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DATE
Wednesday, May 6, 2026 at 4:30 p.m. ET
CALL PARTICIPANTS
- Chairman and Chief Executive Officer — Mark Goldsmith
- Chief Development Officer — Alan Bart Sandler
- Chief Financial Officer — Jack Anders
- President of R&D — Stephen Kelsey
- Chief Medical Officer — Wei Lin
- Chief Global Commercialization Officer — Anthony Mancini
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TAKEAWAYS
- Top-Line Phase 3 Data (RESOLUTE-302) -- Diraxonrasib monotherapy achieved a 60% reduction in risk of death compared to chemotherapy and surpassed one year median overall survival in previously treated metastatic pancreatic cancer.
- Primary and Secondary Endpoints Met -- Diraxonrasib demonstrated statistically significant and clinically meaningful improvements in both overall survival and progression-free survival versus standard chemotherapy in a broad intent-to-treat population.
- Safety Profile -- Diraxonrasib was generally well tolerated with no new safety signals observed in the RESOLUTE-302 and supporting studies.
- Regulatory Path -- Management plans to submit a New Drug Application to the FDA under the National Priority Voucher Program and to file with global authorities; FDA issued a safe-to-proceed letter enabling expanded access treatment protocol for diraxonrasib in the U.S.
- Phase 2 Durability Data (Pancreatic Cancer) -- At six months, Kaplan-Meier estimates for progression-free and overall survival were 71% and 83% for diraxonrasib monotherapy, and 84% and 90% when combined with gemcitabine and nab-paclitaxel.
- RESOLUTE-301 Enrollment Expansion -- Enrollment target in the global phase 3 non-small cell lung cancer trial expanded from 420 to 590 patients to increase statistical power for overall survival; management expects substantial enrollment completion this year.
- Zoldonrasib (G12D Inhibitor) Clinical Activity -- Zoldonrasib produced a confirmed objective response rate of 52%, disease control rate of 93%, and a median progression-free survival of 11.1 months in previously treated non-small cell lung cancer; estimated 12-month survival rate was 73% (median not yet reached).
- Financial Position -- $1.9 billion in cash and investments as of March 31, 2026, supplemented by $2.1 billion in net proceeds from April equity and convertible debt offerings.
- Stock-Based Compensation -- $87.3 million expensed, up from $25.1 million the prior year quarter, with an $80 million increase in projected 2026 stock-based compensation now expected to total $260 million–$280 million for the full year, due to changes in retirement eligibility terms.
- Operating Expenses -- Full-year 2026 GAAP operating expenses projected at $1.7 billion–$1.8 billion, reflecting higher clinical trial, manufacturing, headcount, and commercial readiness costs.
- R&D Spend -- $344 million, up from $205.7 million in the comparable prior-year period, driven by increased activity in diraxonrasib and zoldonrasib programs.
- Net Loss -- $453.8 million, compared to $213.4 million in the prior-year quarter, attributed primarily to higher operating expenses.
- Commercial Infrastructure -- Global commercialization resources and field teams are in advanced stages, with U.S. APAC, and European leadership appointed and launch-readiness activities underway.
- Pipeline Advancement -- First-in-human trial for RMC-5127, a selective KRAS G12V inhibitor, is ongoing with recommended Phase 2 dose identification expected in 2026; preclinical RM055 demonstrated robust antitumor activity in RAS-mutant models and is slated for clinical trial initiation in Q4.
SUMMARY
RESOLUTE-302 top-line results for diraxonrasib established a new survival benchmark for previously treated metastatic pancreatic cancer, with management emphasizing its "practice-changing" impact and broad validation of RAS(ON) inhibition. The FDA’s authorization for expanded access, along with accelerated global regulatory efforts, reflects urgent demand for diraxonrasib. Record capital raises provide Revolution Medicines (RVMD +2.48%) with substantial resources to fund multiple parallel registrational and preclinical programs for its RAS-focused precision oncology pipeline.
- The expansion and statistical powering of the RESOLUTE-301 lung cancer study underscore expectations for an overall survival benefit beyond prior designs.
- Early zoldonrasib efficacy and safety in G12D-mutant lung cancer support management’s intention to advance both monotherapy and combination trials across additional RAS-driven indications.
- RESOLUTE-303 and forthcoming studies will further test diraxonrasib, alone and in combinations, in earlier treatment lines and heterogeneous patient populations, with the design reflecting market-shaping ambitions.
- Preclinical RM055 data suggest potential to address drug resistance mechanisms, with first-in-human studies planned to complement the clinical-stage RAS(ON) inhibitor portfolio.
INDUSTRY GLOSSARY
- RAS(ON) Inhibitor: Small molecule compound designed to inhibit RAS proteins locked in the active, GTP-bound state, frequently found in oncogenic mutations driving tumorigenesis.
- Kaplan-Meier Estimate: Statistical method used to calculate survival probabilities over time from clinical trial data, often reported at specific time intervals for progression-free or overall survival.
- Expanded Access Program (EAP): Mechanism for providing investigational drugs to patients outside clinical trials prior to formal regulatory approval, typically for serious or life-threatening conditions.
- Dual Primary Endpoint: Clinical trial design featuring two equally important endpoints, such as overall survival and progression-free survival, each requiring independent statistical evaluation.
- KRAS G12D Inhibitor: Molecule specifically targeting the KRAS protein bearing a glycine-to-aspartic acid mutation at position 12, prevalent in certain aggressive cancers.
- Adjuvant Setting: Clinical context in which therapy is administered after initial primary treatments (e.g., surgery) to reduce the risk of cancer recurrence.
- Tri-complex Platform: Revolution Medicines approach to designing inhibitors that engage RAS in complex with additional proteins, enhancing selectivity for specific RAS-mediated signaling states.
- PRMT5 Inhibitor: Class of drugs that inhibit protein arginine methyltransferase 5, a target of interest for synergistic combinations with RAS-pathway inhibitors in oncology.
Full Conference Call Transcript
Mark Goldsmith, Revolution Medicines, Inc. Chairman and Chief Executive Officer; Alan Bart Sandler, our Chief Development Officer; and Jack Anders, our Chief Financial Officer. Stephen Kelsey, our President of R&D; Wei Lin, our Chief Medical Officer; and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today’s call. We 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 forward-looking statements.
For a full discussion of these risks and uncertainties, please review our Annual Report on Form 10-Ks and our Quarterly Report 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, 2026 and recent corporate updates. The press release and updated corporate presentation are available on the Investors section of our website at revmed.com. With that, I will turn the call over to Mark Goldsmith, Revolution Medicines, Inc. Chairman and Chief Executive Officer. Mark?
Mark Goldsmith: Thanks, Ryan. It is good to be with you this afternoon to discuss the tremendous progress we have made in 2026. This is a pivotal moment for our organization and for patients worldwide living with pancreatic cancer who are in need of new therapeutic options. It is anchored by the top-line readout for RESOLUTE-302 last month, in which diraxonrasib monotherapy demonstrated an unprecedented improvement in overall survival compared with chemotherapy in patients with previously treated metastatic pancreatic cancer. The RESOLUTE-302 results represent a transformative advance for patients. They also firmly validate our pioneering RAS(ON) inhibitor strategy and reinforce its potential to improve outcomes in RAS-driven cancers.
High investor conviction enabled a historic 2 billion dollar dual-tranche capital raise that will allow us to continue our important work broadly, advancing our current portfolio of four groundbreaking clinical-stage oral RAS(ON) inhibitors and bringing forward the next wave of innovation targeting RAS-addicted cancers, including our new class of catalytic RAS(ON) inhibitors. On today’s call, following my remarks, I will pass the call over to Alan Bart Sandler, who will provide an overview of the recent clinical progress we have made across our portfolio, including the most recent data presented at the American Association for Cancer Research Annual Meeting. Jack Anders will then summarize our first quarter financial results before we open the call to Q&A.
Let me first spend a few moments talking about RESOLUTE-302, the global Phase 3 trial evaluating diraxonrasib monotherapy in patients with previously treated pancreatic cancer. The top-line readout for diraxonrasib marked a major milestone in this disease, significantly raising the bar in the development of new treatments for patients living with pancreatic cancer, the most RAS-addicted of all human cancers. In RESOLUTE-302, diraxonrasib demonstrated unprecedented impact, meeting its primary and key secondary endpoints, and showing statistically significant and clinically meaningful improvement in progression-free survival and overall survival compared to standard-of-care chemotherapy.
In the overall intent-to-treat study population, which includes patients carrying tumors with or without an identified RAS mutation, diraxonrasib drove a 60% reduction in the risk of death compared with chemotherapy and achieved a median overall survival exceeding one year. Diraxonrasib was generally well tolerated and no new safety signals were observed. These are dramatic, practice-changing results, and our focus now is on moving with urgency to bring this potential new option to patients. We intend to submit a New Drug Application to the U.S. Food and Drug Administration under the FDA Commissioner’s National Priority Voucher Program, and we will also execute our plan to file with other global regulatory authorities.
Last week, we reported that the FDA issued a safe-to-proceed letter allowing us to initiate an expanded access treatment protocol for diraxonrasib in patients with previously treated metastatic pancreatic cancer. This will allow us to move as quickly as possible to ensure safe and equitable access to diraxonrasib for eligible patients in the U.S. We were also pleased to announce recently that RESOLUTE-302 will be featured in the plenary session of this year’s American Society of Clinical Oncology Annual Meeting in Chicago. We and the investigators look forward to sharing detailed results with the scientific community at that time. I will now turn the call over to Alan to walk through some recent clinical program updates. Alan?
Alan Bart Sandler: Thanks, Mark. The extraordinary results from RESOLUTE-302 validate our tri-complex inhibitor platform and give us increased confidence in diraxonrasib’s potential in earlier treatment lines in pancreatic cancer. This confidence was reinforced at AACR where we shared updated clinical data from the Phase 2 studies for diraxonrasib monotherapy and in combination with chemotherapy in first-line metastatic pancreatic cancer. Both the monotherapy and combination cohorts demonstrated encouraging preliminary durability data. In the monotherapy study, while median progression-free survival and median overall survival were not mature as of the data cutoff, the Kaplan-Meier estimates at six months were 71% and 83%, respectively.
In the combination of diraxonrasib with gemcitabine and nab-paclitaxel, the Kaplan-Meier estimates at six months for progression-free survival and overall survival were 84% and 90%, respectively. Across both studies, diraxonrasib’s safety and tolerability profile remained consistent with earlier findings in this patient population, with no new safety signals observed. These compelling results strongly support our decision to rapidly advance RESOLUTE-303, our Phase 3 study evaluating both diraxonrasib monotherapy and diraxonrasib in combination with chemotherapy in first-line metastatic disease. The trial is enrolling globally.
In addition to our first- and second-line diraxonrasib registrational studies in pancreatic cancer, patient enrollment is ongoing in RESOLUTE-304, our registrational trial of diraxonrasib monotherapy in the adjuvant setting in patients with resectable disease following conventional surgery and perioperative chemotherapy. We are also making progress in two registrational studies for zoldonrasib, a covalent RAS(ON) G12D-selective inhibitor, in first-line pancreatic cancer. We have initiated RESOLUTE-305, a randomized, double-blind, placebo-controlled, registrational trial evaluating zoldonrasib in combination with investigator’s choice of chemotherapy, either gemcitabine and nab-paclitaxel or modified FOLFIRINOX, compared with placebo plus chemotherapy. We remain on track to initiate RESOLUTE-309, our first registrational study to evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib with diraxonrasib, in the second half of the year.
Moving to non-small cell lung cancer, another focus of development for RAS(ON) inhibitors: with approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, unmet need in non-small cell lung cancer remains a priority that we aim to address through several ongoing and planned registrational studies. Beginning with diraxonrasib, we continue to enroll patients globally in RESOLUTE-301, our global randomized trial evaluating diraxonrasib monotherapy in previously treated patients.
Based on the strength of the Phase 1 results for diraxonrasib monotherapy in non-small cell lung cancer, as well as additional confidence from the recent positive RESOLUTE-302 results, we are expanding the RESOLUTE-301 study to increase the statistical power of the overall survival component of the dual primary endpoint. Enrollment is going well and we anticipate substantially completing enrollment in the expanded study this year. We also expect to disclose our plans regarding diraxonrasib combination therapy in first-line non-small cell lung cancer this year. Turning to G12D non-small cell lung cancer, at AACR we presented updated clinical data for zoldonrasib monotherapy in a subset of patients who had previously been treated with immune checkpoint inhibitors and platinum chemotherapy.
Zoldonrasib was generally well tolerated and demonstrated a safety profile consistent with previously reported findings. Zoldonrasib demonstrated encouraging clinical activity with a confirmed objective response rate of 52%, disease control rate of 93%, and a median progression-free survival of 11.1 months. Overall survival data were immature at the time of analysis. The estimated survival rate at 12 months was 73%, while the median had not yet been reached, which is encouraging at this early look. We continue to believe deeply in the potential of zoldonrasib given its compelling safety and tolerability profile and encouraging clinical activity, which strongly support our plans to advance zoldonrasib across monotherapy and combination settings in lung cancer and other RAS G12D-driven cancers.
Building on the strength of our monotherapy data, we are preparing to initiate in the first half of this year RESOLUTE-308, a global, double-blind, placebo-controlled, registrational trial evaluating zoldonrasib in combination with the KEYNOTE-189 regimen, which is the standard of care in first-line treatment for metastatic non-small cell lung cancer, compared to the KEYNOTE-189 regimen with placebo. For patients with G12C non-small cell lung cancer, elrontinib, a RAS(ON) mutant-selective inhibitor, has demonstrated a differentiated and compelling clinical profile in both G12C inhibitor–naïve and G12C inhibitor–experienced lung cancer patients. We remain on track to share an update on our elrontinib registrational strategy this year.
A preferred RAS-addicted cancer focus is colorectal cancer, which remains an area of high unmet need and interest for the company. We have a range of combination studies underway designed to better understand this genetically complex and heterogeneous disease, including studies to evaluate RAS(ON) inhibitor doublet combinations and RAS(ON) inhibitors in combination with current standards of care and with other targeted drugs. We remain on track to share combination data this year as we work to prioritize registrational opportunities. I will conclude with brief highlights on two of our early-stage programs. We continue enrolling patients in the first-in-human trial of RMC-5127, our fourth RAS(ON) inhibitor. RMC-5127 is selective for KRAS G12V, the second most common KRAS variant in solid tumors.
We expect to identify a recommended monotherapy Phase 2 dose for this compound in 2026. Finally, AACR brought the opportunity to showcase our new class of innovative mutant-targeted catalytic RAS(ON) inhibitors. These inhibitors are designed to promote the conversion of mutant RAS in its active GTP-bound RAS(ON) state back to the inactive GDP-bound RAS(OFF) state, thereby mimicking the normal physiologic regulation of wild-type RAS. These preclinical data demonstrated that at well tolerated doses, RM055 achieved robust and durable antitumor activity across KRAS G12 mutant xenograft models of pancreatic cancer, non-small cell lung cancer, and colorectal cancer. Notably, tumors that had escaped prior RAS inhibitor treatment were sensitive to RM055, which drove deep and durable regression.
Its compelling, differentiated profile warrants clinical investigation of the potential to counter emergent drug resistance and to extend clinical benefit, and we remain on track to initiate a first-in-human clinical trial in the fourth quarter. With that, I would like to pass the call back over to Mark. Mark?
Mark Goldsmith: Thanks, Alan. In addition to the substantial R&D progress we have made across our pipeline, we continue to be very gratified by the buildout of our commercialization infrastructure and operational capabilities to support the company’s global commercialization ambitions. We have established the operational wherewithal required to move with speed and agility, focused initially in the U.S. and extending into priority international regions. We are resourcing our efforts to ensure that we have the best strategies, tactics, operational capabilities, and people to bring diraxonrasib with urgency to patients, pending regulatory approvals. We expect to be launch-ready under best-case approval timing scenarios. We have experienced and talented executives leading our commercialization team, medical affairs, market access, marketing, and sales.
These groups are deeply engaged in market preparedness and assessment, planning, physician and advocacy engagement, sharpening operational capabilities, and conducting other launch-readiness activities. We recently appointed several experienced leaders across the Asia Pacific and European regions, including Neil McGregor as our General Manager for APAC, Ketsuo Endo as General Manager for Japan, and Martin Völkl as General Manager for Germany. I would now like to turn the call over to Jack Anders, our Chief Financial Officer, to summarize our first quarter financial results. Jack?
Jack Anders: Thanks, Mark. We ended the first quarter of 2026 with 1.9 billion dollars in cash and investments, and further strengthened our financial position after the quarter with 2.1 billion dollars in net proceeds from our concurrent upsized offerings of common stock and convertible debt in April. Before we dive into the income statement for the quarter, I would like to highlight that our stock-based compensation expense for the quarter was higher than usual and explain the reason behind it. Stock-based compensation expense was 87.3 million dollars for the quarter ended March 31, 2026, compared to 25.1 million dollars for the quarter ended March 31, 2025.
In 2026, the company updated its equity compensation program to introduce competitive retirement benefits for employees who meet specific minimum age and service requirements. The modification of this program resulted in an incremental 44.6 million dollars in stock-based compensation for 2026. This incremental expense was primarily due to the accelerated timing of recognition of stock-based compensation expense originally scheduled in future periods for outstanding eligible awards. As a result of this timing pull-in, we expect higher, nonrecurring lumpiness in stock-based compensation expense for 2026, with stock-based compensation expense decreasing and returning to a more normalized trajectory in the second half of the year.
As a result of this change, the company is increasing its estimate of full-year 2026 stock-based compensation expense by approximately 80 million dollars and now expects full-year 2026 stock-based compensation expense to be between 260 million dollars and 280 million dollars. Additionally, the company is also updating its projected GAAP operating expense guidance to reflect this expected increase in stock-based compensation expense and now expects full-year GAAP operating expenses to be between 1.7 billion dollars and 1.8 billion dollars. Moving to expenses for the quarter, R&D expenses for the first quarter of 2026 were 344 million dollars, compared to 205.7 million dollars for the first quarter of 2025.
This increase was primarily due to higher clinical trial and manufacturing expenses for diraxonrasib and zoldonrasib due to acceleration of the pace and expansion of these programs. R&D expenses were also higher as a result of increased headcount costs and higher stock-based compensation expense, as described earlier. G&A expenses for the first quarter of 2026 were 101.3 million dollars, compared to 35 million dollars for the first quarter of 2025. The increase in G&A expenses was primarily due to higher stock-based compensation expense as described earlier, increased headcount costs, increased commercial preparation activities, and higher administrative costs. Net loss for the first quarter of 2026 was 453.8 million dollars, compared to 213.4 million dollars for the first quarter of 2025.
The increase in net loss was due to higher operating expenses. That concludes the financial update. I will now turn the call back over to Mark.
Mark Goldsmith: Thank you, Jack. The remarkable start to 2026 is the result of years of unwavering dedication, relentless perseverance, and hard work by our team and collaborators, standing on the shoulders of others. With the unprecedented performance of diraxonrasib monotherapy in the RESOLUTE-302 study, we believe we are in position to change the standard of care for patients living with pancreatic cancer, subject to regulatory review and approval. The global response to the RESOLUTE-302 data has been overwhelming. News brings with it hope and possibility for patients, physicians, and the advocacy community that have all been waiting too long for new, more effective treatment options.
We are now an important step closer to fulfilling our mission of discovering, developing, and delivering innovative targeted medicines to patients living with cancer. We have an extraordinary opportunity, and we take very seriously the responsibility that goes with it. Before I close, I would like to recognize our continuing partnerships with patients and caregivers, health care providers, and investors, as well as the remarkable dedication and efforts of Revolution Medicines, Inc. employees. It requires the ongoing support of all of our partners and constituencies to do revolutionary work on behalf of patients. With that, I will turn the call over to the Operator for the question-and-answer portion of the call.
Operator: Thank you. At this time, we will conduct a question-and-answer session. As a reminder, to ask a question, you will need to press 11 on your telephone and wait for your name to be announced. To withdraw your question, please press 11 again. We ask that each person limit themselves to one question and one follow-up. Our first question comes from the line of Cory Kasimov with Evercore ISI. Cory, go ahead with your question.
Cory Kasimov: Great. Congrats on all of the recent very exciting progress. So I wanted to ask, you recently noted you could share data at a medical meeting that supports the rationale for RESOLUTE-309, the Phase 3 frontline PDAC trial looking at zoldonrasib plus diraxonrasib versus chemo. Would this include durability data or just response rate, as we have seen with some of your initial disclosures? And maybe more importantly, how much additive efficacy would you be looking for here to say it is clinically meaningful to justify the combination over the exciting monotherapy results we have seen with both of these agents? Thank you.
Mark Goldsmith: Thanks, Cory. Appreciate your comments and question. It is probably too early for us to lay out what that presentation would look like. We typically do not forecast it. We will show what we have. We think it will justify our plans, and we will provide that in due course. On the threshold for added value that justifies the combination, we look at the totality of the evidence, we look at historical benchmarks, and ultimately, as you implied in your question, durability is the most important parameter.
Operator: Our next question comes from Charles Xu with LifeSci Capital. Charles, go ahead with your question.
Charles Xu: Good afternoon, everyone. Thank you for taking my questions, and congrats on everything. I had a question on the opposite end of the spectrum. One, how many patients do you—[inaudible]—you can accommodate on your expanded access program for—[inaudible]—and what are the potential implications as you start thinking about—[inaudible]—
Ryan Asay: Charles, we are not able to pick up what you are saying. Stacy, if there is anything you can do on your side to improve the audio quality?
Operator: Charles, are you in a good position to speak with us?
Charles Xu: [inaudible]
Ryan Asay: Okay. Why do we not move on to the next caller and come back to Charles? We will get Charles back queued up.
Operator: Our next call comes from Michael Schmidt with Guggenheim Securities. Michael, go ahead with your question.
Michael Schmidt: Yeah, hey, thanks for taking my question, and again congrats on the RESOLUTE-302 data. Looking forward to the full data presentation at ASCO. A question on the EAP program: I know this was just announced a few days ago, but Mark, could you comment on what you are seeing so far in terms of demand for the EAP program and how many patients could potentially benefit from this prior to officially receiving FDA approval? And then maybe share your view of the size of the second-line pancreatic cancer opportunity based on your market research—how many patients in the U.S. you think would be treatment-eligible for diraxonrasib based on the RESOLUTE-302 study? Thanks so much.
Mark Goldsmith: Thanks, Michael. Nice to hear from you. On the first question, we are working hard to get in a position to be providing drug to those who need it. The demand has been very clear from the moment that it was announced, and we do not expect that to slow down anytime soon. We are putting all the resources that we can on it to help meet that need. I cannot really give you a projection as to the number. We will have to play it out. There is clearly widespread awareness of diraxonrasib, and those calls started coming in within minutes after the announcement.
On the size of the second-line opportunity, we typically think about roughly 60 thousand new cases each year in the U.S. Wei can comment on historical attrition and whether or not diraxonrasib might affect that.
Wei Lin: Happy to do that. These are estimates based on clinical practice. About 60 thousand Americans are newly diagnosed each year with pancreatic cancer. About 50% to 60% of those patients are diagnosed with metastatic disease and will receive first-line therapy for metastatic disease. Typically, because of both the aggressive nature of the disease as well as the toxicity of chemotherapy, about half of the patients who receive first-line metastatic treatment receive subsequent second-line treatment. That gives you a sense of the overall attrition as well as the size.
Mark Goldsmith: And just to add to that, that could change in the context of first-line treatment, but we do not have anything to address on that point today.
Operator: Our next question comes from Faisal Kashib with Jefferies. Faisal, go ahead with your question.
Faisal Kashib: Hey, thank you so much for taking the question. I wanted to ask on the RESOLUTE-301 upsizing. Could you clarify what exactly led to the upsizing, what you were powered for before, and what you are powered for now? And does this change the timeline from enrollment completion to readout?
Mark Goldsmith: Thanks for your question. I will answer the second question, and then Alan will talk about the first. We do not think it will change the timing of the readout given the high pace of enrollment and where we stand today. We do not expect an impact on our projection that we will complete or substantially complete enrollment this year. Alan can comment on the sizing of the trial.
Alan Bart Sandler: An important point is we have realized the importance of overall survival, and given the results that we have seen in RESOLUTE-302 and also the Phase 1 monotherapy data, we have very high conviction in our ability to obtain overall survival benefit. As a result, we are going to further prioritize overall survival in RESOLUTE-301 by expanding enrollment from 420 to 590 patients. That will increase the statistical power of that component of what is a dual primary endpoint. As Mark mentioned, there is great pace in patient enrollment, and we think that we will substantially complete enrollment, even with the expanded study, this year.
Operator: Our next question comes from the line of Brian Chang with JPMorgan. Brian, go ahead with your question.
Brian Chang: Hey, thanks for taking our questions this afternoon. Mark, during the call, you said “best-case timing scenario” for diraxonrasib launch across the globe. How should we think about the timing and cadence for the filing and launches specifically across APAC and European regions? And on the NDA application with the FDA, can you give a bit more granularity on the things that are left to complete?
Mark Goldsmith: Thanks, Brian. We cannot give specific timing with regard to filings outside the United States. Generally speaking, we are starting with the U.S. filing as the initial priority. There will be some sequential framework for filing in other countries, and we are already engaged with regulatory authorities outside of the United States to make sure that we can deliver what they need as timely as possible. For the NDA, we have been fully engaged with the FDA for a long time. With the CMC work and the breakthrough designation, we have had a higher level of engagement than you might otherwise have. We are providing them information as it becomes available and is ready to provide.
Ultimately, the clinical package is the thing that will be provided. I cannot give you a specific timing on that. There is a full-throttle effort to do it. We feel the urgency around it, and we will continue to move this forward as fully as we possibly can.
Operator: Our next question comes from Mark Frahm with TD Cowen. Mark, go ahead with your question.
Mark Frahm: Thanks for taking my questions. Following up a bit on Cory’s question earlier about the zoldonrasib plus diraxonrasib combo: can you speak to the RESOLUTE-309 design, particularly in light of the RESOLUTE-302 finding and the survival data looking better than anything we have seen even in first line? Why is 309 comparing to chemo still the right design, or should it be switched over to consider diraxonrasib monotherapy as the comparator arm?
Mark Goldsmith: That is a good question. Today, standard of care is chemotherapy, and until there is a dataset that moves the FDA to approve a different treatment and that treatment is considered the new standard of care, chemotherapy remains the standard. Of course, we think diraxonrasib has real potential in monotherapy and in combinations in first line. Among those combinations, chemotherapy is one we have already provided early-stage data on and we are excited about, and that combination is in the 303 trial. We already are going into combinations, and it is really a question of when that bar moves. We have high confidence that the combination can deliver something that is differentiated from chemotherapy and even from monotherapy.
We also recognize patient heterogeneity and the value of providing physicians with multiple options that can serve specific needs.
Operator: Stand by for our next question. Our next question comes from Jonathan Chang with Leerink Partners. Jonathan, go ahead with your question.
Jonathan Chang: Hi, thanks for taking my questions, and congrats on the progress. Can you talk about your latest thinking on getting to a chemo-free option in frontline pancreatic cancer? What gives you confidence in being able to achieve this, and what is the best strategy?
Mark Goldsmith: Thanks, Jonathan. We just talked about one strategy for chemo-free frontline, which is diraxonrasib monotherapy. The single-arm data we have shown so far are compelling enough to justify incorporating that into the Phase 3 first-line trial, and we will see how that performs. We have every expectation that it could deliver a chemo-free regimen. The second option is combining a mutant-selective inhibitor with diraxonrasib—that would be a chemo-free strategy. The specific combination of zoldonrasib plus diraxonrasib is for the roughly 40% of pancreatic cancer cases carrying a KRAS G12D mutation. We have other mutant-selective inhibitors directed against additional mutations found in RAS cancers, so we could and likely will fill out that collection of regimens over time.
There are also other combinations to consider, including immunologic agents and other targeted agents. We are already exploring, for example, a PRMT5 inhibitor combination.
Operator: Understood. Thank you. Our next question comes from Charles Xu with LifeSci Capital. Charles, go ahead with your question.
Charles Xu: Hello. Thanks for giving me another stab at this. Can you hear me now? Perfect. RM055—nice to see your presentation at AACR, as well as some of the work supported at Imperial Levitt’s lab that was just published. Can you comment on RM055’s ability to potentially address diraxonrasib resistance mechanisms beyond KRAS amplification? And can you talk about how you might be achieving, at least preclinically, a wider therapeutic window for RAS mutants over RAS wild type than diraxonrasib can achieve? Any color on the mechanism, and whether you can see that in preclinical models as you advance into the clinic?
Mark Goldsmith: Thanks, Charles. Those were loud and clear. Stephen will comment on both topics.
Stephen Kelsey: The RAS amplification can be perceived as a standalone mechanistic basis for escaping diraxonrasib, but it can also be a surrogate for increasing flux through the RAS pathway generally. In most of the experiments we have done, RM055 is a better inhibitor of increased flux through the RAS pathway, particularly when driven by a G12 mutation. There is a general principle of escape from diraxonrasib occurring through reactivation of RAS pathway signaling. It is not just amplification of the mutant allele that can do that, and there is every reason to believe that RM055 may be effective beyond pure KRAS mutant amplification.
Regarding therapeutic index, it relates to the relative importance of hydrolysis of RAS(ON) back to RAS(OFF) between cancer and normal tissue. In normal tissue, most RAS is already in the OFF state, and active RAS is catalyzed back to RAS(OFF) effectively by naturally occurring GAPs. In RAS-mutant cancer, that does not happen; the mutant RAS withstands catalytic hydrolysis back to the OFF state, varying by mutation. We are selectively targeting the inability of mutant, particularly G12 mutant, RAS to be hydrolyzed back to RAS(OFF), by forcing it to be hydrolyzed back. RM055 has almost negligible effect on normal tissue in that respect and a very significant increase in reactivation (deactivation) of mutant RAS in cancer cells.
Operator: Our next question comes from Michael Yee with UBS. Michael, go ahead with your question.
Michael Yee: Thanks, and congrats on the progress. Two quick ones. On the colorectal cancer data coming up, can you help guide expectations on how to think about combination with EGFR given overlapping rash, and how to interpret results given higher efficacy but also trying to mitigate rash? And then, in the first-line pancreatic study, which is enrolling quickly, is it safe to assume there is an interim in that study as well once you complete enrollment?
Mark Goldsmith: On CRC, it is true that diraxonrasib itself has overlap with EGFR antagonists from the perspective of suppression of RAS signaling that drives the skin side effects, so that is a harder combination to contemplate. That does not apply to the mutant-selective inhibitors, which is why the G12C-selective inhibitors that launched the field can be combined pretty readily with EGFR agents, fundamentally addressing the gap in EGFR coverage that occurs in RAS-mutant tumors and the reason EGFR antagonism is typically contraindicated in RAS-mutant tumors. You really need the RAS inhibitor. That combination is, in principle, something that can be pursued. On the first-line study and whether there is an interim analysis, Wei?
Wei Lin: We do not plan to disclose the analysis plan.
Mark Goldsmith: You have heard it from our Chief Medical Officer.
Operator: Our next question comes from Laura Prendergast with Stifel. Laura, go ahead with your question.
Laura Prendergast: Thanks for the update. What are some of the top variables still under consideration for diraxonrasib in first-line lung cancer as far as strategy goes? And on the back of RESOLUTE-302 showing unprecedented OS, what kind of pricing power are you thinking this could unlock, and are there any benchmarks for pricing you are most focused on?
Mark Goldsmith: Nice to hear from you. We cannot really comment on pricing. Of course, the OS impact is something everybody is interested in—from patients and their families to insurers and payers globally—so it will be relevant to their considerations, but that is about all we can say today. On first-line non-small cell lung cancer strategy, there are a couple of things going on. One important variable is that we are now dosing patients with iminezumab, which may potentially become a new standard of care for frontline non-small cell lung cancer. That is something we need to take into account.
Another consideration is that mutant-selective inhibitors are already well established in lung cancer, beginning with the G12C inhibitors that launched the field, and lung cancer care is increasingly genotype-defined. We have a G12D-selective inhibitor performing particularly well, a differentiated and compelling G12C-selective inhibitor, and a G12V-selective inhibitor in the clinic. There are multiple ways to cover the landscape, and that informs the strategy.
Anthony Mancini: On the U.S. commercial field footprint, we are in the final stages of building out our field-based teams across medical affairs, market access, and sales. We have had an MSL team and a thought leader liaison team in place for quite some time. We also have a market access account team engaging with payers and organized customers through pre-approval information exchanges regarding the unmet need in pancreatic cancer, the pipeline, and early clinical data for diraxonrasib. We are in the final stages of onboarding our U.S. sales force.
We are pleased with the team: they have deep expertise in solid tumors across GI malignancies and in oral oncology, and they will be fully trained and ready to engage HCPs if we receive an FDA approval.
Mark Goldsmith: On first-line to second-line attrition, it is a good and important question, but it is hard to get a detailed and clear understanding from records regarding why patients do not proceed. Patients may decide not to proceed because of intolerability, perceived intolerability before trying, personal priorities such as spending time with family rather than receiving chemotherapy infusions, or, sadly, because some patients do not survive to second line. A more convenient and better tolerated regimen—a once-daily pill with a generally well tolerated safety profile—could impact decisions. We will only know if and how much after approval and real-world use.
Laura Prendergast: How should we think about RESOLUTE-303’s enrollment ramp versus the second-line study you just completed, in terms of timing of enrollment completion? And can you remind us whether crossover is allowed in RESOLUTE-303? Separately, any comments on potentially starting a registrational trial with diraxonrasib and a PRMT5 inhibitor?
Mark Goldsmith: Thanks for the questions. On timing of completion, we cannot comment now. We are not at a stage where we can project a timeline with confidence. The more important point is that there is very high interest. Sites that have activated are enrolling, more sites are coming online, and there are patients lined up.
Operator: This concludes our question-and-answer session. Thank you for participating in today’s conference call. You may now disconnect.
