Good day, and welcome to the Revolution Medicines Conference Call. At this time, all participants are on listen-only mode. After the speaker's presentation, there will be a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would now like to turn the call over to Mark Goldsmith, Chairman and Chief Executive Officer of Revolution Medicines. Please go ahead. Good morning, and thank you for joining us today. I'm Mark Goldsmith, Chairman and Chief Executive Officer of Revolution Medicines. Joining me for this presentation are Dr. Steve Kelsey, RevMed's President of R&D, Dr. Wei Lin, our Chief Medical Officer, Dr. Brian Wolpin of Harvard Medical School and the Dana-Farber Cancer Institute, and Jack Anders, RevMed's CFO. Please review our notice regarding legal, legal disclaimers. I'll begin with a few remarks to set the stage. Numerous RAS mutations are recognized to cause human cancers, and large unmet medical needs remain among patients with tumors harboring RAS mutations, including common cancers such as pancreatic cancer. At Revolution Medicines, our goal is to revolutionize treatments for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. Our pioneering oral targeted agents are the first inhibitors designed to bind directly to the hyperactive oncogenic forms of RAS we refer to as RAS(ON) that are responsible for these cancers and thereby suppress key tumor growth signals. Our first three RAS(ON) targeted investigational drugs are undergoing clinical evaluation, and to date, over 700 patients with cancer have been treated with one or more of these RAS(ON) inhibitors. Today, we are focusing on RMC-6236, our first RAS(ON) inhibitor that entered clinical development in mid-2022. RMC-6236 is a groundbreaking RAS(ON) multi-selective inhibitor, which we have reported binds potently and selectively to all oncogenic forms of RAS we have tested, including a wide range of mutant and wild-type RAS protein family members that are involved in the formation or progression of RAS-addicted tumors. Previously, we reported preliminary data from the RMC-6236-001 dose escalation trial that point to encouraging oral bioavailability and drug exposures, clinical safety profile, and antitumor activity from monotherapy RMC-6236 across multiple RAS solid tumor types, including pancreatic cancer. Today, we will share with you updated clinical data from that trial. The findings provide further evidence of compelling antitumor activity, including promising progression-free survival data, or PFS, with RMC-6236 treatment at tolerated doses among patients with previously treated metastatic pancreatic ductal adenocarcinoma, or PDAC. Based on the totality of the data collected to date, RevMed is fully committed to conducting the RASolute 302 study, a global randomized phase III trial in second-line metastatic PDAC patients, designed as a registrational study. Momentarily, Doctors Kelsey and Lin will share with you the scientific foundations, clinical update, and trial plan. Before doing so, we're honored to welcome Dr. Brian Wolpin, a leading expert on pancreatic cancer and treatment, Director of the Gastrointestinal Cancer Center of the Dana-Farber Cancer Institute, Director of the Hale Family Center for Pancreatic Cancer Research, Professor of Medicine at Harvard Medical School, and a clinical investigator for RMC-6236. Dr. Wolpin will briefly describe pancreatic cancer, the unmet medical needs, and the current treatment landscape as context for considering the update on RMC-6236. Brian? Thank you. As many people know, pancreatic cancer is one of the most devastating of human diseases, taking the lives of over 50,000 Americans in 2023 and many more outside the United States. This year, more than 60,000 Americans will be diagnosed with pancreatic cancer, and the vast majority of them, unfortunately, will succumb to their disease. 50%-60% of these patients will be diagnosed with metastatic pancreatic cancer at the time of their initial presentation, and among those who are diagnosed initially with non-metastatic pancreatic cancer, most will progress to develop metastatic disease. This difficult reality makes pancreatic cancer one of the highest unmet needs in medicine. The current standard of care for pancreatic cancer is combination chemotherapy, which has significant toxicities, requires substantial supportive care to deliver, and offers modest benefit to many patients. Pancreatic cancer is the most RAS mutated of all cancers. Over 90% of patients have tumors that harbor a RAS mutation that, in principle, could be responsive to treatment with a RAS inhibitor. However, today's available RAS inhibitors that target G12C mutations are relevant to only 1% of patients with pancreatic cancer. Thus, pancreatic cancer is really ideal for a treatment paradigm shift to targeting RAS with a broadly active RAS inhibitor. The current treatment paradigm in metastatic pancreatic cancer globally is centered on combination chemotherapies that require regular IV infusions, either a 5-FU-based regimen or a gemcitabine-based regimen as first-line therapy, followed by the alternative regimen as second-line therapy. Intensive supportive care measures are needed to manage these combination chemotherapies, and the side effects from chemotherapy can adversely affect patients' quality of life during the time of treatment. Overall survival is commonly less than a year in treatment-naive patients with metastatic disease, regardless of treatment regimen, and six months in patients who start second-line treatment. Next-generation DNA sequencing is recommended in national guidelines for patients with metastatic pancreatic cancer, but few of the identified alterations can be targeted with currently approved medications. The development of a broadly active RAS inhibitor has the potential to change the treatment options available for these patients. The table you see in the slide summarizes the results for various chemotherapy regimens and unfortunately illustrates the poor clinical outcomes reported for patients receiving second and third-line therapies for metastatic pancreatic cancer. These results from clinical trials show consistent, modest impact for chemotherapy in the second-line setting and also reflect the difficult day to day experience of oncologists and patients. In trial after trial, regardless of the chemotherapy regimen that was evaluated, the median progression-free survival in these studies has ranged between two and 3.5 months in the second-line setting, with median overall survival between six and seven months. Outcomes in the third-line setting, unfortunately, are worse, with median PFS of around two months and median OS around five months among those patients who are able to receive third-line therapy. In general, these treatments have not been well-tolerated, and many patients require dose and schedule modifications. In spite of decades of efforts, with cytotoxic chemotherapies, we have not been able to improve the survival of patients with previously treated metastatic pancreatic cancer substantially beyond six months. It's really straightforward to see that patients with metastatic pancreatic cancer need better outcomes, with meaningfully longer survival and better quality of life, which will require new therapies, particularly those designed to be applicable to the vast majority of patients who have RAS-dependent pancreatic cancer. Thank you very much, Brian. I'll now ask Dr. Steve Kelsey, our President of R&D, to briefly describe the role of RAS proteins in pancreatic cancer and to introduce our investigational drug, RMC-6236. Steve? Thank you, Mark. As just described by Dr. Wolpin, pancreatic ductal adenocarcinoma, or PDAC, is a common, aggressive, and inevitably fatal disease with approximately 60,000 new diagnoses in the U.S. each year, matched by a similar number of deaths due to inexorable and typically rapid disease progression, even with the best available treatment options. We have known for about 40 years that most human pancreatic cancers carry a mutated RAS gene, encoding a RAS protein variant that was presumed to be a main cancer driver, based primarily on experimental work in preclinical models of cancer. The discovery of the first targeted KRAS G12C selective inhibitors enabled a formal test of this hypothesis in humans, and tumor shrinkage observed in some patients treated with these compounds made a compelling case that the KRAS G12C variant, in fact, can serve as a primary driver of several different human solid tumors, including pancreatic cancer. By extension, this critical finding provides the rationale for developing other RAS inhibitors designed as potential treatments for pancreatic cancer. RAS dominates pancreatic cancer more than any other major tumor type. Remarkably, approximately 92% of pancreatic cancers harbor a recognized and detectable oncogenic variant of RAS. Notably, the well-known variant, KRAS G12C, that is found frequently in non-small cell lung cancers, is quite uncommon in pancreatic cancer. Less than 2% carry this mutant allele. The most common RAS mutants in pancreatic cancer are RAS variants G12D and G12V, found in approximately 68% of pancreatic cancers. Other mutations affecting amino acid position 12 account for around another 17%. Therefore, RAS mutations at amino acid 12 are present in approximately 85% of pancreatic cancers. We refer to this major subgroup as G12X to denote the range of oncogenic mutations at this position in the protein. Approximately another 7% of pancreatic tumors carry mutations at RAS amino acids 13 or 61, variants we refer to as G13X or Q61X. A small percentage of tumors have no detected RAS mutation, but there is reason to believe that some of these tumors are nonetheless dependent on activation of RAS signaling pathways. Extrapolating from the early clinical findings with G12C inhibitors in a small subset of patients with G12C pancreatic cancers, the field presumed that the other more commonly found RAS variants in pancreatic tumors were also drivers of these cancers and therefore worthwhile therapeutic targets. We at Revolution Medicines have embraced this opportunity and designed a large collection of innovative compounds that bind to and inhibit RAS proteins. These inhibitors have three key features. First, they bind exclusively to the activated or on conformation of their RAS target. This represents a paradigm shift in the RAS field, since essentially all compounds preceding this work targeted the inactive or off conformation. We have reported preclinical evidence that it is biologically favorable to inhibit the on form as it represents the oncogenic state of the protein that drives cancers. Second, unlike preceding compounds in the field, these compounds bind to a site on active RAS proteins that is in close proximity to the three mutation hotspots, G12, G13, and Q61, despite no obvious druggable pocket anywhere on the protein surface. As shown on the left on this graphic, they do so by engaging a widely abundant cellular protein, Cyclophilin A, to form a tricomplex in the cell with an inhibitor binding pocket formed between the two protein surfaces. This mechanism allows for concurrent targeting of multiple RAS variants with a RAS(ON) multi-selective inhibitor. Third, the rapid assembly of the tricomplex within a cell immediately and potently inhibits RAS oncogenic activity. RMC-6236 is designed to bind to a site that is common to all forms of RAS. We've published extensive preclinical, biochemical, cellular, and in vivo studies that have demonstrated that RMC-6236 is orally bioavailable with good drug-like properties. It is highly selective for RAS mutant and wild-type proteins, that, in addition to being primary cancer drivers, are also central to multiple mechanisms by which the RAS signaling pathway becomes reactivated after treatment with RAS off inhibitors. RMC-6236 rapidly, deeply, and durably inhibits oncogenic RAS signaling, and in preclinical models, administration of RMC-6236 significantly shrinks and or suppresses the growth of a wide variety of solid tumors carrying a RAS mutation, including pancreatic cancer models. Importantly, contrary to prior predictions from other experts in the field, RMC-6236 exerts these antitumor effects at a dose of 25 mg per kg that was generally well-tolerated in these preclinical models over relatively prolonged treatment periods. To illustrate the preclinical antitumor activity of RMC-6236, shown on the right is a plot of results from a mouse clinical trial experiment with tumor xenografts representing a range of G12X RAS mutant pancreatic cancer models. In this study, the time to doubling of tumor volume is used as a mirroring surrogate for clinical progression-free survival. As expected, in the vehicle-treated or control group, we observed a rapid decrease in the number of animals who were progression-free. In contrast, the vast majority of animals treated with RMC-6236 at 25 mg per kg per day experienced durable inhibition of tumor growth. As shown here, there was a significant decrease in the number of animals in which the tumor volume doubled. Indeed, most animals, the tumor did not progress during this experiment. Please note three important findings. First, the prolonged antitumor impact of RMC-6236 observed across RAS G12X variants at a well-tolerated dose provides one of the earliest significant pharmacologic validations of the RAS driver hypothesis for RAS mutations beyond G12X in PDAC models. Second, the group of xenografts carrying G12X mutations, that is, mutations at position 12 that represent 85% of all human pancreatic cancers, experienced significantly prolonged progression-free survival during daily treatment with RMC-6236, and did not reach the median during the extended observation period. This finding is consistent with our published analyses of a large number of cancer cell lines that revealed that these common G12X mutants are the most responsive to RMC-6236 among all RAS mutant tumors. Third, we also observed significant slowing of progression with RMC-6236 in a broader group of xenografts that includes tumor models carrying non-G12X RAS mutant and/or wild-type RAS proteins, intended to simulate the 100% or all-comer pancreatic cancer patient population. In summary, based on the large body of experimental evidence we have reported, including this mouse clinical trial, RMC-6236 is potent and well-tolerated and demonstrates robust antitumor activity in preclinical models that are representative of a wide range of human pancreatic cancers. Based on these promising observations, we began the RMC-6236-001 first-in-human study two years ago to evaluate safety, tolerability, and antitumor activity of RMC-6236 in patients with RAS-driven cancers. Initially, this study focused largely on KRAS G12X pancreatic cancer and non-small cell lung cancer tumors, and later expanded to include tumors with a broader range of RAS mutations. I'm now pleased to hand the microphone over to Dr. Wei Lin, our Chief Medical Officer, to provide a clinical update focused on the expanded PDAC component of this study and to describe the first pivotal study that we will conduct in this disease. Thank you, Steve. Our clinical experience with our RAS(ON) tri-complex platform has been extensive, including over 400 patients dosed with RMC-6236 as monotherapy or in combination. Now, I will share our clinical experience in patients with pancreatic cancer treated with RMC-6236 monotherapy in our first-in-human trial. In the following slides, I hope to demonstrate why we believe that the safety and tolerability profile of RMC-6236 and its monotherapy efficacy, as measured by preliminary progression-free survival and overall survival, support its advancement into a registrational phase III trial in patients with second-line metastatic pancreatic cancer. As of the data cut-off date, RMC-6236 monotherapy has been evaluated in 369 patients with advanced solid tumors harboring RAS mutations. Nearly half were pancreatic cancer patients. Based on the totality of data and with alignment with the FDA, we've selected 300 mg daily as the go-forward dose in our planned phase III trial in second-line metastatic pancreatic cancer, which we call RASolute 302. This figure shows the measured clinical exposures of RMC-6236 in solid tumor patients dosed orally at 80 mg -400 mg daily. Dose-dependent increases in exposure were evident across this dose range, with inter-patient variability that is typical of oral cancer drugs. Almost all patients dosed between 160 mg-300 mg daily were able to achieve steady state exposures that are within the exposure range defined in mice treated with 10 mg per kg-25 mg per kg, in which xenograft tumor models responded to RMC-6236 with regressions. About half of patients dosed with 300 mg daily were able to achieve exposures equivalent to or above the 25 mg per kg exposures in mice. Furthermore, population PK modeling and simulation suggest that compared with lower doses, 300 mg daily has a higher probability of achieving drug exposure comparable to 25 mg per kg dose in mice, that is associated with persistent, greater than 90% RAS pathway inhibition. This finding provides pharmacokinetic support for the selection of 300 mg daily as the dose for our planned phase III pancreatic cancer trial, since the goal is to give each patient the greatest chance of reaching therapeutic exposure levels. Baseline characteristics are shown in this table for patients with metastatic pancreatic cancer treated with RMC-6236 at doses between 160 mg - 300 mg daily in the first-in-human trial. In general, they were typical of late-line cancer patients enrolled in a phase I clinical trial. The majority had metastatic disease, were initially diagnosed with pancreatic cancer, had ECOG performance status of one, had liver metastasis at baseline, and had two or more lines of prior therapies in the metastatic setting before beginning RMC-6236, all of which are well-established poor prognostic factors for pancreatic cancer patients. These characteristics are worth calling out because they indicate that the patients we are about to review are comparable to, or even more enriched in these poor prognostic factors than the populations in the benchmark trials Dr. Wolpin discussed earlier. So we believe that the comparisons we make may be conservative and not biased by patient selection in favor of RMC-6236. Here, we see the treatment-related adverse events in pancreatic cancer patients treated at 160 mg-300 mg daily of RMC-6236. Both any grade and grade three or higher adverse events are listed for the 127 patients treated at these dose levels. We pooled these patients for the safety analysis because the AE rates were similar across these dose levels, and the larger data set provided a more robust assessment of the safety profile. The treatment-related AEs that occurred in 10% or more patients are listed in the top half of the table. All common AEs reported to date are believed to have been on target and associated with inhibition of wild-type RAS in normal tissue. They mainly fall into three categories: dermatologic, which include rash and paronychia, GI, which include nausea, vomiting, and diarrhea, and mucosal, which include stomatitis and mucositis. Most AEs were low-grade, with around one in five patients experiencing grade three or higher AEs. This compares favorably against standard care chemotherapy, which is associated with much higher rates of AEs. For example, in the NAPOLI -1 phase III trial and the more recent GEMPAX trial published this year, four in five patients treated with combination chemotherapy experienced grade three or higher AEs. Rash, a bundle term that included acneiform and maculopapular, as well as other types of skin eruptions, occurred in nearly 90% of patients. These were mainly low-grade, with around 6% of patients experiencing grade three rash. Like the rash associated with EGFR inhibitors, it is predominantly acneiform. They were typically early in onset and responsive to the same management used for EGFR inhibitors. Therefore, we plan to implement rash prophylaxis with oral antibiotics in the randomized phase III trial I'll describe shortly. Based on the experience of rash prophylaxis with EGFR inhibitors, we hope to see a significant reduction in both the frequency and severity of rash, and if this potential outcome is observed, an improvement in the tolerability of RMC-6236 in patients. The lower half of the table lists several notable AEs that are uncommon in patients treated with RMC-6236. These include hepatotoxicity, as measured by liver enzyme elevations, cardiac toxicity, as measured by ECG QT prolongation, and hematologic toxicity, specifically neutropenia and thrombocytopenia. These rates, especially in hematologic and liver toxicities, compare favorably to standard of care chemotherapy and enhance the chance for combinability with other agents, including standard care and immunotherapy. Here, we see how the treatment related AEs affected patients' ability to remain on RMC-6236 treatment. Among these 127 patients, the impact of AEs on dose modification has been modest, as shown in the top half of the table. Less than 30% of patients required any dose modification. The majority of these were dose interruptions, with only around 10% requiring dose reductions, most commonly one step down, and no patients among these 127 discontinued RMC-6236 due to treatment-related AEs. These numbers translate to a dose intensity of 92% or higher and compare favorably against reported values for standard care chemotherapy, where the rates of dose interruption and reduction are typically two to three times as high as in the case of nal-IRI plus 5-FU, with over 10% of patients discontinuing treatment due to AEs. Here, we present the progression free survival analysis as of the May 11, 2024, data cut-off date. Important data our investors and the scientific and clinical communities have been anxious to see. Because PFS differs significantly between lines of therapy, as Dr. Wolpin showed earlier, we focused the metastatic pancreatic cancer patients in this first analysis to pure second-line to match our planned phase III population. In other words, we've included in this figure only the pancreatic cancer patients who would be eligible for our phase III trial. To increase the sample size and the robustness of the analysis, we have included patients in the 160 mg-300 mg daily dose range, doses that we know to be highly active. The green line is a PFS curve for patients with a KRAS G12 mutation. The estimated median PFS is 8.1 months. This point estimate compares favorably against the benchmark of two-3.5 months for median PFS in the second-line setting from prior phase III trials, as Dr. Wolpin described earlier. It is notable that the lower bound of the 95% confidence interval excludes the benchmark by a sizable margin, which gives us added confidence in the potential technical success of our proposed phase III trial. The upper bound cannot be estimated at this time. The blue line is a PFS curve for patients with any RAS mutation. Defined as any KRAS, NRAS, or HRAS mutation at codon G12, G13, or Q61. A group of patients we have studied only recently. Recall that extensive preclinical work showed that mutations other than G12X are often sensitive to RMC-6236, although G12X cell lines and tumors tended to respond better. At AACR earlier this year, we described a case report of a patient with a tumor carrying a Q61 mutation, who achieved a partial response when treated with RMC-6236. In the broad RAS mutation patient group, the estimated median PFS is 7.6 months. This point estimate also compares favorably to the benchmark of two-3.5 months for median PFS in the second-line setting from prior phase III trials. Again, the lower bound of the 95% confidence interval excludes the benchmark by a sizable margin, and the upper bound cannot be estimated at this time. Hence, both patients with a RAS G12 mutation and a broader group that includes non-G12X RAS mutations showed encouraging progression-free survival. While we have aggregated the 160 mg-300 mg daily dose levels for this analysis, we expect that a pure 300 mg cohort will perform at least as well by PFS, if not better. A relatively small number so far make differentiation among these doses difficult to discern. We showed earlier that exposures are higher with the 300 mg dose, and our exposure response analysis showed that 300 mg had an edge over the other in PFS for a pivotal trial. If these results are replicated in our planned randomized phase III trial, the magnitude of PFS improvement would more than double that of the current standard of care in second-line metastatic pancreatic cancer. In fact, this median PFS for RMC-6236 will be longer than the median overall survival reported in the literature for the current standard care, which is six to seven months in the second-line setting. We've also enrolled 62 KRAS G12 mutated pancreatic cancer patients, who received RMC-6236 as their third or later line of therapy. These patients had received two to five prior lines before beginning RMC-6236. The PFS analysis of these patients is shown as a dashed green line on the graph here. The PFS curve for the second-line pancreatic cancer patients is reproduced from the previous slide for comparison and shown here as a solid green line. As expected, the estimated median PFS of the third line plus pancreatic cancer patients was shorter than that of the second-line pancreatic cancer patients. Nevertheless, the estimated median PFS is 4.2 months, more than double the second-line plus benchmark of 1.9 months for this patient group with advanced disease. Furthermore, the lower bound of the 95% confidence interval is 4.1 months, which excludes the benchmarks for second-line as well as third-line plus treatment in metastatic pancreatic cancer. The comparison of the second line and third line plus PFS is helpful in two regards. First, the doubling of PFS in two distinct treatment settings suggests a consistent treatment effect across two different lines of therapy, which increases our overall confidence in the activity observed in the second-line setting, where we plan to conduct our phase III trial. Second, no therapy has previously demonstrated consistent efficacy in the third-line plus setting due to the aggressive nature of the disease. This preliminary sign of efficacy by RMC-6236 in a late-line setting is consistent with direct targeting of RAS, which is likely to remain the primary oncogenic driver, regardless of the line of therapy. A waterfall plot showing antitumor activity of RMC-6236 across individual second-line plus metastatic pancreatic cancer patients, dosed at 160 mg-300 mg daily, is presented here. By combining second-line and third-line plus patients and pooling patients treated within this range of dose levels, we're able to report in this ORR analysis, 79 patients with KRAS G12 mutant pancreatic cancer, or 97 patients, including all RAS mutant tumors. The larger sample sizes allow a more accurate estimate of the ORR at the expense of including later-line patients and patients dosed below 300 mg. The waterfall plot shows the best percentage change in target lesions in 92 efficacy-evaluable patients. That is those with at least one post-baseline scan. Five of the 97 patients included in the denominator for the ORR analysis did not have a post-baseline scan and are not included in this waterfall plot. Disease control was achieved in nearly 90% of all patients, most of whom showed some level of tumor shrinkage, and disease progression at first scan was rare. The majority of patients remained on RMC-6236 as of the data cut-off date, as indicated by the individual arrows at the waterfall plot. Reductions in tumor size were seen both in patients with tumors carrying KRAS G12 mutations, signified by green bars on the waterfall, and in those with other RAS mutations, signified by blue bars, supporting the evaluation of pancreatic cancer patients with any RAS mutation in the registration trial. For the ORR analysis shown in the table, patients were grouped by RAS mutation group, as I noted, and by duration of follow-up, as determined by the number of potential scans. The ORR 14+ week column includes all patients who received their first dose of RMC-6236 at least 14 weeks prior to the data cut-off date, which allows for at least two potential scans. The ORR 20+ week column is defined analogously, but allows for at least three potential scans. In contrast to the efficacy-evaluable method used to report most phase I trial results, where patients discontinued due to AE or PD before the first scan are not accounted for, they're included in our analyses. Therefore, this approach is more consistent with how ORR is calculated in phase III trials, enhancing the likelihood of reproducing these results in the pivotal trial. In other words, patients reported here as having an unconfirmed PR, have had one positive scan and not yet had a confirmed PR scan, whereas those who had an initial response that was not subsequently confirmed on the next scan, are classified as stable disease. The estimated ORR at 14+ week is 20%-21%. The estimated ORR at 20+ week is 26%-27%. This difference is due to the fact that approximately one-third of initial responses were identified in later scans after longer treatment, as we've reported previously. We expect that the ORR at 20+ week will be more reflective of the final ORR when data are fully mature. While these numbers may continue to evolve, they currently compare favorably against the 8% ORR benchmark for nal-IRI 5-FU, the approved combination of chemotherapy in second line metastatic pancreatic cancer. While we believe that the proof of concept for RMC-6236 in second-line metastatic pancreatic cancer has been achieved by a clinically meaningful improvement in the observed PFS, compared to the current standard of care, the ultimate clinical benefit will be measured by the translation of this PFS improvement to overall survival. Here we present an earlier interim look at OS in second-line metastatic pancreatic cancer in patients dosed with RMC-6236 at 160 mg-300 mg daily. Again, these include all pancreatic cancer patients treated with RMC-6236, who would be eligible to participate in our planned phase III trial. The OS curve for patients with KRAS G12 mutant pancreatic cancer is labeled in green, and the OS curve for patients with RAS mutant pancreatic cancer, broadly, is labeled in blue. These two curves in the table on the right are remarkable in two aspects. First, median OS has not been reached at this time for either patient group. Second, the lower bound of the 95% confidence intervals for the median OS estimate exclude the benchmark median OS in second-line metastatic pancreatic cancer. We recognize that this graph represents a relatively immature data set, but in the context of PFS curves shown earlier, we felt that it may provide a meaningful complement to the overall analysis. Having reached alignment with the FDA on 300 mg as the recommended monotherapy dose for RMC-6236 in the pivotal trial and achieved clinical proof of concept in second-line metastatic pancreatic cancer, we're excited to share with you the design and preliminary timeline for our global registrational phase IIII trial. In our planned phase III trial, all patients with metastatic pancreatic cancer previously treated with one line of systemic therapy will be eligible. Including patients with tumors harboring RAS G12 mutations, other RAS mutations, and without an identified RAS mutation. We will randomize approximately 460 patients to either monotherapy RMC-6236, or an investigator's choice of standard chemotherapy. The dual primary endpoints will be PFS and OS in patients with pancreatic cancer harboring a RAS G12 mutation. After efficacy has been demonstrated in this core population, PFS and OS will be evaluated in all enrolled patients. Additional secondary endpoints include ORR, DOR, and quality of life measures. In this nested design, the statistical testing of the primary and secondary endpoints will be performed following a hierarchical sequence. The primary analysis will be performed in the core population of pancreatic cancer patients with RAS G12 mutations, which make up approximately 85% of all pancreatic cancer patients. Because the proof of concept was established mainly in these patients, limiting the primary analysis to this population is designed to increase the probability of success. The testing in the expanded population will include all enrolled patients, incorporating patients with tumors harboring G12, G13, or Q61 mutations, as well as those with wild-type RAS without an identified RAS mutation. Patients with RAS wild-type tumor without actionable non-RAS mutations, for which there are approved target therapies available, will also be eligible. This nested design with hierarchical testing is designed to maximize the probability of trial success based on the core population, while retaining the opportunity to gain a broader label in all second-line metastatic pancreatic cancer patients. Because biomarker testing in pancreatic cancer is not as well established as in lung and colon cancer, the goal of an all-comer label without the need for RAS testing will remove a significant barrier for treating pancreatic cancer patients with RMC-6236, if it is approved. Since availability of tumor tissue and difficulty for some patients to wait for testing results before initiating therapy, both affect patient access to a biomarker-selected therapy. A label that does not require biomarker testing could have an enormously favorable impact on access. We continue to anticipate initiating the RASolute 302 phase III trial later this year. Given that the median PFS in the control arm is expected to be in the range of three months, the primary analysis for PFS may occur relatively quickly. The OS readouts include interim and final analyses and span a wider window. We expect that RASolute 302 trial will be the most significant global phase III trial in second-line metastatic pancreatic cancer during the time of its conduct. We've aligned with the FDA on the recommended dose and high-level trial design. The final protocol is in preparation and will be submitted shortly for FDA review. We've garnered tremendous enthusiasm from pancreatic cancer investigators worldwide and expect rapid enrollment. Back to you, Mark. Thank you, Wei. And I'd like to acknowledge Brian, Steve, and Wei for their clear remarks characterizing the unmet medical needs for patients with pancreatic cancer. Pancreatic cancer is a common and inadequately treated RAS disease. The unprecedented RAS(ON) multi-selective inhibitor, RMC-6236, the compelling clinical basis for advancing this investigational drug into a pivotal trial for patients with previously treated pancreatic cancer, and our plan for doing so shortly. You've heard today evidence that nearly all pancreatic cancers are dependent on RAS, and RMC-6236 is the first targeted investigational drug undergoing clinical evaluation that binds to and inhibits the wide range of RAS mutant and wild-type proteins that support RAS addiction in these tumors. In clinical evaluations so far, RMC-6236 has exhibited a favorable safety and tolerability profile at therapeutic doses and compelling antitumor activity as measured by frequent tumor regressions, high rates of disease control, and encouraging projections for durability of potential antitumor impact in patients with previously treated pancreatic cancer carrying RAS mutations broadly, and particularly among those with RAS G12X mutations, accounting for 85% of all pancreatic cancer patients. These observations define an encouraging profile, pointing to the potential for RMC-6236 to become an important new treatment option for patients with pancreatic cancer. Based on the totality of the compelling preclinical and clinical evidence we and collaborators have reported over the last couple of years. With input from clinical investigators and thought leaders and alignment with the FDA on dose and the trial design we showed earlier, we are excited to move forward as quickly as possible with RASolute 302, a global randomized phase III clinical trial comparing RMC-6236 to chemotherapy as second-line treatment of patients with metastatic pancreatic cancer. Fortunately, we have the organization and financial wherewithal to support execution of this robust plan. As of March 31st of this year, we have a strong balance sheet with $1.7 billion in cash, cash equivalents, and marketable securities. This financial strength, coupled with increased confidence in RMC-6236, driven by our substantial progress and encouraging results, enables us to make important additional investments, including acceleration of the PDAC phase III trial described today, scaling for commercial supply, and investigation in earlier lines of pancreatic cancer treatment. Taking into account these planned investments, we are updating our expected 2024 GAAP net loss guidance to a range of between $560 million and $600 million, which includes expected non-cash stock-based compensation expense of approximately $70 million-$80 million. Our cash runway guidance remains unchanged, and we continue to project that current cash, cash equivalents, and marketable securities can fund planned operations into 2027 based on our current operating plan. With these remarks, we conclude today's prepared presentation, and Steve, Wei, and I will now entertain questions. Thank you. If you would like to ask a question, please press star one, one. If your question hasn't answered and you would like to remove yourself from the queue, press star one one again. The company has approximately 25 minutes available to take questions. We ask that you limit yourselves to one question each. One moment for questions. Our first question comes from Marc Frahm with TD Cowen. Your line is open. Yes, thanks for taking my questions, and congrats on the data here. Maybe first from a kind of a housekeeping perspective on the PFS curves. It looks like there's maybe 104 kind of being evaluated in there versus a 127 enrolled. Can you explain kind of the gap there and kind of median follow-up? And then maybe a little bit more forward-looking, just, you know, everything you're talking about is second line, but maybe can you speak to the experience of how PFS may even improve looking towards first line and the status of the kind of the ability to dose on top of chemo to get to that setting? Mark, thanks for your question. I'll ask Dr. Lin to comment on both of those questions. So the analysis was done, the safety data set and the F3 data set were slightly different, because the safety data set included patients not necessarily limited by lines of therapy, and both used a dose range of 160 mg- 300 mg. The second question is regarding how the data may evolve when it comes to the first-line setting. We do, and currently, I think the numbers are actually looking fairly competitive, even when compared to the first line benchmark, which typically for the PFS is around six months, for OS is about 10 months - 11 months. So obviously, our OS data is not mature yet, but the PFS data is looking very favorable. We have a dedicated cohort that's planned in our first human study that will be enrolling first-line patients, so we'll be generating data accordingly. Maybe if I can just clarify on that first part. I think on the analysis by, if you add the second-line patients and then the third-line plus, you get to 104. So, are there some patients where just when you look at the charts, you can't quite definitively call it, define a line, or just kind of what's that gap? Mark, slide 18 refers to G12X only. There are no G13 or Q61 patients on that curve, and so that's how the denominator comes down from 127 to 104. Okay. Very helpful. Thanks. Thank you. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open. Good morning, and let me offer my congrats on these data. Very impressive. I understand that your phase III trial, RASolute 302, is going to be the path to registration here with 6236. But I wonder, just given how differentiated these data both are on PFS and perhaps even OS, in second-line, did you perhaps, I guess, what potential is there for filing on the basis of the 001 trial, either with the data in hand or perhaps with some expansion? Was that something that you discussed with the agency at all? What was their feedback, perhaps, to that proposal? Thanks, Eric. I think Steve Kelsey will comment on that. Well, let's start with the— Sorry, I want to start with a bigger picture regarding the environment for filing on the basis of phase I trials. The world moved on somewhat last spring, where it became very clear that the Food and Drug Administration were somewhat less willing to accept filings on the basis of single-arm non-randomized data, particularly from phase I trials, where the dose ranges were somewhat diverse. So I think there's a generic challenge there. The data are no doubt very encouraging. We are not going to exclude any possibility of negotiation with the FDA regarding filing of data or their willingness to consider it for approval. But we feel very committed to a full approval based on an overall survival endpoint, and we feel confident that the data we have so far from the study should get us to that point, providing we, as expected, are able to conduct the planned phase III trial properly. So, I think we're going to move forward with the phase III trial the way it was described to you, and any subsequent discussions with the agency will be partly our willingness to engage and partly their willingness to consider data for review. If I could add to that, Eric. As you know, we've talked pretty consistently over the last 6 months-12 months about the importance of pursuing a rigorous randomized trial to establish really the clear and definitive profile for this compound. It might be one of our few opportunities to do that. Once it's approved, of course, it makes study in those indications much more difficult. And we've seen that, as you know, from recent experience with the first G12C inhibitor that ran into difficulty having that accelerated approval, it compromised, to some degree, the phase III trial. So, we're going to keep our heads down and focused. Now, with that said, there will be the opportunity for an early look at the PFS, potentially even OS. And at that point, if the FDA has an interest in looking at it for an earlier, interim kind of approval, conditional approval, of course, we'd be happy to talk with them about that. But, as you pointed out in the context of your question, our focus right now is to get the rigorous trial done and to establish an OS benefit for RMC-6236, which would have profound impact for the use of the drug and for its future. Great. Appreciate that. Thank you. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is open. Hi, good morning. It's Yige on for Michael. Thanks for taking our questions, and let me add our congratulations on the data as well. I guess two quick questions from us. Number one, ORR improves over time, and would you expect the same response dynamics in other tumor types, or do you think it's more sort of PDAC specific? And then second question, you mentioned the phase III trial has a PFS and OS co-primary endpoint. Just to clarify, do you need to achieve statistical significance on both endpoint for the trial to claim success, or do you only need a sort of like a more directional OS for the trial to be positive? Thank you. Hi, Yige. Thanks for your question. On the first question, we're not—I think today we're going to keep the scope of our comments to pancreatic cancer rather than discussing other tumor types, as that just opens up topics that we're simply not covering with data today. So, I'll confirm that in pancreatic cancer, we have seen that over time a patient has a greater chance of developing a response the longer they stay on the drug. Your second question, could you just repeat that? Yeah, sure. It's about the phase III trial. So looks like you have a PFS and OS co-primary endpoint. Yeah. I think we believe that OS is really the important endpoint, and that therefore that will drive ultimately definitive approval. I think beyond that, it's sort of an FDA review issue. It's really up to them what they would want to do with any other information. But it's important, I think, that the whole scientific community, clinicians, patients, and we do look at PFS without any doubt, but whether or not that's used in an approval will be up to the FDA to decide. All right. That's super helpful. Thank you very much. Congrats on the data again. Thank you. Thank you. Our next question comes from Jonathan Chang with Leerink Partners. Your line is open. Hi, guys. Congrats on the update, and thanks for taking my question. On dose selection, do the clinical data also support the 300 mg dose, as in, do you see the best clinical efficacy at that dose? Or is the dose selection primarily a function of the exposure levels you presented? And also, how are you thinking about dose selection in lung cancer? Thank you. Thanks, Jonathan. I don't think we'll comment on lung cancer today. As I mentioned, we'll keep the discussion to focus on pancreatic cancer. You know, there are three factors that drove the decision around the dose, exposure, safety, and efficacy. And I think, Wei went through that pretty carefully. On the exposure level, clearly, 300 mg gives an edge to patients to achieve a higher exposure, and higher exposure, certainly pre-clinically, was strongly associated with better outcomes. From a safety point of view, as Wei mentioned, we really have trouble discerning differences among those doses, and so there's really nothing at the safety level in pancreatic cancer patients that would point us to a different dose. And then from an efficacy point of view, we also had difficulty discerning differences among those three dose levels, 160 mg, 200 mg, and 300 mg. And although at various points in time, depending on the maturity of the data, we have seen differences, I think today we simply don't feel that we can declare a definitive difference among those doses, although we would expect that in a large enough study, I don't know if 300 or 400 patients would be a large enough study, but maybe with thousands of patients, one likely would see some difference. But it's not important because the risk-benefit calculation now points to 300 mg, and that's the go-forward dose, and the FDA has aligned on that dose. Understood. Thanks for taking the question. Thank you. Our next question comes from Ami Fadia with Needham. Your line is open. Hi, good morning. Congrats on the strong data, and thank you for taking my question. With regards to first-line PDAC, can you elaborate on how you're evaluating the first-line patients, whether it's both as monotherapy as well as in combination with chemotherapy? And, just your current view on what that benchmark would be. And, you know, would you sort of run a first-line study in parallel with the second-line pivotal trial, and maybe any sense of timeline around that? Thank you. Yeah. Thanks, Ami. You know, clearly first line is now in our sights. I think with our confidence having been increased by this evaluation of the second line data, we clearly are now turning our attention heavily towards first line and increasing our investment to evaluate it. As I'm sure you know, one of the options here is to add RMC-6236 to standard of care chemotherapy, and we're currently evaluating the safety and tolerability of doing so. So that's underway, and we'll intensify that as indicated, as the data roll in, we'll determine whether to expand that, if so, what subsets of patients, et cetera. As you point out, the data simply looked at today suggest that monotherapy in this single-arm, you know, non-comparative trial, but referencing the benchmarks, appears to be superior to, competitive with, superior to, first-line chemotherapy. We don't have much experience in first-line patients with RMC-6236 monotherapy. History would suggest that moving from a later line to an earlier line will yield improvements. But even without that, if these data hold up in a phase III trial in second line, one certainly would believe that it would be competitive in first line. So that remains an option, and we've just simply not decided yet, and we'll make the investments to determine it, whether or not we should have a three-arm trial or a two-arm trial. A three-arm trial is attractive in that it could evaluate both monotherapy and combination therapy relative to standard of care, and that could increase the range of options for clinicians based on stratifying patients who may or may not be able to tolerate chemotherapy. It's an exciting idea, but we do need to have some safety and tolerability data to establish for us whether or not that combination should be in that trial. That's, that's a high priority for us. We're doing everything we can this year to establish that information and the foundations for a decision around that and to design a first-line trial and to be prepared, we hope, by 2025 or sometime in 2025, to be able to make that decision and, and to move forward. We will not wait for the results of the Phase III, second-line trial. That will not be a determinant, I guess, unless things, for some reason, slow down and we can't make the decision until then, that would be possible, but we don't have it in the critical path of our decision-making. I should also point out, first line really ought to be thought of as early line therapy, that there are multiple opportunities in early lines. We talk about first line, that defines a particular subset of patients, but there are other subsets as well. And we're certainly enthusiastic about pursuing multiple early lines of, treatment. Thank you. Thank you. Our next question comes from Ellie Merle with UBS. Your line is open. Hey, guys. Thanks for taking my question, and congrats on the data. Just curious what your expectation is for the chemo monotherapy performance between the G12X mutations versus the other mutation types, and if you expect there to be any difference in response to chemo between the different mutations? Thanks. Thanks, Ellie. I think, you know, the question is whether or not chemotherapy historically has shown differences among the different genotypes, and there's a little bit of data out there, but not a great deal. Yeah, and there's been some data that's been published. I think they tend to be single institution like ones, like there's a recent publication from MD Anderson. Some of them indicate there may be some performance differences in some of the RAS mutations versus the others, but they vary from trial to trial. I think it's hard to conclude. But overall, I think because we're enrolling essentially an all-comer population in our trial, the benchmark numbers we referenced and Dr. Wolpin had shared during the presentation should stand fairly well and we expect should be replicated in our phase III trial. Got it. Thanks for the color. Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open. Thank you. Thanks for the update today. Really appreciate it. Just a question around the dose response. If you're seeing a dose response, whether it's in PFS or OR, or indeed in the safety profile. Thank you so much. Thanks, Peter. I think we've mentioned that a couple of times here, that we have not discerned very clear patterns within that 160 mg-300 mg range. Obviously, below 160 mg, there's no question that there is less activity and fewer side effects. But within the 160 mg-300 mg range, which is not really a very large range, of course, you know, it's at best sort of twofold difference. And the exposures reflect that there's a great deal of overlap between 160 mg and 200 mg, between 200 mg and 300 mg, and even between 160 mg and 300 mg. So one wouldn't, from the PK, predict that there would be marked differences in either activity or on target as to side effects. But at 300 mg, we do see a higher exposures. In the exposure-response relationships, maybe Steve Kelsey can comment on our exposure-response relationship. Yeah. Generally speaking, the activity, and in particular, PFS, is higher with higher exposures. It, depending on how you dichotomize patients by drug exposure, we tend to use steady state exposure as both as measured and predicted from a pop PK model. And if you dichotomize the patients by the upper half as the lower half, then the upper half patients, there is a trend in favor of them doing better than the patients in the lower half. But it's very difficult to map that back to discrete doses per se, and there are a number of reasons for that. One is obviously the interpatient variability, which I think is very evident to you from the PK slide that we showed. The second is the dose modifications that occurred during the course of the study, with, because we allowed both intra-patient dose escalations to occur, and there were some downward modifications, based on, based on tolerability as well. So it's much easier to, map the efficacy to exposure, and because, as Mark said, the, the probability of any patient getting an exposure in the upper half of the range is greater if you start with a higher dose, we've leaned in favor of that 300 mg dose. Maybe I'll also make one other point, which, I think was alluded to in the prepared remarks, but just to, just to reiterate it. We think it's advantageous to have doses that are lower than 300 mg but are showing significant antitumor activity, because some patients do require dose reductions, and we went through that in the table. And so the ability to offer investigators or clinicians the chance to dose reduce, but to reduce at a level that we are sufficiently excited about, and in fact, have some trouble differentiating efficacy from 300 mg, creates a real opportunity for patients. So I think we're very good in that range. And we're very comfortable with initiating treatment at 300 mg and to manage each patient on a case, case-by-case basis. Perfect. Thank you so much. Thank you. Our next question comes from Alec Stranahan with Bank of America. Your line is open. Yeah. Hey, hey, guys. Thanks for taking our questions, and congrats from us on the data as well. I had one question on resistance mechanisms relating to durability of response. In your recent publication in lung cancer, you cited a population of slow-growing cancer cells as leading to resistance to G12C-specific inhibitors. Wondering if you also think this is the case in patients to approve G12C inhibitors, and whether you see this being the case in PDAC to, say, a G12D-specific inhibitor as well, or if this phenomena is more isolated to lung cancer? Thanks. Thanks, Alex. Yeah, of course, we're familiar with that publication. You know, that was a study done in preclinical context. I think it's yet to be established how that might translate or not, or to what degree, to patients. We haven't reported really anything about resistance mechanisms yet, in patients, where we're obviously have been collecting blood samples, doing genomic analyses. We have not been collecting tumors, tumor samples, biopsies. That's very difficult to do, and there will be dedicated sub-studies in which that's done, going forward, but we just don't have any of that information. And so while it's an important scientific observation, at this point, it's hard for us to really even comment on exactly how that relates to PFS or OS. Probably the best reference document that exists right now is Andy Aguirre's presentation at AACR from earlier this year. Admittedly, a lot of that all of that was in pancreatic cancer, and a lot of it was done with Mirati's G12D inhibitor, MRTX1133. But some of the concepts that he put forward in that presentation were not dissimilar to the cetuximab concepts and..But some of them were also different. Whether or not how much of that actually ultimately will translate into the clinic, and particularly how much of it will remain true with a RAS multi inhibitor versus a G12D selective inhibitor, I think we just don't know. Maybe at a high level, you know, I think we can, we continue to believe conceptually that reactivation of RAS or some, some method by which RAS signaling is rescued, will be, will continue to be an important component of resistance mechanisms, but what percentage of resistance that accounts for versus cellular phenotypes and, and other kinds of changes, we just, we just don't know yet. Very helpful. Thank you. Thank you. We have time for one more question, and our last question comes from Jay Olson with Oppenheimer. Your line is open. Oh, hey, congrats on these results, and thank you for the update. For the RASolute 302 study, when patients in the standard of care chemo control arm progress, can you share any thoughts on crossing over to RMC-6236? Thank you. Thanks, Jay. I think Wei could comment on crossover plans. Yeah. So, because the overall survival is, we believe, it's gonna be the endpoint that's gonna be needed for full approval, the current plan is we will not allow crossover during the clinical trial until the study has read out positive for overall survival. Got it. Thank you. Thank you. There are no further questions. I'd like to turn the call back over to Mark Goldsmith for closing remarks. Thank you, operator. I'm very proud to acknowledge the tireless effort by employees at Revolution Medicines on behalf of patients, as well as the dedication by clinical investigators, their support teams and scientific collaborators, and importantly, to recognize and express our gratitude to patients and their families for participating in clinical studies sponsored by Revolution Medicines. Thank you to everyone for joining us, and wishing you a good day. Thank you for your participation. This does conclude the program, and you may now disconnect. Good day.