Good day, and thank you for standing by. Welcome to the Revolution Medicines Q1 2025 Earnings Conference Call. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to our first quarter 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer; Dr. Steve Kelsey, our President of Research and Development; Dr. Wei Lin, our Chief Medical Officer; and Jack Anders, our Chief Financial Officer. I would like to inform you that certain statements we make during this call will be forward-looking. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended March 31, 2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. Along with an updated investor presentation, which we will be referencing during today’s call. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. It's good to be with you this afternoon. Today, I'll highlight some of the progress we've made this quarter against the strategic priorities we outlined earlier this year. I'll then pass the call over to Dr. Steve Kelsey, who will walk through a strategic framework for our developing plans in non-small cell lung cancer. Dr. Wei Lin will then highlight updated data from several of our ongoing non-small cell lung cancer cohorts that provide support for our plans in lung cancer. Jack Anders will then provide a summary of our first quarter financial results before I share closing remarks and open the call to Q&A. At Revolution Medicines, we remain committed to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. We continue to make important strides in pursuit of this mission as we execute, advance, and extend our understanding of our novel RAS(ON) inhibitors. We believe and have increasingly been able to demonstrate that our compounds have the potential to become important therapeutic options for patients living with RAS-addicted cancers. Our first three clinical stage RAS(ON) inhibitors with highly differentiated and promising clinical profiles include daraxonrasib, a groundbreaking RAS(ON) multi-selective inhibitor; elironrasib, a distinguished G12C selective covalent inhibitor; and zoldonrasib, a highly innovative G12D selective covalent inhibitor. We continue to make substantial progress advancing these programs with a vision to maximize the clinical impact across tumor types and lines of therapy through a mix of single agent and combination strategies. Pancreatic cancer is an important priority and our strategy involves executing on the ongoing Phase three RASolute 302 trial of daraxonrasib in patients with previously treated disease, while moving aggressively into earlier lines of therapy. We're working quickly to prepare for the initiation of two additional Phase 3 studies with daraxonrasib in pancreatic cancer in the second half of 2025. One of these trials will be in patients with first-line metastatic disease and is expected to compare a reference arm of patients treated with chemotherapy to two investigational arms, one with patients treated with daraxonrasib monotherapy and one with patients treated with daraxonrasib plus chemotherapy. The other early line trial will be as adjuvant treatment for patients with resectable pancreatic cancer, who have undergone surgery and perioperative therapy, typically including chemotherapy. In addition to this robust plan for daraxonrasib to play an important role in the treatment of pancreatic cancer across lines of therapy, we have similar ambitions for broad development in RAS mutant non-small cell lung cancer. The principal focus of today's call is to provide further color and support for our non-small cell lung cancer strategy, and I'd like to invite Dr. Steve Kelsey to walk you through our current conceptual framework. Steve?

Thanks, Mark. Improving treatment options for patients with RAS mutant lung cancer is an important priority for Revolution Medicines. The majority of patients with non-small cell lung cancer are either diagnosed with or later develop metastatic disease. Treatment objectives for these patients include symptom improvement by reducing tumor burden, delaying disease progression, prolonging survival, and improving quality of life. Thirty percent of patients with non-small cell lung cancer harbor a RAS mutation. There are still no full regulatory approvals for RAS inhibitors in any RAS mutant lung cancer. Nevertheless, due to the commercial availability of KRAS G12C(OFF) inhibitors by accelerated and conditional approval mechanisms, RAS mutant non-small cell lung cancer has effectively evolved into two diseases and treatment paradigms. G12C mutant disease represents around 12% of non-small cell lung cancer and other RAS mutant non-small cell lung cancer, which we are referring to as non-G12C RAS mutant non-small cell lung cancer. The second group counts for around 18% of non-small cell lung cancer. We expect segmentation of the RAS mutant non-small cell lung cancer space to continue into mutational groups as other mutant selective inhibitors advance through clinical development and receive regulatory approvals. Our aim at Revolution Medicines is to establish our portfolio of RAS(ON) inhibitors as the leading therapies for patients with RAS mutant non-small cell lung cancer across all RAS mutations and lines of therapy. We strive to develop first and/or best-in-class RAS(ON) inhibitors and combinations. Our strategy for metastatic disease depends on a number of variables. First, which RAS mutation the tumor harbors and whether a mutant selective RAS(ON) inhibitor has achieved proof of concept. Second, the line of therapy for metastatic disease as the expectations and standards of care are different between initial therapy and salvage therapy. Daraxonrasib has shown encouraging anti-tumor activity in patients with tumors harboring a wide range of RAS mutations. Nonetheless, in the face of RAS-addiction by such tumors, we expect that mutant selective inhibitors should also have a role in treating tumors with corresponding RAS driver mutations. Combining these mutant selective inhibitors with a RAS(ON) multi-selective inhibitor may play an important role by delivering deeper target inhibition and overcoming resistance mechanisms in a way that neither approach can achieve on its own. Our previously published data show that daraxonrasib is active against a broad range of RAS mutations that have been frequently identified as mechanisms of escape from mutant selective KRAS inhibitors. Consistent with this and as we recently presented at AACR, new RAS point mutations are an infrequent cause of escape from daraxonrasib in pancreatic cancer. A RAS(ON) inhibitor doublet combination has the goal of improving outcomes and potentially providing a chemotherapy sparing option for patients with RAS mutant non-small cell lung cancer. In the previously treated metastatic setting, use of a single agent RAS inhibitor may be sufficient to improve outcomes over the current chemotherapy standard of care. This is the approach we're taking with daraxonrasib in patients with previously treated RAS mutant non-small cell lung cancer in the RASolve 301 study. For first-line treatment of metastatic disease, the dominant standard of care includes immune checkpoint inhibitors, primarily pembrolizumab. Demonstrating safety and tolerability with pembrolizumab is critical as a means of enabling first-line therapy and maximizing the durability of any clinical benefit. These concepts have currently been reduced to practice by Revolution Medicines. Single agent daraxonrasib provides a foundation for the investigation of RAS(ON) inhibitors in all RAS mutant non-small cell lung cancer in the second-line and beyond setting. As recently presented at AACR, zoldonrasib has encouraging activity as a single agent in second-line RAS G12D mutant non-small cell lung cancer. In the first-line, RAS G12C non-small cell lung cancer setting, we aspire to develop a chemotherapy sparing RAS(ON) inhibitor doublet of daraxonrasib plus elironrasib with pembrolizumab and thereby reserve platinum-based chemotherapy for second-line treatment. Doing so has the potential to contribute to an improvement in overall survival. In first-line RAS non-G12C non-small cell lung cancer, we plan to develop daraxonrasib in combination with standard of care. Eventually, zoldonrasib with its encouraging monotherapy profile may offer a path to another chemotherapy sparing RAS(ON) inhibitor doublet for patients with RAS G12D tumors. And similar doublet approaches may be possible with other RAS mutant selective inhibitors such as RMC-5127 targeting RAS G12V. I will now turn the call over to Dr. Wei Lin to provide an update across our non-small cell lung cancer clinical programs. Wei?

Thank you, Steve. I'll start by providing monotherapy updates across our portfolio. Beginning with daraxonrasib, our most advanced RAS(ON) inhibitor. This multi-selective inhibitor has demonstrated compelling results across multiple tumors, including lung cancer, and is currently being evaluated in a Phase 3 registrational study for patients with previously treated non-small cell lung cancer. We're currently activating study sites for RASolve 301. The study randomized approximately 420 patients to either daraxonrasib monotherapy or docetaxel. These patients must have received either one or two prior lines of therapy, including immunotherapy and platinum-based chemotherapy given either concurrently or sequentially. RASolve 301 incorporates a nested design with a primary analysis being performed in the core population of non-small cell lung cancer patients with RAS G12X mutations, excluding G12C. The extended population will incorporate all patients with RAS mutant non-small cell lung cancer, including those with tumors harboring G12C, G13, or Q61 mutations. The study has dual primary endpoints of progression free survival and overall survival. Moving to G12D non-small cell lung cancer. We've previously shown promising activity by daraxonrasib in patients with these tumors and the ongoing RASolve 301 recreational study includes such patients. Last month at AACR, initial clinical results were presented for zoldonrasib, our RAS(ON) G12D selective covalent inhibitor from a non-small cell lung cancer cohort. I'll walk you through these data. Zoldonrasib was well tolerated with manageable and predominantly low-grade treatment related adverse events as shown on the safety table. As of the December 02, 2024, data cutoff, at the 1200 mg once daily dose, two Grade 3 adverse events were reported among ninety patients with only two dose interruptions and no dose reductions. Zoldonrasib achieved a favorable mean dose intensity of 98%. Zoldonrasib monotherapy at the 1200 mg daily dose demonstrated encouraging antitumor activity. The waterfall plot shows the best percentage change in tumor size for patients with non-small cell lung cancer who received their first dose of zoldonrasib at least eight weeks prior to the data cutoff date. The objective response rate was 61%, including patients with a confirmed response or a response that was pending confirmation. The disease control rate was 89%. We'll continue following these patients to define durability. Now I'll move to our RAS(ON) G12C mutant selective covalent inhibitor, elironrasib, in non-small cell lung cancer. We reported the first clinical data on elironrasib in non-small cell lung cancer at the Triple meeting in 2023. And today, I'll share updated elironrasib monotherapy data that includes more patients and longer follow-up as a foundation for combination strategies to move into first-line metastatic and eventually earlier lines of non-small cell lung cancer. As of the April 07, 2025 data cutoff, 36 patients who had received prior treatment with standard care were treated with elironrasib monotherapy at 200 mg twice daily. Elironrasib was generally well tolerated with treatment related adverse events consistent with previously reported data. The most frequently observed treatment-related adverse events were gastrointestinal and asymptomatic QTc prolongation. Elironrasib achieved a favorable mean dose intensity of 94%. Here, we show the clinical activity in the same 36 patients treated with elironrasib monotherapy, the dose of 200 mg twice daily. The objective response rate in these patients was 56%. The disease control rate was 94%. The estimated median progression-free survival in these patients was 9.9 months. I'll now cover our combination of clinical development to enable our goal of improving treatment outcomes for patients with RAS mutant non-small cell lung cancer in the first-line metastatic setting. The need for improved treatment options for patients with metastatic non-small cell lung cancer remains high. In the first-line setting, two regimens are widely used globally. Pembrolizumab plus chemotherapy is the most commonly used treatment for all patients regardless of their tumor PD-L1 expression status as measured by Tumor Proportion Score or TPS. And pembrolizumab monotherapy is the preferred regimen in patients with TPS greater than or equal to 50%, which accounts for about one-third of patients with non-small cell lung cancer. While the introduction of immunotherapy has been transformative for patients with non-small cell lung cancer, especially those with high PD-L1 expression. As the data in this table indicate, non-small cell lung cancer remains a disease with high unmet need. Because among the approximately two-thirds of patients who have tumors with lower or no PD-L1 expression, even the best available standard care has not resulted in reported response rates above 40%. In RAS mutant non-small cell lung cancer in the second-line and beyond, treatment is generally either the chemotherapy docetaxel or a KRAS G12C(OFF) inhibitor. As illustrated in the table, reported response rates for docetaxel have been less than 15%, even with the commercially available KRAS G12C(OFF) inhibitors of sotorasib and adagrasib. Reported patient outcomes have been modest with response rates of approximately 30%. Combinations are likely to remain a foundation of first-line metastatic treatment for non-small cell lung cancer. And our main objective is to determine the best way to bring targeted RAS inhibitors into combination with immunotherapy for the first-line treatment of RAS mutant non-small cell lung cancer. These figures from preclinical experiments illustrate two concepts that guide our clinical approaches. The first concept shown on the left is that two RAS(ON) inhibitors can be combined to increase anti-tumor activity. In this experiment with a KRAS G12C non-small cell lung cancer model, either elironrasib or daraxonrasib alone significantly increased progression-free survival compared to control as measured by time to tumor doubling. Notably, the combination of elironrasib plus daraxonrasib prolonged progression-free survival even further, indicating additive durability from the RAS(ON) inhibitor doublet. The second concept shown in the experiment on the right is that this RAS(ON) inhibitor doublet significantly synergizes with immunotherapy. In this experiment, we used a refractory KRAS G12C non-small cell lung cancer tumor that was unresponsive to anti PD-1 inhibitor alone and only partially responsive to anti PD-1 combined with either RAS(ON) inhibitor. Essentially, no progression was seen in this model during 100 days of treatment with anti PD-1 combined with the RAS(ON) inhibitor doublet. Encouraged by preclinical results of this sort, I will now describe new clinical data from our evaluation of pairwise combinations of daraxonrasib plus pembrolizumab, elironrasib plus pembrolizumab, and elironrasib plus daraxonrasib that suggest these concepts may translate in patients with KRAS G12C non-small cell lung cancer. The first combination data set I'll review is daraxonrasib plus pembrolizumab with or without chemotherapy. Daraxonrasib plus pembrolizumab with or without chemotherapy has been generally well tolerated in patients with non-small cell lung cancer. Previously, we showed acceptable tolerability for the combination of daraxonrasib with pembrolizumab in later line patients. And with further follow-up, the tolerability profile in those patients has remained stable. Today, we're focusing on patients with first-line disease. While the follow-up is shorter for patients in the first-line setting, the tolerability profile of daraxonrasib plus pembrolizumab is consistent with what has been observed in the second-line setting with or without the addition of chemotherapy. No new safety signals were seen and the overall tolerability profile is consistent with that of daraxonrasib plus standard care agents. Rash, gastrointestinal toxicities, and stomatitis mucositis remain the most commonly observed adverse events for daraxonrasib, and neutropenia and thrombocytopenia emerged with the addition of chemotherapy. The tolerability profile supports the further development of daraxonrasib plus pembrolizumab with or without chemotherapy. Dose reductions and discontinuations of daraxonrasib or pembrolizumab in this combination were modest. Daraxonrasib achieved a favorable mean dose intensity of 93% in combination with pembrolizumab and 90% with additional chemotherapy. Only a limited number of first-line patients have had sufficient follow-up to have had a tumor assessment, and we're encouraged by the antitumor activity seen to date. In the left figure, patients had tumors with TPS greater than or equal to 50% and were treated with daraxonrasib plus pembrolizumab, consistent with the population who would have received pembrolizumab monotherapy of standard care. Of these seven efficacy valuable patients who had undergone at least one tumor assessment, 86% of these TPS greater than or equal to 50% patients had a RECIST response and all had achieved disease control and remained on treatment. While the dataset will continue to evolve with the addition of more patients and longer follow-up, this is a very encouraging start. In the figure on the right, patients with TPS less than 50% were treated with daraxonrasib plus pembrolizumab and chemotherapy, consistent with the roughly two-thirds of first-line patients who would likely receive pembrolizumab plus chemotherapy of standard care. Of the 10 efficacy valuable patients who had undergone at least one scan, 60% of these TPS less than 50% patients had a RECIST response and 90% achieved disease control. These data support the continued development of daraxonrasib plus standard care in first-line RAS mutant non-small cell lung cancer. I'll now touch on the elironrasib plus pembrolizumab combination. Demonstrating the safety of this combination is important as we take a pairwise approach toward our goal of developing a chemotherapy sparing triplet combination of elironrasib, daraxonrasib, and pembrolizumab in patients with first-line metastatic KRAS G12C non-small cell lung cancer. We previously showed acceptable tolerability for the elironrasib plus pembrolizumab combination in the second-line plus setting. With further follow-up of a few of those patients, we have not observed an increase in additive toxicity. Today, we'll focus on initial results in patients with first-line non-small cell lung cancer. As of the February 10, 2025 data cutoff, the combination of elironrasib with pembrolizumab showed a well-tolerated profile with few Grade 3 or higher treatment related adverse events. No new safety signals were observed. This tolerability profile translated to an acceptable dose modification rate in either the second-line or first-line setting. And elironrasib maintained a favorable mean dose intensity of 85%. The combination of elironrasib with pembrolizumab showed encouraging preliminary antitumor activity. Among five efficacy valuable patients with first-line non-small cell lung cancer and a TPS greater than or equal to 50%, all achieved a RECIST response. Our development strategy in the first-line RAS G12C mutant non-small cell lung cancer is to replace the standard care with the triplet regimen of elironrasib, daraxonrasib, and pembrolizumab as a chemo sparing regimen. I've just shown data supporting the combinability and anti-tumor activity of daraxonrasib plus pembrolizumab and elironrasib plus pembrolizumab. The third pairwise combination needed to support this triplet regimen is the RAS(ON) inhibitor doublet of elironrasib plus daraxonrasib. This RAS(ON) inhibitor doublet concept is supported by strong results in preclinical models, including models that are refractory to monotherapy approaches. In these preclinical models, deep and durable responses are seen in RAS(ON) inhibitor doublets. In December 2024, we shared initial clinical data for the RAS(ON) inhibitor doublet of elironrasib plus daraxonrasib to establish the mechanistic proof of principle for this combination. We evaluated a challenging population of colorectal cancer patients who had been previously treated with not only standard care chemotherapy, but also with KRAS G12C(OFF) inhibitors and anti-EGFR antibodies. These early results demonstrated an acceptable tolerability profile along with encouraging antitumor activity in a very difficult to treat patient population. These results provided strong rationale for continued development of this RAS(ON) inhibitor doublet approach across tumor types and lines of therapy. Today, I'll share initial dose finding data from this RAS(ON) inhibitor doublet in patients with non-small cell lung cancer. The data in this table demonstrate the combinability of elironrasib with daraxonrasib with a tolerability profile that is largely consistent with that of daraxonrasib itself. Even with longer follow-up, hepatotoxicity did not emerge as a safety signal in this larger cohort of lung cancer patients. QT prolongation on ECG was not symptomatic and is not common with a Grade 3 rate of only 3%. This tolerability profile translated to no treatment discontinuations and a favorable mean dose intensity of 95% for elironrasib and 85% for daraxonrasib. The combination of elironrasib plus daraxonrasib showed encouraging preliminary antitumor activity in 26 patients with previously treated KRAS G12C non-small cell lung cancer, who had been previously treated with a KRAS G12C(OFF) inhibitor. Because dose optimization of the RAS(ON) inhibitor doublet is ongoing, we're sharing daraxonrasib at doses ranging from 100 mg to 200 mg. On the left, we're showing the elironrasib monotherapy data in patients who were previously treated with a KRAS G12C(OFF) inhibitor. Response rate and disease control rate for elironrasib monotherapy were 42% and 79%, respectively. On the right, for the combination of elironrasib and daraxonrasib, the response rate was 62% and the disease control rate was 92%, well above the activity seen in this population with elironrasib monotherapy. The majority of patients on the combination remained on treatment as of the February 10, 2025 data cutoff date. Taking a step back and looking at our data-driven lung cancer strategy, we believe we have a clear path to pursuing our ambition to change the standard of care for patients with RAS mutant lung cancer, both in first-line metastatic and in earlier lines of treatment. We launched our initiative in non-small cell lung cancer with our registrational study for daraxonrasib monotherapy in previously treated patients with RAS mutant lung cancer. The emerging zoldonrasib data point to clear opportunities to continue evaluating zoldonrasib in patients with RAS G12D mutant non-small cell lung cancer as monotherapy and in combination. The three pairwise combinations of daraxonrasib plus pembrolizumab, elironrasib plus pembrolizumab, and the RAS(ON) inhibitor doublet of elironrasib plus daraxonrasib all show acceptable tolerability and encouraging antitumor activity and create options in the first-line treatment setting. For patients with tumors harboring RAS G12C, we plan to pursue a chemotherapy sparing RAS(ON) inhibitor doublet treatment, including the elironrasib plus daraxonrasib along with checkpoint inhibitor. For patients with non-G12C disease, we plan to develop daraxonrasib in combination with standard care chemotherapy along with checkpoint inhibitor. We believe each compound in our clinical stage RAS(ON) inhibitor portfolio has the potential to transform treatment for patients living with RAS mutant non-small cell lung cancer. With that, I'll turn the call over to Jack.

Thanks, Wei. We ended the first quarter of 2025 with $2.1 billion in cash and investments, which we project can fund planned operations into the second half of 2027 based on our current operating plan. R&D expenses for the first quarter of 2025 were $205.7 million compared to $118 million for the first quarter of 2024. The increase in R&D expenses was primarily due to increases in clinical trial-related expenses and manufacturing expenses for our three clinical stage programs, with daraxonrasib being the largest driver of the increase given the program is now in two Phase 3 trials. Personnel-related expenses and stock-based compensation expenses also increased in 2025 due to additional headcount. G&A expenses for the first quarter of 2025 were $35 million compared to $22.8 million for the first quarter of 2024. The increase in G&A expenses was primarily due to increases in personnel-related expenses and stock-based compensation associated with additional headcount and commercial preparation activities. Net loss for the first quarter of 2025 was $213.4 million compared to $116 million for the first quarter of 2024. The increase in net loss was due to higher operating expenses. We are reiterating our 2025 financial guidance and continue to expect projected full year 2025 GAAP net loss to be between $840 million and $900 million, which includes estimated non-cash stock-based compensation expense of between $115 million and $130 million. That concludes the financial update. I'll now turn the call back over to Mark.

Thank you, Jack. We are making meaningful progress as we successfully execute on our 2025 strategic priorities in pursuit of our goal to revolutionize treatment for patients with RAS-addicted cancers. A key focus this year is executing on the daraxonrasib registrational studies in both previously treated pancreatic and non-small cell lung cancers. I'm pleased to share that RASolute 302, our ongoing global Phase 3 trial in patients with second-line metastatic pancreatic cancer, continues its strong pace of enrollment in the U.S. following regulatory clearances in the E.U. and Japan. We've also begun enrolling patients in those geographies. We are confident that we'll be able to substantially complete enrollment this year to enable an expected data readout in 2026. We are also currently activating study sites for RASolute 301, our Phase 3 trial in patients with previously treated RAS mutant non-small cell lung cancer. We're making good progress toward advancing daraxonrasib into earlier line randomized pivotal trials with planning underway to initiate registrational trials for daraxonrasib in first-line and adjuvant pancreatic cancer in the second half of this year. Today, we've shared important data that create exciting opportunities for us in both previously treated and first-line metastatic non-small cell lung cancer and eventually earlier lines of treatment, including treatment approaches that include our mutant selective inhibitors. We continue to expand our clinical programs and follow study patients to enable the initiation of one or more pivotal combination trials in 2026. Progressing our earlier stage pipeline, including advancing next generation innovations, continues to be an important priority. At AACR recently, our RMC-5127, our G12V mutant-selective RAS(ON) inhibitor was presented in the new drugs on the horizon session. We continue to advance the program and expect to reach a clinical stage later this year to enable the initiation of a Phase 1 study next year. Finally, we continue to make substantial progress growing our commercial and operational capabilities and in advancing launch readiness activities in support of our first potential product launch. We are making good progress in building our commercialization capabilities in the United States across functions, including onboarding our U.S. field medical team. We also recognize our important responsibility for ensuring patient access to daraxonrasib globally pending regulatory. I am very pleased to announce that Anthony Mancini, Revolution Medicines, as our Chief Global Commercialization Officer and member of our senior management team. Anthony, who will oversee the comprehensive commercialization strategy and operations for our portfolio, brings substantial experience from his successful decades-long career in the biotech and biopharmaceutical industry, having led significant product portfolios, launches, and organizational builds in the U.S. and major international markets as well as overseeing significant strategic partnerships. He will contribute additional strength, both to our approach to the U.S. market and to our evaluation of options for reaching patients internationally. Our vision remains to create the industry-leading targeted-medicine franchise for patients with RAS-addicted cancers. This vision is built on three foundational pillars. First, our pioneering clinical stage RAS(ON) inhibitors have shown our discovery capabilities to be among the most innovative and productive in the industry. Second, our first-class development capabilities have been demonstrated by efficiently progressing multiple assets through first-in-human studies and advancing into late-stage development. Third, we are building high quality organizational capabilities to ensure we can successfully deliver products to patients. Underlying all of this is an exceptionally strong financial position that gives us the wherewithal to continue executing on our strategy and solidifying our position as leaders in the treatment of patients with RAS-addicted cancers. As we continue to deliver compelling clinical observations and build on our track record of execution, we never lose sight of our primary focus, patients living with cancer. Before we open the call for the Q&A session, I'd like to thank the patients and caregivers, clinical investigators, scientific and business collaborators, advisors, and shareholders for their commitment. Without this support, none of the progress we've made would be possible. I'd also like to recognize the extraordinary efforts of Revolution Medicines employees who embody tireless commitment to patients in the work they do every day. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.

Thank you. Our first question comes from the line of Michael Schmidt of Guggenheim. Your line is now open.

Hi, thanks for taking my questions and congrats on all the progress. A lot of new information here to digest today. But I had a question on your first-line non-small cell lung cancer strategy. Obviously, there are interesting new data disclosed today for some of the various doublets. And based on your slide, it seems like for the KRAS G12C, first-line patient population, you're sort of focusing in on a triplet of elironrasib, daraxonrasib and pembrolizumab. Is probably the only combination where we haven't seen data yet today. But just looking at some of the other doublets, perhaps could you just comment on your confidence and tolerability of that triplet just based on some of the rash rates that we're seeing in some of the doublets and some of those reductions there?

Hi, Michael. Thanks for your question. Maybe Wei can speak to that.

We're optimistic given the profile we've seen so far. Obviously, we're still in the dose optimization and we have not yet defined the final dose for the triplet combination. I think we have characterized the monotherapy fairly well and we're not seeing any new safety signaling emerging. And regarding safety signals that are known characterized such as rash, regarding daraxonrasib as well as the QTc, both are within what we have expected to observe with the monotherapy. So I think when we have longer follow-up and define the dose, we'll be sharing those prior to initiating our Phase 3 trial.

Thank you. Our next question comes from Marc Frahm of TD Cowen. Your line is now open.

Hi, thanks for taking my questions and congrats on all of the data sets today. Maybe just looking across the various combination data sets you presented, I'm struck by, I mean, it looks like the vast majority of the responders are still ongoing as of the last data cutoff. Again, PFS is clearly immature, but maybe can you give us a sense of just kind of the average follow-up in those cohorts to maybe give a sense of where durability and PFS may be headed? And then kind of looking longer term, what type of dataset do you think you need to gather before you can kind of formally declare Phase 3 intent for these various combinations? Do you just need to get a little bit more data to get more comfortable on safety and select the final dose? Or is it you need real robust PFS estimates? Just kind of what's needed there?

Hey, Marc. Thanks for your question. I think the first question really is something that refers back to the swimmer plots that we provided in December. And I think those are available. So I'd recommend just taking a look at those in terms of follow-up time for those. We don't have an update today on that because we haven't done a fresh data cut, but the December data had those duration of treatment parameters listed. Your main question I think is about what's really gating now to the triplet. Steve, you want to comment on that?

Yes, there is a distinction between the G12C program and the non-G12C program. The non-G12C program is mostly unrestricted and revolves around operational execution. We have clearly demonstrated that adding daraxonrasib to the KEYNOTE-189 schedule is well-tolerated and shows impressive efficacy. Therefore, we feel no additional data is necessary to proceed. We simply need to navigate the operational and regulatory milestones required to launch a study. As mentioned by Wei in his prepared remarks, the G12C program is currently restricted because we are optimizing the dose of the RAS(ON) doublet, which is a combination of daraxonrasib and elironrasib. Since this is a new combination being tested in untreated non-small cell lung cancer patients, it is crucial to determine the proper dosage to satisfy our company, regulators, payers, and prescribers. We are close to finalizing this, operating within a specific range, and we don’t anticipate it will take much longer. This is what is currently limiting the progress of the G12C first-line non-small cell lung cancer program.

And a subpart of that was, is PFS required? Are we waiting for PFS? And I think that's a simple answer that. PFS is really not driving that decision. We understand PFS based on the second-line data, and now we have confidence that the response rates are very competitive. So I think we're good to go from that perspective.

Yes. We should say we should add that both from the published literature and historical data and from our own very pretty intense in-house analysis, the response rate is a reasonable correlate of PFS in non-small cell lung cancer. That has not been the case for pancreatic cancer, but for lung cancer it is. So we're more confident about the link between our response rates that we've just disclosed in lung cancer patients and the predicted PFS that we will achieve. And of course, PFS in lung cancer is more compelling as a regulatory endpoint, unlike in pancreatic cancer where we have the overall survival. So lung cancer has got a lot more going for it.

Thank you.

Thank you. Our next question comes from Eric Joseph of J.P. Morgan. Your line is now open.

Thanks for taking the questions and let me also just concur. Lots of data updates here and a lot to digest. Maybe Steve, I could get you to expand a little bit on your last comment, the types of datasets, publications perhaps that grant you confidence that response rate higher response rates will be a predictor for better PFS outcomes, sort of outside of your own pipeline work. I'm also curious to know whether you are continuing to enroll the frontline lung cancer cohorts to sort of build upon the dataset that you are observing so far? And then we finally on the safety side, I know this is more than one question, but, on the safety side, this nonclinical, this subclinical QT signal that you're seeing with fair wide combinations, you're confident that it won't become something greater with the triplet regimen? Thank you.

I believe the first part of the question was about the literature demonstrating the predictive utility of response rates for durability. We can provide some references later. It's worth noting that we've received similar questions from investors over the past several years regarding why we don't utilize response rates more frequently. This is generally well understood, and our observations align with that. Would you like to add anything? What was the second part of your question? Do you want to comment on that?

Yes. We have not seen that to be the case. Certainly, we've reported the QTc signal; it's fair. It's actually on par with even lower than what was monitored. Obviously, for longer follow-up and larger patient sample, we do not expect there is going to be an enhancement of QT. So I think QT is well within line of what osimertinib has reported in their label. So I don't think it will be.

And consistent with the larger earlier on and longer for elironrasib dataset that we showed at the beginning here, which I think makes that point pretty clear.

The other question was on whether you're continuing to enroll these chronic cohorts.

Well, there's dose optimization, yes, ongoing, so pretty much answers that.

Okay. Thanks for taking the questions. Congrats on the updates.

Thank you.

Thank you. Our next question comes from Jonathan Chang of Leerink Partners. Your line is now open.

Hi, guys. Thanks for taking my question. How are you thinking about the duration of clinical benefit of daraxonrasib versus the mutant-selective inhibitors like zoldonrasib and elironrasib? What are the reasons for why one could be more durable than the other? And how could this and other factors impact how you're thinking about future development strategies? Thank you.

Thanks, Jonathan. Maybe I'll comment on that and then if Steve or Wei wants to add anything to it. I don't think we have any direct head-to-head comparison because the daraxonrasib study was done in tumors that carry different mutations than the elironrasib study. So we really can't compare those. So we can't say which is superior to the other and they're not matched for other prognostic factors as well. So I don't think we have any information on it. If you're wondering what we might predict, I don't know. We'll see. And ultimately, we're combining these anyway, as both Wei and Steve have talked about. And so one ought to get the benefit of whatever the pros are on each side of that. Is there anything more specific that you're trying to get out there?

I was just thinking about how in situations where you might be considering, advancing the multi-RAS or a mutant-selective one or maybe the combination of both, how you might consider things like duration of clinical benefit and how long patients may stay on treatment, in addition to other considerations?

It's the number one consideration. Because that's the key driver of the sort of patient experience, assuming that we obviously have a combination that patients can tolerate for the time that they're on treatment without having a miserable life. It's the number one consideration. The mechanisms of escape from the mutant-selective inhibitors are very different from the mechanisms of escape from daraxonrasib. We have only disclosed mechanism of escape data for daraxonrasib in pancreatic cancer, but it's very different pattern of escape from what's being disclosed for mutant-selective inhibitors in non-small cell lung cancer. And that's why we're so enthusiastic about the combination because all of those putative mechanisms of escape are covered by the combination. The novel RAS mutations that emerge on the mutant selective inhibitors are inhibited by daraxonrasib, and the putative amplification of mutant KRAS that we might see in lung cancer, which we have seen in pancreatic cancer, is suppressed by hitting the mutant harder with the combination of the two RAS(ON) inhibitors together. So we do expect the PFS to be longer with the combo than with either agent alone. And as we described, the increase in response rate is a good harbinger of that. We just have to wait for that data to mature in order for it to be worthwhile disclosing publicly because immature PFS data isn't helpful to anybody.

Yes. And Steve's comments are entirely consistent with what we have reported in the preclinical context. And I think Wei showed two figures, representative of a much larger dataset that we presented over several scientific meetings that the combination does tend to deliver significantly greater benefit, including the figure on the right side of that slide, I'm not sure what it is in your deck, but that right figure shows the combination of the doublet plus anti PD-1 basically provided for no progression in any of the animals in that experiment across 100 days. So I think the totality of the evidence is supportive of what Steve suggested.

Got it. Thanks for taking the question.

Thank you.

Thank you. Our next question comes from Kelly Shi of Jefferies. Your line is now open.

Hi, this is Clara on for Kelly. Thanks for taking our question. Congrats on the data. So for non-small cell lung cancer with all the combination updates and it seems like you have really multiple paths to pursue the opportunity in lung and you also have total pancreatic development as well as maybe other early initiatives such as G12V. So maybe from a resource allocation perspective, what are the key criteria driving priorities between all those developments? And also for lung cancer specifically, how should we think about the cadence of initiating pivotal combination trials? And you mentioned you might initiate combination trials in 2026. Thank you.

Okay. Thank you, Clara. Let me start with the second comment about timing. I mean, we have provided some timing, and I think that's all we can provide today. We do have, of course, daraxonrasib in non-small cell lung cancer already underway in the 301 study. But then in terms of first-line and combination studies, we'd expect to begin rolling those out in 2026. In terms of resource allocation, I don't think there's a simple single word or sentence answer to help clarify that for you. It's obviously a pretty complex and rich set of opportunities. It's sort of an embarrassment of riches that each clinical study we've done so far opens up pretty exciting new pivotal trials that we could consider doing. So, it certainly does create some need for prioritization. We start with the clinical data, the biological rationale behind the data. We look at the competitive landscape. As Steve pointed out, ultimately what's most important is to provide durable clinical benefit. So that's a key characteristic that gets ranked in all of this. So many, many factors. And at this point, we're able to proceed with a large chunk of the priorities that we have defined. We're basically moving everything forward right now that is ready to be moved forward in 2025, and we'll continue to do that into 2026, constantly looking at justification for the investments, but also trying to achieve the goal that we've alluded to several times here, which is to deliver significant changes on behalf of patients across RAS mutations, tumor types, and lines of therapy, and we think we're best positioned in the industry to do that.

Thank you. Our next question is from Ellie Merle of UBS. Your line is now open.

Hey, guys. Thanks for taking the question and congrats on all the progress. Just curious your latest thinking on a potential commercial strategy ex U.S. And your general philosophy around potential partnering. And then just in terms of the designs for the pivotal combination, trial or trials. Could you give us maybe any more color on when you might expect to meet with the FDA to discuss the designs and when we might be able to learn more about the specifics of the designs from our end? Thanks.

Hi, Ellie. Thanks for your question. On the second point, unfortunately, no, we don't typically sort of lay out the time line for our future interactions or ongoing interactions with the FDA. Our pattern that we try to establish is once we definiteize a plan or close to a definitive plan, we often provide some sort of update including the data to support whatever commitment we're making. But beyond that, I can't give you any further higher resolution answer to it. With regard to the ex-U.S. strategy, that's obviously very much on our minds as I think it is on our investors. Since I first raised almost two years ago now the possibility that we might engage with others to help us commercialize outside the U.S., while we would certainly focus on retaining the U.S. market. We have had strong interest from multiple global pharma companies. We've had concrete and productive dialogue with them. And without a doubt, we could enter an attractive partnership and that's really creates a great deal of optionality for us. We've also felt no need to rush into such a partnership and we've continued to use time to our advantage. We've continued tracking the portfolio, tracking the assets, progress trajectory. We've also tracked organizational progress and trajectory and all of those have continued to exceed our expectations. So now we're in the position to assess the pros and cons of all the options that are available to us. And we have to make a strategic judgment, which we're just not ready to make today, which is what's the best approach for serving patients not only in the U.S., but also internationally and that also serves our business. And we are continuing to look at that, but now through the lens of where we are in 2025 with a very different organization in terms of depth and breadth, program maturity, and also with the addition now of Anthony, who joins the team and can bring a very broad commercial perspective to it as well. So we will complete that analysis at some point and continue to provide updates as appropriate.

Great. Thanks.

Thank you. This now concludes the question-and-answer session. I would now like to turn it back to Mark Goldsmith for closing remarks.

Thank you, operator. Thanks to everyone for participating today and for your continued support of Revolution Medicines.

Thank you for participating today and for your continued support of Revolution Medicines.