6236. There just seems to be little question that inhibiting RAS is far different from inhibiting something upstream or downstream of RAS. As like the guiding light here, is that just, is it really like the PK and are you achieving the concentration thresholds that are needed, or is it really about efficacy? I think the guiding light here is how much efficacy can we get at a tolerated dose. So far we're encouraged by the efficacy signal we're seeing so far at tolerated doses. I mean the PK is not gonna make a decision for us. It's gonna be the clinical outcomes. Yep. Okay. Okay. Thanks so much. I appreciate it. Thank you. Please stand by for our next question. Our next question comes from Alec Stranahan with Bank of America. Your line is now open. Hey, guys. Thanks for taking our questions. Congrats from me as well on your initial responses. Interesting that the 2 PRs are G12D. Could you give us a sense of the G12X makeups for the other 10 patients in the FK group? Was it entirely G12D and G12C or something else? Well, there's no G12C patients in this study. Right now those patients are all being channeled into our KRAS G12C inhibitor study, RMC-6291. The patients in the group overall really cover the full range of KRAS G12 mutations and the ones on the waterfall are indicated. You can see that there are really only three types here, G12V, G12D, and G12A. If I'm counting correctly here, there are 1, 2, 3, 4, 5, 6, 8 of the 12 have G12D mutations. That just, I think is completely consistent with the epidemiology of the KRAS mutations in these particular histopaths. Got it. That's helpful. Just to follow up, thinking through the balance of safety efficacy, you know, you said your goal is to maximize responses. Would this be through the lens taking this forward as a monotherapy, or would you take a hit on efficacy at a lower dose if safety is good with an eye towards combinations? Since I know you've shown in the past some pre-clinical data combining 636 with anti-PD-1. Yeah, that's a great question. I don't think we're there yet. I just don't think that we know enough about the tolerability profile or what's going to be dose limiting to know whether either, you know, to know at what level of toxicity we would be prepared to tolerate as a single agent or indeed in combination with anything. It's really too early. I would say it's a very reasonable question, but it's just one which we don't have an answer to right now because as you know, toxicities are not all created equal, you know. I mean, some toxicities are very well managed and easily tolerated, and some are absolutely horrible and unpleasant and are gonna be clearly dose limiting. We're just gonna have to keep dose escalating and following these patients to see what happens. With a view to maximizing the dose for response, that's not actually the primary. It's not the primary driver here. The main driver is durability. We're looking for durability because there are only two approvable endpoints that are gonna make people prescribe this drug. One of them is progression-free survival, and the other is overall survival. A response rate per se, without either of those two things is not particularly helpful for patients. We're really looking for. We're really looking not just for tumor shrinkage, but the durability of that. Yeah. I thought that I had just one small point. Yeah, one small point. You know, on the combinations, we've shown data that RMC-6236 can combine with, for example, RMC-6291 effectively at a dose lower than the dose that we typically use for monotherapy studies in the mouse. We have a lot of flexibility in the combination realm. Determining the recommended phase 2 dose for monotherapy doesn't necessarily dictate the limits of what we can really do pre in combinations where we may lower the dose impact and sure, in a combination study, we'll start with a lower dose. Okay. Okay, that makes sense. Just on the duration versus ORR point, it sounds like the midyear update, you know, the median follow-up's just not gonna be long enough to get to that duration question, and it's gonna be more about just the gross responses, correct? I can't answer that because we don't really know. You know, again, no, all 12 of these patients are still on study, and, you know, in pancreatic second-line cancer, one doesn't have to wait 18 months to find out whether or not you've got a drug that's active compared to standard care. I think one has to really talk about individual indications in order to know what the reference, you know, the benchmark is for that particular indication. Okay. Okay, one last quick one, if I may. Just on the differences between RMC-6236 and RMC-9805 as it relates to the binding to KRAS G12D, you know, whether it's covalent inhibition or another aspect that you think could result in different clinical profiles beyond just the therapeutic window that was mentioned before. Right. Well, you know, it has the differentiating feature that it is selective for G12D. It forms a covalent but selective bond with the G12D RAS, and hence it is basically irreversible. RMC-6236 is non-covalent. It's reversible. Its binding will go up and down with whatever the plasma levels are or the intracellular concentrations are at that minute in time. The trade-off is you capture the activity against a wider range of RAS proteins that might be part of the overall oncogene addiction for a RAS tumor cell. There are trade-offs between those, and I think it's just really yet to be determined which of those is more favorable. Obviously, overlaid on top of that is tolerability, how much dose can you give, et cetera. I just think it's too early to be making projections about, you know, which is better. You know, I tend to think that RMC-6236 may be the mother of all RAS inhibitors, but for us to be effective in treating all RAS cancers, we're probably gonna need a whole family of RAS all inhibitors, and that's why we design our portfolio the way we did. Okay. Thanks, and congrats again on the progress. Thank you. Please stand by for our next question. Thank you. Our next question comes from Ami Fadia with Needham. Your line is now open. Thank you for taking the question and the data. My first question is just around how to interpret sort of evolution of response with duration of treatment. If I'm reading the chart on slide 12 correctly, some of the patients who were somewhere in the chart are cycle 7, day 1, on stable disease. Mm-hmm. There are the last 2 patients in that chart, which are cycle 5, and they seem to have shown a response rate. I'm just trying to understand. Those patients in cycle 7 clearly were on treatment longer. Is that a fair way to look at it? You know, overall, is this just too short of a duration for us to really interpret, you know, responses over time? We definitely need more data, and we need more time on study to collect those data. You're right. That lung cancer patient who shows cycle 7, day 1, that means that patient has been on long enough to have likely a 3rd scan. That's what cycle 7 would be. Cycle 7, day 1 would be a 3rd scan. That patient at 40 milligrams, if I'm interpreting this correctly. Yep. that we're talking about the same patient. Yeah. Has stable disease with some tumor volume reduction, but not a PR. We don't know if they'll go on to achieve a PR. We're not trying to imply that they will or won't. We don't know. We'll have to follow them. I don't know how else to comment on it. I don't know. No, I mean, I think that you know, directionally you are correct in inferring that whether a patient has a response by RECIST is a function of both dose and time on treatment. Clearly what this chart is beginning to perhaps indicate is that responses at 40 milligrams might be uncommon. Which is why we've dose escalated to 3 times that dose level where- Yeah. We are beginning to see, you know, responses if we wait long enough. As Mark said earlier, we don't know whether there is a dose at which the majority of responses will be seen at the first response evaluation or not. It's just not clear to us whether increasing the dose changes the kinetics of response. Again, I wanna re-emphasize here that these two diseases are diseases where chemotherapy induces responses, but it doesn't last very long. That's what we're trying to solve for. We're trying to solve for the very short duration of response or benefit that patients get with cytotoxic chemotherapy. The median time to progression for patients with pancreatic cancer that have received prior therapy is three and a half months, and we're trying to solve for that. It's really about how long it takes the tumor to get to 30% or 31% reduction isn't really the point. The point is how long do they stay on study before they progress again. We would like to push that beyond three and a half months. Yep. Okay. That's, that's helpful. Just clarify for me, after how many cycles did a patient receive a scan? Is it every two cycles? Every 2 cycles. Yeah. Okay. Got it. Every two cycles for the first six cycles, then it goes, I think it goes to every three after that. Yeah. Cycle three, day one means they've completed two cycles. It's the day after they've completed two cycles. Got it. Got it. Okay. Just with regards to safety, you know, you mentioned that you dosed up to 40 milligrams per kg in sort of the preclinical models before you started to see some safety. What type of safety emerged at that point? You know, what was that, and then at maybe, you know, what duration of treatment? Okay. This is very species-specific. Mice, we just see weight loss. The tox species were mice and cynomolgus monkeys, and obviously the monkey is a little bit more representative of what happens in humans. There we saw very clearly wild-type RAS-mediated toxicity, predominantly gastrointestinal toxicity, and some suppression of myeloid hematopoiesis. Now interestingly, in the human studies so far, we have seen some GI toxicity. It's not. It's a little bit diverse in terms of the exactly which part of the GI tract is affected and how that manifests itself. Sometimes we've seen nausea, sometimes we've seen diarrhea, sometimes we've seen loss of appetite, for instance. It's a constellation of gastrointestinal effects that almost, well, all of them have either been grade 1 or grade 2 and very easily manageable. The predominant toxicity, the one that's coming through with increased frequency is skin rash, which we were not able to detect in the preclinical tox species, largely because we're limited by what we can detect in those species. It is interesting, the one organ in which we showed in our JPMorgan presentation that it is the one organ where the clearance of the drug is slightly delayed compared with the other organs. Nowhere near as much as tumor, by the way, but it is, the clearance of the drug from skin is slower than from, for instance, colonic epithelium or other organs in the body. It may be that the tissue kinetics of RMC-6236 are contributing to the skin rash. That makes its... The pattern of toxicity a little different in humans compared with the preclinical species. Understood. Okay. Please remind me, I don't know if you mentioned exactly what dose the patient was on, the patient that had to, you know, pause the dose and then restart at a lower dose? I don't remember. I'll have to take that offline. I'm sorry, I don't remember where we were. Okay. I think we have time for one more question. Is that right? From this, another speaker. I think there's one other person. Please stand by. Please stand by for our next question. Our last question comes from Jay Olson with Oppenheimer. Your line is now open. Oh, hey, thank you for the update and for taking the questions. We had a couple on 6236. What are you expecting to be the minimally effective dose? Is there any saturation of target occupancy that could lead to a plateau of efficacy? What dose would you see that plateau? Since the AE table excluded events that occurred in fewer than 4 patients, can you just comment on what those AEs were and if any of them were Grade 3 or 4? Thank you. Well, it's easy for me to answer the second question. We haven't seen no grade 3 or grade 4 events other than that 1 bowel perforation that we described, which was a grade 4 AE and also a serious adverse event. As you said, the bowel perforation was most likely due to the efficacy of the drug, not due to the toxicity of the drug on the gastrointestinal epithelium. Hang on. The question about MAD. There's no other. There is no plateau in our dose response. We continue to see increases in efficacy up to the point where the drug becomes intolerable due to inhibition of wild-type RAS. There is no acceptation of a plateau as we continue to dose escalate. This makes this really important because this compound, so far, everything we know about RMC-6236 does not follow the paradigm for Project Optimus. We continue to see increase in efficacy as we see increase in toxicity. They are absolutely related to each other, but we are seeing efficacy at doses that are tolerable, and that is incredibly important both for the platform and for the further development of the compound. Okay, great. Thanks for taking the questions. Thank you. I would now like to turn the conference back to Mark Goldsmith, Chief Executive Officer, for closing remarks. Thank you, operator. Thank you to everyone for participating today and for your continued support of Revolution Medicines. This concludes today's conference call. Thank you for participating. You may now disconnect.