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DATE
Wednesday, Nov. 5, 2025 at 4:30 p.m. ET
CALL PARTICIPANTS
Chief Executive Officer — Mark A. Goldsmith
Chief Medical Officer — Wei Lin
Chief Development Officer — Alan Sandler
Chief Financial Officer — Jack Anders
Chief Commercial Officer — Anthony Mancini
President, Research and Development — Stephen M. Kelsey
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TAKEAWAYS
Doraxonrasib Special Designations -- Awarded Breakthrough Therapy, Orphan Drug Designation, and an FDA commissioner's National Priority Voucher, highlighting potential to accelerate pancreatic cancer treatment innovation.
Phase I Doraxonrasib Efficacy in Pancreatic Cancer -- Median overall survival reached 13.1 months (G12X) and 15.6 months (all RAS mutants), both exceeding historical controls for standard regimens (6%-7% months second-line, ~11 months first-line).
First-line Monotherapy Response -- Objective response rate of 47% and disease control rate of 89% in first-line metastatic pancreatic cancer at the data cutoff, with most patients ongoing on therapy at the cutoff and data noted as immature for survival estimates.
Ongoing and Upcoming Trials -- Global enrollment winding down for Phase III RASLU-302 in second-line metastatic PDAC; RESLUENT 303 (first-line Phase III, three-arm design) and adjuvant Phase III trials (500-patient, post-resection) initiated or on track for 2025 start.
Sotomiracid Combination Plans -- Combination with doraxonrasib demonstrated improved preclinical response; registrational trial in first-line metastatic PDAC expected in 2026.
Lung Cancer Program Progress -- RESOLVE-301, a global registrational trial (doraxonrasib vs. docetaxel) enrolling in the U.S. Europe, and Japan; first-line regimen with pembrolizumab and chemotherapy planned for 2026 initiation.
Eleerionrasib (RAS-on G12C) Results -- Achieved a 42% confirmed objective response rate in heavily pretreated non-small cell lung cancer, as presented at the triple meeting in October 2025, A 79% disease control rate was observed for eleerionrasib monotherapy in heavily pretreated G12C non-small cell lung cancer patients, with data presented at the triple meeting in October 2025. Median duration of response and progression-free survival were both 11.2 months in heavily pretreated non-small cell lung cancer patients; At 12 months, 62% of heavily pretreated non-small cell lung cancer patients were alive, with median overall survival not reached.
RMC-5127 Clinical Timeline -- KRAS G12V selective inhibitor expected to enter first-in-human studies by Q1 2026, targeting an estimated 48,000 annual U.S. cancer diagnoses.
Cash and Investments -- $1.93 billion in cash and investments as of the end of 2025, including $250 million received from Royalty Pharma in June 2025; $1.75 billion additional committed capital remains under this agreement.
R&D and G&A Expenses -- R&D expenses in 2025 were $262.5 million (up from $151.8 million in 2024) and G&A expenses in 2025 were $52.8 million (up from $24 million in 2024), primarily due to ongoing clinical trials, manufacturing, expanded headcount, and commercial readiness activities.
Full-Year Net Loss Guidance -- Projected full-year 2025 net loss between $1.03 billion and $1.09 billion, including $115 million to $130 million in estimated non-cash stock-based compensation for FY2025.
Key Appointments -- Addition of Alan Sandler as Chief Development Officer; Alicia Gardner and Gurwin Winter named regional General Managers for U.S. and Europe, respectively, to strengthen commercialization infrastructure.
SUMMARY
The call highlighted several potential market-moving updates across clinical development, cash position, and organizational growth. Initiation and progression of multiple Phase III trials, including two in pancreatic cancer and registrational lung cancer studies, could impact future competitive positioning and timelines. Notably, doraxonrasib received three FDA designations, including a National Priority Voucher, which CEO Goldsmith said, "it's the only oncology product that's featured in that particular set," creating optionality for accelerated review. Financially, CFO Anders stated the company had $1.93 billion in cash and investments as of FY2025, with further significant capital committed, providing runway for planned expansion.
Goldsmith indicated ongoing preparatory efforts to "be ready at the earliest possible time for launching a product," with no anticipated hurdles under the CNPB process for doraxonrasib's NDA timing.
Wei Lin reported that Phase I and anticipated Phase III doraxonrasib trial populations are "fairly representative" in prognostic and predictive characteristics, suggesting continuity of results into registrational outcomes.
Management cited robust commercial readiness in both U.S. and international markets, with specialized teams in place and focus on market access and organizational launch capabilities.
Stephen M. Kelsey described resistance mechanisms as still under investigation in NSCLC, distinguishing between genomic and non-genomic factors, and stated, "all bets are off really mapping mechanisms of resistance in pancreatic cancer to mechanisms of resistance in non-small cell lung cancer."
Guidance was maintained on the financial outlook, with explicit affirmation of expense drivers and anticipated loss ranges, but no changes to previously issued expectations.
INDUSTRY GLOSSARY
PDAC: Pancreatic ductal adenocarcinoma; the most common type of pancreatic cancer.
SHP2: An intracellular protein and enzyme that mediates signaling downstream of several growth factor receptors; key in many cancer-driving pathways.
GMP: Gemcitabine and NAB-paclitaxel combination chemotherapy, commonly used as standard-of-care in pancreatic cancer.
CNPB: FDA Commissioner's National Priority Voucher; a pilot initiative that grants accelerated NDA review for select designated drugs.
ORR: Objective Response Rate; percentage of patients whose tumors shrink or disappear after treatment.
DCR: Disease Control Rate; percentage of patients achieving complete response, partial response, or stable disease.
FOLFIRINOX: Chemotherapy regimen of fluorouracil, leucovorin, irinotecan, and oxaliplatin, used in pancreatic cancer.
R0/R1: Surgical margin classifications indicating complete (R0) or microscopic (R1) tumor removal.
KOL: Key Opinion Leader; experts engaged to inform clinical and commercial strategy.
PRMT5: Protein arginine methyltransferase 5, a novel target in certain cancers.
bispecific PD-one VEGF inhibitor: A biologic that targets both PD-1 (programmed death-1) and VEGF (vascular endothelial growth factor) pathways, key in immuno-oncology.
Full Conference Call Transcript
Mark Goldsmith: Thanks, Ryan, and good afternoon. At Revolution Medicines, Inc., we are tireless in our commitment to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. We are building the leading global RAS-targeted medicines franchise that we believe has the potential to transform treatment for patients living with pancreatic, lung, and colorectal cancers. In the quarter, we continued to make substantial progress as we scale the organization and advance our pipeline to fulfill our global development and commercialization ambitions. Today, we'll begin by highlighting recent progress across our pipeline, beginning with doraxonrasib in pancreatic cancer.
I'd like to note that doraxonrasib has received three special designations from the FDA recognizing its potential role in treating patients with pancreatic cancer, an aggressive disease that is nearly always caused by a RAS mutation. It has breakthrough therapy status, and recently it received both orphan drug designation and an FDA commissioner's National Priority Voucher for accelerating review of a new drug application. These highlight the significant unmet medical needs in pancreatic cancer and the potential of this investigational drug to transform treatment for patients living with this devastating disease. I'd like to invite Doctor Wei Lin to walk through our most recent clinical updates in pancreatic cancer.
Wei Lin: Thanks, Mark. Doraxonrasib is our RAS-on multi-selective inhibitor with a promising clinical profile in multiple indications, including pancreatic cancer. In September, we presented long-term follow-up data from the phase one doraxonrasib monotherapy cohort of patients with second-line metastatic pancreatic cancer. These results reinforce our understanding of its strong clinical antitumor activity and durability. The acceptable safety and tolerability profile remained consistent with earlier findings, with no new safety signals observed. Slide 10 shows that with longer follow-up, durability outcomes remain encouraging. The estimated median progression-free survival for patients with both the RAS G12X and all RAS mutant groups exceeded eight months.
The estimated median overall survival was 13.1 months and 15.6 months for patients in the G12X and RAS mutant groups, respectively, with a lower bound of 95% confidence interval approximately 11 months. These results are particularly compelling, especially in the context of standard of care cytotoxic chemotherapy regimens that were reported in randomized control trials to provide a median overall survival of six to seven months in second-line and approximately 11 months in the first-line setting. Revolut 302, our phase three registrational trial in patients with second-line metastatic PDAC, is winding down enrollment globally. As we near completion of enrollment across all U.S. and international sites, we remain on track for an expected data readout in 2026.
In September, we also shared encouraging initial results for doraxonrasib in first-line metastatic pancreatic cancer, both as monotherapy and in combination with standard care chemotherapy. As shown in slide 11, doraxonrasib monotherapy induced tumor regressions in most patients, with an objective response rate of 47% and disease control rate of 89%. The majority of patients remained on study treatment as of the data cutoff. While the data were not sufficiently mature to estimate the median progression-free survival or overall survival, we continue to follow these patients to assess the durability of clinical benefit.
The acceptable safety profile of doraxonrasib monotherapy in the first-line metastatic setting was generally consistent with gemcitabine, NAB paclitaxel, or GMP, represented by deep and sustained tumor regressions. Most patients remained on treatment as of the data cutoff. Again, longer follow-up is required to estimate median progression-free survival and overall survival. As with monotherapy, the combination regimen showed an acceptable safety profile. The rates of treatment-related adverse events were additive of individual agents. No new safety signals were observed. We expect to share updated data from patients treated with doraxonrasib with or without GMP in first-line PDAC, including preliminary durability in 2026.
Building on the encouraging early phase data in the first-line and second-line settings, we are advancing RABLU-303, a randomized three-arm phase three trial in patients with first-line metastatic PDAC. As shown on slide 13, this registrational trial will compare doraxonrasib monotherapy or doraxonrasib plus GMP followed by doraxonrasib monotherapy to a comparator arm of GMP alone. The design of this three-arm study provides two distinct opportunities to demonstrate potential survival benefit for patients. Treatment with doraxonrasib as monotherapy in first-line followed eventually by chemotherapy in second-line, or alternatively, treating concurrently with both doraxonrasib and chemotherapy in first-line. Both strategies have scientific and clinical merit and deserve to be evaluated. We remain on track to initiate RESLUENT 303 this year.
I'd like to provide an overview of the current standard of care in the setting of resectable PDAC. While surgery along with perioperative cytotoxic chemotherapy offers patients the possibility of a cure, the relapse rate is high at approximately 80%. The current standard of care for perioperative treatment is cytotoxic chemotherapy, either modified FOLFIRINOX or gemcitabine capecitabine. The publicly reported disease-free survival rate on these chemotherapy regimens ranges from 13.9 months to 21.6 months. Our three-year disease-free survival ranges from approximately 20% to 40%. We believe there remains significant room for improvement and may be served with RAS-targeted therapy.
The strength of the doraxonrasib monotherapy data so far in both first and second-line metastatic disease provides a compelling rationale for advancing doraxonrasib into the adjuvant setting. And slide 15 shows our Phase III trial design. We plan to evaluate approximately 500 patients after surgical resection and four months or more of perioperative therapy with the local standard of care, either FOLFIRINOX or gemcitabine, capecitabine, administered before and/or after surgery. Patients will be randomized to either observation or doraxonrasib monotherapy, 300 milligrams daily, for two years. The primary endpoint will be disease-free survival with secondary endpoints of overall survival and safety. We have initiated this trial and site activation is currently underway.
Also, touch briefly on sotomiracid, our covalent, RAS-on G12D selective inhibitor in pancreatic cancer. Sotomiracid has demonstrated a compelling clinical profile with encouraging antitumor activity and a particularly favorable safety tolerability profile. With this differentiated profile, we believe sotomiracid has high potential to contribute as a key component of a combination therapy in first-line PDAC with current standard care chemotherapy and/or with doraxonrasib as a RAS inhibitor doublet. The potential for this doublet was featured at last month's triple meeting, where new preclinical data demonstrated that the combination of sotomiracid and doraxonrasib can maximally inhibit RAS G12D and improve both depth and durability of response.
We expect to initiate our first sotomiracid combination registrational trial in first-line metastatic PDAC in 2026. We look forward to sharing the trial details and additional supporting data around that time frame. I'll now return the call to our CEO, Mark.
Mark Goldsmith: Thank you, Wei. Following closely behind pancreatic cancer, our non-small cell lung cancer clinical program remains an area of strategic priority, and we are progressing well in our efforts. Focusing first on doraxonrasib, the RESOLVE-301 registrational trial studying doraxonrasib versus docetaxel in previously treated patients with RAS mutant non-small cell lung cancer continues to enroll patients across sites in the U.S., and is now also enrolling in Europe and Japan. We also continue advancing plans to initiate a registrational trial in the first-line setting in 2026, evaluating doraxonrasib in combination with pembrolizumab and chemotherapy. We expect to disclose study details around the time of initiation.
As a reminder, this plan was based on the encouraging initial data we presented in May showing the combination of doraxonrasib with pembrolizumab with or without chemotherapy was well tolerated and demonstrated encouraging early antitumor activity. In the G12C non-small cell lung cancer space, we continue to make progress with eleeronrasib, our RAS-on G12C inhibitor. Last month at the triple meeting, we presented encouraging monotherapy data in heavily pretreated patients with G12C non-small cell lung cancer who had received a median of three prior lines of therapy, including treatment with a G12C OFF inhibitor.
As shown on slide 22, eleeronrasib demonstrated a confirmed objective response rate of 42%, a disease control rate of 79%, and a median duration of response of 11.2 months. On slide 23, the median progression-free survival was 11.2 months in these heavily pretreated patients. While the median overall survival had not yet been reached, 62% of patients were alive at 12 months. We are encouraged by the strength of these data in late-line KRAS G12C off-inhibitor experienced patients and continue to expand enrollment in this and other eleeronrasib monotherapy and combination studies while exploring a number of options for continued development of this differentiated RAS-on G12C selective inhibitor.
Regarding zolvonrasgon in lung cancer, we are evaluating a Phase I monotherapy expansion cohort of patients with previously treated non-small cell lung cancer as well as exploring combination regimens including with pembrolizumab and zolvonrasib with doraxonrasib. In addition to plans mentioned earlier to initiate a registrational trial for a zolvonrasib combination in patients with first-line metastatic pancreatic cancer in 2026, we expect to initiate one or more additional pivotal combination trials in 2026 that incorporate either zolvonrasib or eleeronrasib. We also continue to advance RMC-5127, an oral tri-complex RAS-on G12V selective inhibitor.
As a reminder, approximately 48,000 patients are diagnosed with a KRAS G12V mutant cancer in the U.S. each year, including non-small cell lung cancer and gastrointestinal cancers such as pancreatic and colorectal. RMC-5127 has been shown to induce deep and durable regressions in preclinical models, and it has been advancing toward clinical development. We are on track to initiate the planned first-in-human trial in Q1 2026. Based on the progress we've made across our three clinical-stage assets, we are confident in the potential of our RAS-on inhibitor portfolio to change the standards of care across pancreatic, lung, and colorectal cancers.
We also have several discovery and clinical collaborations designed to expand the range of strategies we can bring to bear for patients with RAS-addicted cancers. These collaborations enable us to explore diverse combinations of our RAS-on inhibitors with inhibitors of novel disease targets, including Ovapimetostat, a PRMT5 inhibitor under our agreement with Tango Therapeutics, and ivonestumab, a bispecific PD-one VEGF inhibitor, under our agreement with Summit Therapeutics. With our rich, promising clinical and preclinical pipeline, we continue making efforts to scale our organization to meet the extraordinary range of opportunities it affords. In support of this work, we've made new key appointments across late-stage functions.
In our R&D organization, we announced that Doctor Alan Sandler joined Revolution Medicines, Inc. as our new Chief Development Officer. As an accomplished leader in oncology with a strong track record in cancer drug development, Alan brings valuable insights and expertise to our organization. We likewise expanded and strengthened our global and regional commercialization capabilities with additional appointments across our commercialization functions, including two key regional leaders. Alicia Gardner was appointed Senior Vice President and General Manager of the U.S. region, and Gurwin Winter recently joined Revolution Medicines, Inc. as Senior Vice President and General Manager of the European region. I'd now like to turn the call over to Jack Anders to summarize our third-quarter financial results.
Jack Anders: Thanks, Mark. We ended the 2025 with $1.93 billion in cash and investments. This balance includes the receipt of the first royalty monetization tranche of $250 million in June 2025 from our partnership with Royalty Pharma. There remains an additional $1.75 billion in future committed capital under this arrangement. Turning to expenses, R&D expenses for the 2025 were $262.5 million compared to $151.8 million for the 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 doraxonrasib being the largest driver of the increase given the ongoing phase three trials. Personnel-related expenses and stock-based compensation expense also increased in 2025 due to additional headcount.
G&A expenses for the 2025 were $52.8 million compared to $24 million for the 2024. The increase in G&A expenses was primarily due to increases in personnel-related expenses and stock-based compensation expense associated with additional headcount, increased commercial preparation activities, and increased legal expenses. Net loss for the 2025 was $105.2 million compared to $156.3 million for the 2024. The increase in net loss was primarily driven by higher operating expenses. We are reiterating our 2025 financial guidance and expect projected full-year 2025 GAAP net loss to be between $1.03 billion and $1.09 billion, which includes estimated non-cash stock-based compensation expense of between $115 million and $130 million. That concludes the financial update.
I will now turn the call back over to Mark.
Mark Goldsmith: Thank you, Jack. We are highly encouraged by continuing momentum as we seek to build the leading global targeted medicines franchise for patients living with RAS-addicted cancers. We believe our strong financial position, expansive development plans for our compelling pipeline assets, and global commercialization ambitions will allow us to establish new global standards of care. We've made great progress across our pancreatic and lung cancer clinical programs and continue to generate encouraging data that informs our plans in colorectal cancer. Underpinning the passion and drive at Revolution Medicines, Inc. is our collective commitment to patients.
November is recognized globally as both Pancreatic Cancer Awareness Month and Lung Cancer Awareness Month, which align with two highly visible cornerstones of the clinical development efforts by our organization. We have expanded our partnerships with the advocacy community to better understand the dynamics that affect a patient's experience with RAS-driven cancers. Insights from these engagements will continue supporting our development of patient-friendly clinical protocols, access solutions, and educational initiatives. We hope you will join us in supporting the high-impact work by advocacy organizations as they seek to improve outcomes for patients through educational resources, support, and research.
Before closing, I'd like to acknowledge the continued support of our patients and caregivers, clinical investigators, scientific and business collaborators, advisors, shareholders, and importantly, the remarkable team of revolutionaries who drive exciting steps forward on behalf of patients. This concludes our prepared remarks. And I'll now turn the call over to the operator for the Q&A session.
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. Once again, we ask you please limit to one question and one follow-up question. Please standby, we will compile the Q&A roster. Our first question comes from the line of Jonathan Chang of Leerink Partners. Your line is now open.
Jonathan Chang: Hi, guys. Thanks for taking my question. How are you thinking about the impact of receiving the commissioner's national priority voucher on doraxonrasib timelines and your plans?
Mark Goldsmith: Jonathan, thanks for your question. Well, obviously we're very proud to have received one of the first nine vouchers. Actually, it's the only oncology product that's featured in that particular set. The stated goal of that voucher program, the pilot program, is to accelerate the review timelines by some significant amount, potentially making the review timeline shorter by one to two months. And we'll do everything we can to support that. But we've been aggressively preparing for the data readout and then an expected submission of an NDA. And to be ready at the earliest possible time for launching a product.
I don't think at this point in time we anticipate that we would have any difficulty meeting whatever timeline might be delivered under the CNPB process.
Jonathan Chang: Understood. Thanks for taking my question.
Operator: Thank you. Our next question comes from a line of Charles Xu of LifeSci Capital. Your line is now open.
Charles Xu: Hello. Good afternoon/evening, and thank you for taking our questions, and congrats on the progress. I got a couple regarding RasLeak 304, the adjuvant doraxonrasib trial. This might be a little naive, but can you help us understand and perhaps educate us on the decision to randomize against observation in the post-perioperative chemotherapy setting? And is there, you know, I guess, clinical value in maybe at some point evaluating whether or not one could displace chemotherapy in this particular disease setting as well? Can you also help talk about, help us understand, talk about the requirement for at least four months of perioperative chemotherapy as an eligible criteria prior to, you know, randomizing against the two arms? Thank you.
Mark Goldsmith: Thanks a lot, Charles, for your question. I think Doctor Sandler would be happy to comment on the RasLeak 304 trial.
Alan Sandler: Great. Yeah, thanks. It sounds like it's a three-part question, and hopefully I'll remember all three parts. So the aspect of the I'll start with the four months of therapy. That's considered to be the standard of care that's been established previously. And so we wanted to add to that. So we're requiring that patients receive standard of care therapy for that, and that's at least four months of therapy. So that's number one. Then the idea is to randomize patients to no further treatment or two years of additional adjuvant therapy with doraxonrasib. And the idea then is to build upon the success that has been seen. It's modest success that has been seen with chemotherapy in this setting.
And so this, I think, offers the best approach to patients with resectable pancreatic cancer. Your last question I think was to potentially replace chemotherapy. And I think based on what we see from the adjuvant study, we'll reassess a plan accordingly. But I think we're very excited about this particular opportunity already and are looking forward to initiating the trial.
Charles Xu: Excellent. Thank you very much for taking the questions, and congrats on all the progress.
Mark Goldsmith: Thank you.
Operator: Thank you. Our next question comes from the line of Michael Schmidt of Guggenheim. Your line is now open.
Michael Schmidt: Hey, thanks for taking my questions and congrats on all the progress. A couple of questions on PDAC. So as we think about RASLU-302, how would you expect results from the Phase II study to translate to the large global Phase III study? Are there any anticipated differences, for example, in patient characteristics when you go from a smaller Phase II to a larger global study? And secondly, I guess, in anticipation of positive data next year, how are you tracking towards commercial readiness in terms of CMC manufacturing capacity and then ramping up commercial infrastructure?
Mark Goldsmith: Thanks, Michael. Appreciate the questions. Maybe Doctor Lin can first comment on the phase three versus phase one, two question. How do you do that?
Wei Lin: Thanks for the question. So it's certainly an important question that we thought very deeply before initiating Phase III. So we looked extensively at the patients enrolled in the phase one cohort compared to the Phase III randomized studies that have been reported historically. I think our patient populations are actually fairly similar in looking at all the baseline characteristics that are prognostic or predictive of response to either chemotherapy or our own therapy. Almost all the metrics are either comparable or, in some measures, historical phase 3s were actually a little worse. So I think we do have a patient population in the Phase I setting that's fairly representative of what we expect to enroll on the Phase III.
And furthermore, the RASLU-302 study, while it's a global study, the predominant enrollment will occur in the U.S., with representative enrollment in Europe and in Japan. And therefore, another reason why we feel that the population on the phase one would translate to the phase three. So and then finally, look at historically, the trial after trial, there's a degree of consistency over a period of performances with the chemotherapy. Again, I think we expect the performance, certainly, of the control arm will perform historically similar. So all these give us a large measure of reassurance that we can replicate to a large measure because the patient population as well as the proprimacy of the treatment historically are fairly representative.
Thanks.
Mark Goldsmith: And then the question regarding commercial readiness, maybe I'll answer a comment on part of it and then Anthony Mancini can comment on the other part. With regard to manufacturing, we have a very strong organization and supply chain that's really been prepared over the last number of years. We're already scaling at the proper level to be able to support whatever level of uptake there might be should we be able to launch a product. So I think we're in a very strong position there and don't anticipate anything that could pose a significant problem for us. With regard to commercialization readiness, beyond that, maybe Anthony can comment.
Anthony Mancini: Yeah. Thanks, Mark, and thanks, Michael, for the question. We're really pleased with how our launch readiness plans are advancing. We've, as was outlined earlier, we now have experienced and talented executives leading our commercialization team, including now building into the region. So across multiple functions, including medical affairs, market access, marketing, sales. And we're deeply engaged in market shaping activities and planning, in KOL and ad organization engagement and building broader organizational capabilities around launch readiness. We continue to add highly experienced and talented team members as we advance our organizational launch readiness, including U.S. field-based teams. And we're making great progress there.
We're confident in our ability to continue to attract the right talent with the right experience and capabilities, which is a key success factor for a successful launch, and we're confident that we can do that.
Operator: Thank you. Our next question comes from the line of Andrea Newkirk of Goldman Sachs. Your line is now open.
Morgan (for Andrea Newkirk): Hi, team. Thank you for taking my question. This is Morgan on for Andrea. Based on the initial frontline metastatic PDAC data, how do you think about the efficacy of combination treatment relative to monotherapy, whether greater time on treatment could increase the delta on ORR and DCR? And then with regard to updated doraxonrasib monotherapy and combination data in the first half of next year in frontline metastatic PDAC, how should we be thinking about durability? Thank you so much.
Mark Goldsmith: Thanks for the question, Morgan. Wei would like to comment on those. The first question being, the difference, what level of difference is there between monotherapy versus combination, and will that clarify over time?
Wei Lin: Yeah. So, the monotherapy versus combination in frontline, I think, as we discussed previously, really test two very distinct hypotheses. I think one is really the sequential treatment by introducing an additional line of therapy because currently standard of care only two lines of therapy exist for patients, a GEM-based and a five P VU-based. And by using doraxonrasib monotherapy, we've used a third monotherapy. And could that introduction of a third line therapy with very promising data in the second-line setting translate to prolongation survival? And then the other chemo combination arm really tests a very distinct hypothesis, which is it's a potential synergy by combining the two.
Those patients still get two lines of therapy, but then the first-line therapy is actually a combination regimen of a RAS inhibitor plus a standard chemotherapy. So it's both endotoxic synergy extending the PFS regular survival that can also transfer to longer overall survival. So I think these hopefully will translate into survival benefit as well as different options for patients who can tolerate a more potent regimen versus who are seeking better quality of life. And that provides by monotherapy.
Mark Goldsmith: And just to add that, of course, there's really no way to answer the question about how those two regimens compare except to test them both. And they're both very credible and meritorious scientific hypotheses. The second question, I think, had to do with what sort of update can be expected next year with regard to the durability of the effects that we have already reported.
Wei Lin: Yeah. We do intend to provide an update in 2026.
Morgan (for Andrea Newkirk): Okay. Thank you.
Operator: Thank you. Our next question comes from the line of Brian Chang of JPMorgan. Your line is now open.
Brian Chang: Hey, guys. Thanks for taking our questions this afternoon. Just first on your voucher, what additional pieces of information have you learned on the use of it since you received it mid-October? So specifically, do we know which line of setting the voucher is for since the language on the press release seems to be more broadly applicable to beat the PDAC? And then we have a follow-up. Thank you.
Mark Goldsmith: Yeah. Thanks for your question, Brian. We don't really have any additional information to share with you today. We are certainly in ongoing dialogue with the FDA and learning more about how this voucher system will work and what impact it might have on how we approach preparing an NDA, but no other comments available today.
Brian Chang: Okay. And then just quickly on sodon's combo phase three in frontline PDAC. You know, now that you have 303 on track to start later this year, I'm just curious, you know, if you can talk a little bit about just some consideration that you currently have when it comes to the selection of the doublet versus triplet. And I think also the active comparative piece. How should we think about which active comparator arm you should put in to make it, you know, make sure that physicians understand how they look at sodon combo in the future.
Mark Goldsmith: Yeah. That's a great question. And it perfectly tees up when we present some information about that. We'll be able to address all of those questions. But I assure you we will comment on all of that. Maybe the big picture right now is just that we are taking multiple approaches to treating this devastating disease. And, you know, we're in the second or third inning of this battle. And we're going to keep investing in it until we've really moved the needle as much as we possibly can. So we're excited to bring that approach forward and we'll give you more color about it when we are able to lay that out much more explicitly.
Brian Chang: Great. Thank you.
Operator: Thank you. Next question comes from the line of Mark Fromm of TD Cowen. Your line is now open.
Mark Fromm: Hi, thanks for taking my questions and congrats on all the progress. Maybe just sort of on that Zolgensma Rasib first-line trial, just you have the idea of only pursuing combinations. I guess, should we read into that the monotherapy maybe doesn't seem as durable as doraxonrasib as a monotherapy since you were interested in pushing forward the monotherapy in first-line in that setting. And then I'll likely have a follow-up.
Mark Goldsmith: Thanks, Mark. I'm not sure about that last comment. I'm not sure that we ever gave any inclination with regard to solonaracid in first-line and what sort of strategies we might pursue. So I don't think we need to explain something that I don't think we ever committed to. DuraXomemuracid alone we're setting in first-line as monotherapy. We're going to learn a lot from that study. And zoldon rasid is an ideal combination agent because of its pretty remarkable safety and tolerability profile. So it is a real opportunity to see, you know, how far we can push things and in terms of further differentiating options for patients we will certainly continue to be committed to that.
So I don't think you should infer anything from that decision and that strategy other than we're looking for the best possible ways to deliver impact for patients that would complement the other options that are coming out of our portfolio.
Mark Fromm: Okay. That's helpful. And then on 03/2002, now that, you know, you're getting pretty close to the end of enrollment, you can maybe speak to kinda how the event rate has been trending maybe relative to kinda how you guys were projecting it when you designed the trial? And then as the interim start to get taken, just what's the latest thoughts on disclosure? Will you inform investors whenever an interim is taken and whatever the result of that was or likely only speak, you know, if the interim results in some sort of stoppage of the trial?
Mark Goldsmith: Personally, Mark, I think you're open to on those questions. Anything to comment on either of those this time?
Mark Fromm: Alright. Fair enough.
Operator: Thank you. Our next question comes from the line of Leonid Timoshev of RBC. Your line is now open.
Leonid Timoshev: Hey, thanks for taking my question. Just wanted to ask on the commercial opportunity. I mean, given that you recently hired President of EU Strategy, just how you're thinking about the landscape in the European Union, with respect to where patients lie in terms of commercial opportunity, the concentration there, you know, awareness, diagnostics, opportunities, just anything you can speak to how you think the European strategy might take shape. Thanks.
Mark Goldsmith: Thank you. Appreciate the question. It's a gigantic question, so I'm immediately going to ask Anthony to address.
Anthony Mancini: Look, it has been a lot of thought put into how we're thinking about bringing doraxonrasib to patients. Clearly, different from many companies' opportunities with a first launch and a first indication. We think the second-line pancreatic cancer indication is a meaningful one. So you can look at the epi and you know, in the key European markets, starting with Germany and the EU four and beyond, and there are many patients to treat. We think that will bring a compelling, you know, value proposition in Europe, and we think it's gonna be a meaningful opportunity in Europe, in the U.S., and Japan. And so we're pursuing that.
I think there's nothing more to comment on except that those are our priority markets, and we intend to put our best foot forward.
Operator: Alright. Thank you. Our next question comes from the line of Clara Dong of Jefferies. Your line is now open.
Jenna (for Clara Dong): Hi. Good afternoon. Thanks for taking our questions. This is Jenna on for Clara. Could you talk about if there were any rationale behind starting the adjuvant study before the first-line study? Thank you.
Mark Goldsmith: Jenna, thanks for your question. That's pretty straightforward. Nothing profound underneath it. It's a simpler study, obviously. It's a single treatment arm. And we're just able to get that up and running a little bit earlier. But don't think it will materially differ in terms of the overall conduct of it. Of course, that is going to be a longer study in terms of the readout given the timelines that we talked about. So it doesn't make much difference. And it just happened that we were able to proceed with it.
Jenna (for Clara Dong): Got it. Thank you so much.
Operator: Thank you. Our next question comes from the line of Astika Gunawaradin of Truist Securities. Your line is now open.
Astika Gunawaradin: So you described what resistance mechanisms emerge with doraxonrasib in PDAC. And you should have a considerable amount of data with doraxonrasib in non-small cell lung cancer too under hood. So I'm just wondering, do you expect non-small cell lung cancer to also follow a similar path of resistance as PDAC? Or are there any new resistance mechanisms that are emerging that you can tell us about? I'm wondering how this guided your choice selecting pembro and chemo for the combination versus just a chemosparing pembro combo. And then I have a follow-up.
Mark Goldsmith: Thanks for your question. That's sort of a subtle comment at the end of that question. Maybe Doctor Kelsey can discuss resistance, what we know about PDAC, expectations across other tumor types, and how has that affected our thinking for trial.
Stephen M. Kelsey: The data that we have on emerging mechanisms of resistance to doraxonrasib in non-small cell lung cancer is probably not sufficiently mature for public disclosure at this stage. There are a number of confounding issues around that. The first is, as you know, we declared our recommended phase two dose for non-small cell lung cancer after we had declared the recommended phase two dose in pancreatic cancer. So the information that we have would only really be important at the recommended phase two dose. The second is the number of people that actually have progressed and been documented to progress.
And the third issue there are the number of patients with progression that actually have detectable circulating CTD in order to make an assessment of whether there's anything to see. The other thing is that, you know, traditionally in non-small cell lung cancer, there appear to be from the literature that's available, a lot of resistance mechanisms that are possibly not even genomic. And so, it's gonna take a little bit more time to figure that out. And I think that all bets are off really mapping mechanisms of resistance in pancreatic cancer to mechanisms of resistance in non-small cell lung cancer.
We already know that the biological resistance mechanisms in colorectal cancer, for instance, the GTOC inhibitors are different from the biological resistance mechanisms to GTOC inhibitors in non-small cell lung cancer. They are qualitatively similar and overlap, but they're not identical, and I don't think that we can infer anything at this stage. With regards to how that information informs how we move forward with combinations, it really has no bearing on it. The selection of pembrolizumab as a partner for any of our RAS-on inhibitors is driven really by two things. One is the almost ubiquitous inclusion of pembrolizumab or an equivalent checkpoint inhibitor into the standard of care for non-small cell lung cancer.
And the second is the increasingly compelling body of evidence that suppressing RAS does actually make pembrolizumab more effective because it profoundly changes the immune microenvironment and allows the immune system much more access to the tumor for a whole load of reasons that we have published and a number of other groups have published. So when we have the data, we will disclose it, and it may influence how we move forwards. And it may not. But they're really two separate issues, I think.
Astika Gunawaradin: Thank you for that color. And then if I can just tag on to Charles' previous question. By requiring in the in the by requiring patients to have four months of chemotherapy, does this help select outpatients who are deemed to be borderline resectable?
Alan Sandler: Hi. I'll take that. No. The first, we'll talk about the purpose of it was, again, the four months of standard of care. The question about your borderline and the, you know, the readily resectable. What we've done is we've allowed those patients to undergo the standard treatment that they would locally. And whether they're surgically resectable or not. And then the only way they're able to enter on study is if they are pathologically completely resected. Either with totally clear or narrow margins. The R0 or R1 that was shown on the slide. And then those patients are then randomized to the treatment as such. In a sense, it eliminates those patients who were not able to be resected.
But it also allows those patients with the borderline resectable an opportunity to receive adjuvant therapy if their perioperative therapy and surgery was successful. So it broadens the number of patients who have access to this therapy in the study.
Mark Goldsmith: I also had one point about the question of why four months. You know, there is a variety of different approaches that people take in treating that disease. They all center around using chemotherapy before, after, or both before and after, and by requiring a standardized duration of treatment we can make the patient population more uniform and easier to compare the two groups to each other and avoid imbalances in their treatment regimen.
Operator: Alright. Thank you. Our next question comes from the line of Alex Stranahan of Bank of America. Your line is now open.
Alex Stranahan: Hey guys. Thanks for taking our questions and congrats on the update. Two from us. First on Zolonarasib. Curious how you're thinking about the opportunity for on top of chemo versus Draxonrasib plus chemo in RASLU-303? Do you plan to enroll similar patients in both studies, or maybe try to subset the frontline opportunity? And secondly, how important is the RAS doublet in terms of your ideal commercial strategy longer term, specifically thinking about Zoltanratib, Giraffatib, Rasib in the frontline PDAC. Thank you.
Mark Goldsmith: Okay. Maybe I can just comment on the second one, and then maybe Wei can comment on your first question. So with regard to RAS-on inhibitor doublets, we still have high conviction about it. We just showed some data on ZolomRACED plus DuraXonorasib in preclinical models just last month, at the triple meeting. And we feel like it's a compelling option. Just stay tuned as we roll out the various studies that will be coming in the future. I think we have high interest in that. The first question, I think, had to do with Zoldon versus Duraxon each in a first-line population and are we selecting patients differently between those?
Obviously, one is all RAS mutations, and the other is just KRAS G12D mutations. There's that difference between them, but are there any other differences, Wei?
Wei Lin: Clinically, the eligibility otherwise are no different, and I think in the Phase I setting when we're doing the combination with the chemotherapy, it's really the eligibility are really mainly designed to make adequate organ function about the delivery of chemotherapy. So they're actually also very, very similar.
Mark Goldsmith: Alright. Great. Thank you.
Operator: Thank you. Our next question comes from the line of Joe Catanzaro of Mizuho. Hey, great. Thanks so much for taking my question. Just maybe one quick one from me. As it relates to CRC, just wondering if there are any sort of key data points you are looking towards before maybe committing to earlier line, later stage trials and whether we should expect any of those data points in 2026? Thanks.
Mark Goldsmith: Thanks for your question. Thanks for joining us. Steve, do you want to comment on CRC?
Stephen M. Kelsey: Yeah. I'm happy to do that. I'm not gonna comment on timing because we haven't really guided to data disclosure with regards to colorectal. But I think we have previously made it pretty clear that due to the biological complexity of RAS mutant colorectal cancer, we believe that combination therapy is absolutely essential in order to maximize clinical benefit. The studies that are designed to figure out which combinations are most efficacious in that context are currently ongoing. And so, as we've figured it out, then we can plot a path forward. You know, we also don't forget that we have the there are several dimensions to this issue.
I mean, you mentioned one of them, which is line of therapy. Whether or not we go into the first-line metastatic setting or whether we just tackle patients in the third and fourth line who are essentially being salvaged after chemotherapy has failed. There are several different biologically rational combinations, including combinations within our own portfolio with RAS-on doublets. And so we just need the opportunity to figure that out. It's a very complex colorectal cancer, very complex disease. It's not entirely clear that RAS, mutant RAS is the only driver, the only oncogenic driver even in situations where it's actually mutated. So we've got we're just gonna sort it out.
Joe Catanzaro: Okay. That's helpful. Thanks so much.
Operator: Thank you. Our next question comes from the line of Sean McCutcheon of Raymond James. Your line is now open.
Young (for Sean McCutcheon): Hi. Good afternoon, team. This is Young on for Sean. We have two quick ones. The first one regarding the first one, LCC with Darzan Russiib. What kind of threshold for efficacy by looking at anticipating that you have the update for the frontline. And also commenting on the and combination in the first line LCLC. Thank you.
Mark Goldsmith: Thanks for your questions. Let me make sure I understand the first question had to do with an update on first-line EDAC with Dirac's No. No. Oh, sorry.
Young (for Sean McCutcheon): Yeah. That's all. Non-small cell lung cancer, frontline thyroid thoracic what's the threshold efficacy you're looking at?
Mark Goldsmith: Okay. So in lung cancer, since we indicated that we'll proceed with a trial and we'll provide information later, yeah, I mean, we look at standards of care and what we see in a single-arm trial versus standards care, even though they're not immediately comparable since it's not randomized data. But we'll look at standard care and see if we can improve upon that. We typically wouldn't provide guidance as to what we consider an acceptable improvement that's a complicated topic and that's between us and the statistical analysis plan and the FDA and so on. So no pre-guidance to be able to offer you today on that. And your second question?
Young (for Sean McCutcheon): Yes. The second question is related to the combination potential with your pan rest and g twelve c erelibrone receipt in first line and CLC.
Mark Goldsmith: Okay. That's back to the RasOn inhibitor doublet. In this case, it's the doublet of aleuron plus doraxonerasib. And that too is a very interesting combination. I think I'd just reiterate that we believe that the combination of a mutant selective inhibitor with the transmutant inhibitor provides potentially benefits of both of those compounds as complementary and delivering the greatest impact, and we've now shown two clinical data sets that support that, one in colorectal cancer and one in lung cancer. Both of which were directionally quite similar. To how we prioritize that relative to other options, that's a very complex matrix of considerations. And don't have anything to be able to guide you to specifically today about that.
Operator: Okay. Thank you. Our next question comes from the line of Laura Prendergast of Stifel. Your line is now open.
Laura Prendergast: Congrats on the quarter. I was just curious if it's possible any type of accelerated approval pathway could be there for first-line PDAC. Whether that's an early cut for the phase three study or something or anything else. Also, how are you factoring doraxonrasib being approved in second line? How you're thinking about the statistics for OS in the first-line study?
Mark Goldsmith: Okay, Laura, thanks for your questions. Maybe I'll comment on the AA question. And then maybe Wayne can comment on the doraxonrasib. No comment. That's basically that's always a question for the FDA. That's not so much of a question for us. And, you know, I think there's no doubt that the initial data that we showed were quite encouraging. And I'm sure they're viewed that way by many people. With you know, what the FDA how they view it in a formal sense, what they wanna do with it, would be the subject of, you know, of future dialogue and so on. Really nothing that we can say about that.
I would say just generally speaking, we've had a pretty strong habit of focusing on full approval strategies. Which I think has served us well with regard to PDAC for sure so far. You know, we're not at the end game yet, but it seems to have made sense. We'll continue to prioritize that. There may be some situations in which an accelerated approval can make sense to get something to patients as early as possible. Where we think it makes sense. And the FDA, more importantly, thinks it makes sense, then we could always welcome that opportunity.
Wei Lin: Yeah. Regarding the design statistics of the frontline, given our second line. Efforts and data. I think probably there's several layers to maybe that question. I mean, on the first layer is, we're still designing a fully powered randomized trial to enable registration based on overall survival. So from that regard, doesn't really impact the fact that we deliver on overall survival. We do intend to deliver over cell in front line, even after we get from over the second line. I think second line data that we have reviewed so far I think gave us further confidence about the monotherapy benefit and therefore give us confidence about the arm with molecule P as well as a combination.
Therefore, we're actually fully evaluating and fully powering both arms and independent testing them. So that does affect in that. So that's the second layer. The third layer is I think you may be hinting at, is a question we addressed previously, is, with the second approval in The U.S, there may be impact on crossover and whether that would impact our design. It doesn't really impact our design per se. It only impacts our operational footprint I think, we'll certainly, assign the sites more ex-US to minimize the impact of crossover due to the availability of doraxonrasib for prostaglandin patients in The U.S.
Laura Prendergast: Got it. Thank you very much.
Operator: Thank you. Our next question comes from the line of Ami Fadia of Needham. Your line is now open.
Ami Fadia: Hi, good afternoon. Thanks for taking my question. And apologies if this has been asked already. I've been dropping some calls here. So my question is regarding the acquired alterations post DARA monotherapy that was presented at the triple meeting. How do you see that potentially impacting the durability of response in first line? And, you know, where you're studying in combination with chemo, would you consider exploring combinations with, you know, other mechanisms at this stage? Thank you.
Mark Goldsmith: Thanks, Ami. I'm trying to get to the gist of that question. Would we consider combining Draxon Rastiv with other compounds that target other potential drivers that are resistance mechanisms in order to increase durability? Sure. We're already considering it. We're already actively exploring some of those. And are open to and may well expand that. There's obviously many potential targets that could influence the outcome if you were to inhibit them. And we look at these opportunities all the time. We have significant operations studying those, and we have a lot of inbound requests to combine things.
And we try to prioritize them based on their scientific the scientific data behind them and for sure we'll continue to do that.
Operator: Thank you. This concludes the question and answer session. Would now like to turn it back to Mark for closing remarks.
Mark Goldsmith: Thank you, operator. Thank you to everyone for today and for your continued support of Revolution Medicines, Inc.
Operator: This does conclude the program. You may now disconnect.