Revolution Medicines (RVMD) Earnings Transcript

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DATE

Wednesday, Feb. 25, 2026 at 4:30 p.m. ET

CALL PARTICIPANTS

• Chairman and Chief Executive Officer — Dr. Mark A. Goldsmith
• Chief Financial Officer — Jack Anders
• President of Research and Development — Dr. Stephen M. Kelsey
• Chief Development Officer — Dr. Alan Bart Sandler
• Chief Medical Officer — Dr. Wei Lin
• Chief Global Commercialization Officer — Anthony Mancini

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TAKEAWAYS

• Cash and Investments -- $2.03 billion at year-end, with the first $250 million tranche from Royalty Pharma received, and $1.75 billion of future committed capital remaining under this arrangement.
• R&D Expense -- $294.9 million for 2025, up from $188.1 million, reflecting increased clinical trial activity, manufacturing, and higher personnel costs.
• G&A Expense -- $66.7 million for 2025, increased from $28.2 million due to scaled commercial preparation, and expanded personnel costs.
• Net Loss -- $364.9 million for 2025, including $33.7 million stock-based compensation, $12.6 million noncash warrant expense related to EQRx acquisition, and $11.9 million noncash interest related to Royalty Pharma; all increases were directly tied to operational expansion.
• 2026 Expense Guidance -- Expected GAAP operating expenses of $1.6 billion-$1.7 billion, with noncash stock-based compensation comprising $180 million-$200 million, reflecting expansion in both clinical development and commercial readiness.
• Pipeline Clinical Progress -- Over 2,500 patients dosed with RAS(ON) inhibitors, eight ongoing or planned Phase 3 registrational trials, and new assets advancing, including the first-in-human study initiation for RMC-5127 (G12V-selective inhibitor).
• Regulatory Designations -- Daraxonrasib received FDA breakthrough therapy and the Commissioner's National Priority Voucher; zoldonrasib awarded breakthrough designation, making three RAS(ON) programs designated as breakthrough therapies.
• Key Trial Milestones -- Global enrollment for RESOLUTE-302 in second-line pancreatic cancer completed, with data readout expected in 2026; new registrational trials (RESOLUTE-305 for zoldonrasib combo, and RESOLUTE-303/304 for daraxonrasib) initiated or announced for multiple pancreatic and lung cancer settings.
• First Commercialization Initiatives -- U.S. field sales and commercialization leadership hired, with team buildout underway to support initial market launch.
• Strategic Collaborations -- Active partnerships with Tango Therapeutics (NASDAQ:TNGX), Bristol Myers Squibb (NYSE:BMY), and Summit Therapeutics (NASDAQ:SMMT) to investigate pipeline combinations with PRMT5 inhibitors, and novel bispecific antibodies for expanded solid tumor treatment opportunities.

SUMMARY

Revolution Medicines (NASDAQ:RVMD) detailed a substantive year marked by surging R&D and G&A investments, reinforcing a multi-asset pipeline with significant trial advancement in RAS-driven cancers. Management emphasized the pivotal readiness for data disclosures in 2026 from a fully enrolled global trial, while mapping out the expansion into first-line and adjuvant pancreatic, as well as non-small cell lung cancer initiatives. Regulatory momentum was highlighted by multiple breakthrough designations and the first FDA Commissioner's National Priority Voucher for daraxonrasib, positioning the company at the forefront of RAS(ON) targeted therapy approvals. Shifts in guidance from net loss to GAAP operating expenses were introduced to increase investor clarity, alongside detailed commentary on the use of noncash items embedded in financial statements. Strategic alliances were affirmed as a core pillar for pipeline differentiation and breadth, with multiple externally derived combinations progressing clinically in tandem with accelerated in-house commercialization hiring.

• Daraxonrasib and zoldonrasib Phase 3 agendas encompass standalone and combination protocols, with readouts and trial initiations sequenced to address unmet needs across several indications.
• Management confirmed "the study is powered for OS," in RESOLUTE-302, clarifying statistical design and regulatory expectations for upcoming readouts.
• Protocols for treatment beyond progression were not enabled in RESOLUTE-302, though adoption of this approach is being evaluated in subsequent trials, reflecting evolving investigator and regulatory perspectives.
• Multiple RAS mutation-specific strategies are operational, with G12D, G12C, G12V, and other genotypes being precisely targeted by next-generation clinical candidates.
• Collaboration with Summit Therapeutics advanced dosing of patients in studies with ibimesumab, a PD-1/VEGF bispecific, aiming to diversify immune-oncology combinations, and hedge against evolving standards of care.
• A new class of RAS inhibitors, exemplified by preclinical candidate RM055, demonstrated deep and durable responses in resistant models, with clinical entry planned for this year.
• Management shifted financial guidance rationale, stating the move "is intended to provide expectations on our anticipated level of spend for 2026 in a more straightforward and easier to follow manner," reflecting a drive for transparent capital allocation signaling.

INDUSTRY GLOSSARY

• RAS(ON) Inhibitor: A drug designed to block the active, GTP-bound state of a mutant RAS protein that drives oncogenic signaling in cancer cells.
• Commissioner's National Priority Voucher (CNPV): An FDA-issued program voucher offering expedited regulatory review for drugs addressing significant unmet needs, awarded in rare circumstances.
• PRMT5 Inhibitor: A targeted therapy inhibiting protein arginine methyltransferase 5, often combined with RAS inhibitors for synergistic anticancer effects, particularly in MTAP-deleted tumors.
• Ibimesumab: A bispecific antibody that targets both PD-1 and VEGF pathways, used experimentally for its dual immune and anti-angiogenic mechanisms in solid tumor treatment.
• RESOLUTE-302/303/304/305/308/309: Company-defined nomenclature for pivotal and registrational clinical studies in pancreatic and lung cancers evaluating different RAS(ON) inhibitors and combination regimens.
• MTAP Deletion: A specific genomic alteration occurring in certain cancers, relevant for the design of combination therapies in RAS-driven malignancies.

Full Conference Call Transcript

Ryan Asay: Thank you, and welcome, everyone, to our fourth quarter and full year 2025 earnings call. Joining me on today's call are Dr. Mark A. Goldsmith, our Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Stephen M. Kelsey, our President of Research and Development, Dr. Alan Bart Sandler, our Chief Development Officer, Dr. 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. Before we begin, I would like to remind everyone that certain statements we make during this call will be forward-looking.

Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K that is filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter and full year ended 12/31/2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. With that, I will turn the call over to Dr. Mark A. Goldsmith, Revolution Medicines, Inc.'s Chairman and Chief Executive Officer.

Mark A. Goldsmith: Thanks, Ryan. Good afternoon, and thank you for joining us. We will keep our prepared remarks brief today, highlighting the substantial progress and growing momentum for our pioneering RAS(ON) inhibitor pipeline, and outlining several important priorities for the year ahead. Jack Anders will summarize our financial results along with financial guidance for the year ahead. At Revolution Medicines, Inc., we remain steadfast in our commitment to revolutionizing treatment globally for patients living with RAS-addicted cancers through the discovery, development, and delivery of innovative, targeted medicines directed against these common mutational drivers of human cancers.

As pioneers in the RAS targeting field, with a singular focus on RAS-addicted cancers and a great deal of validating data behind us, we are well positioned to continue building on important scientific, drug discovery, and clinical breakthroughs that have the potential to change standards of care for patients. Our efforts throughout 2025 strengthened our leadership position as we advanced our robust pipeline that includes four novel investigational drugs that target the major oncogenic RAS drivers: daraxonrasib, our most advanced program of groundbreaking RAS(ON) multi-selective inhibitor; eleronrasib, a differentiated, highly active, and well tolerated RAS(ON) G12C-selective inhibitor; zoldonrasib, an innovative, highly active, and well tolerated RAS(ON) G12D-selective inhibitor; and our newest clinical compound, RMC-5127, a promising RAS(ON) G12V-selective inhibitor.

We have eight ongoing or planned Phase 3 registrational trials and extensive clinical experience to date with more than 2,500 patients having received one or more of our RAS(ON) inhibitors in the aggregate. This clinical work is built upon the foundation of a strong discovery and preclinical platform that continues pushing the boundaries. Our virtuous cycle of innovation fuels how we discover new ways of targeting RAS through our highly productive tri-complex platform, develop novel investigational drugs through robust and parallel clinical development plans, and systematically expand our commercialization and operational capabilities to deliver potential new therapies to patients globally. I will provide an update on our clinical activities in pancreatic cancer, our most advanced clinical program.

With more than 90% of pancreatic cancers being RAS-driven, there is a profound need for RAS-targeted therapies, which we aim to address with multiple registrational trials underway or that we plan to initiate in 2026. Daraxonrasib, our pioneering RAS(ON) multi-selective inhibitor, has shown an unprecedented clinical profile across RAS mutations and lines of therapy, either alone or in combination with standards of care. Our broad conviction around daraxonrasib was further strengthened by the U.S. FDA designation of daraxonrasib as a breakthrough therapy and its award of one of the agency's first Commissioner’s National Priority Vouchers based on its potential to address significant unmet needs in pancreatic cancer.

We are currently evaluating daraxonrasib in three randomized registrational studies in pancreatic cancer across lines of therapy. RESOLUTE-302, a randomized registrational trial evaluating daraxonrasib monotherapy in second-line metastatic disease. As a reminder, RESOLUTE-302 employs a nested trial design, the largest population of patients with tumors carrying a RAS G12 mutation in the core, and the expanded population that includes patients with tumors carrying other RAS mutations, and tumors without a detected RAS mutation. The trial employs hierarchical testing to maximize the probability of success in the core population, and potentially enable a broad label not requiring biomarker testing. With global enrollment now complete, we expect a readout to occur in 2026.

In earlier lines of therapy, two randomized studies were recently initiated. RESOLUTE-303 is evaluating both daraxonrasib monotherapy and daraxonrasib in combination with chemotherapy in first-line metastatic disease. Evaluating both monotherapy and combination approaches may enable treatment optionality for physicians and patients. RESOLUTE-304 is evaluating daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease after receiving conventional surgery and perioperative chemotherapy. The data we have collected to date support our strong conviction that these studies have the potential to establish new global standards of care across lines of treatment for patients living with pancreatic cancer. Zoldonrasib, our covalent G12D-selective inhibitor, is another first-of-its-kind compound that has shown a highly differentiated safety and tolerability profile.

We recently disclosed encouraging initial data from patients with metastatic pancreatic cancer receiving first-line treatment with the combination of zoldonrasib and modified FOLFIRINOX. The initial safety and tolerability profile for the combination of both treatments was largely consistent with the well-known profile of modified FOLFIRINOX alone, and a high zoldonrasib dose intensity was maintained. As of the data cutoff date, 63% of patients achieved a partial response, either confirmed or pending confirmation. The disease control rate was 95%, and the vast majority of patients remained on treatment. With these data reinforcing confidence in this compelling G12D-selective inhibitor, we plan to advance two first-line registrational combination studies this year. Today, we are pleased to announce that RESOLUTE-305 has been initiated.

RESOLUTE-305 is a randomized, double-blind, placebo-controlled trial evaluating zoldonrasib in combination with investigator’s choice of either gemcitabine + nab-paclitaxel, or modified FOLFIRINOX chemotherapy, compared to investigator’s choice of chemotherapy with placebo. RESOLUTE-309 will evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib plus daraxonrasib, and we plan to initiate this trial in 2026. We plan to share clinical data from the initial trial of the zoldonrasib plus gemcitabine + nab-paclitaxel combination and the zoldonrasib plus daraxonrasib RAS(ON) inhibitor combination in PDAC at one or more medical meetings this year. A second area of focus in which we have shown continued clinical advancement is non-small cell lung cancer.

Approximately 30% of non-small cell lung cancers harbor a RAS mutation, including 18% with non-G12C mutations. This tumor type remains a key priority. To date, we have shown encouraging initial safety, tolerability, and antitumor activity in patients with RAS-mutant lung cancers across our three lead compounds, supporting their potential to establish new standards of care, and we are building a set of registrational trials accordingly. RESOLUTE-301, our global randomized trial evaluating daraxonrasib monotherapy in previously treated patients, continues enrolling patients across sites both in the U.S. and globally. We anticipate substantially completing enrollment this year. We also expect to disclose our plans for advancing daraxonrasib combination therapies in first-line non-small cell lung cancer this year.

With zoldonrasib and eleronrasib, we have reported highly encouraging safety, tolerability, and antitumor activity data from previously treated patients with lung tumors harboring RAS G12D or G12C mutations, respectively. A zoldonrasib monotherapy expansion cohort is fully enrolled, and earlier this year, zoldonrasib was awarded breakthrough therapy designation, making it our third RAS(ON) inhibitor to have received this distinction. Building on these milestones, we are preparing to initiate RESOLUTE-308, a first randomized registrational trial of zoldonrasib in combination with standard of care as a first-line treatment for patients with metastatic RAS G12D non-small cell lung cancer.

For eleronrasib, we continue to evaluate this compelling G12C-selective inhibitor that has demonstrated a differentiated clinical profile in both G12C inhibitor–naïve and G12C inhibitor–experienced lung cancer patients. We have reported encouraging results with monotherapy or in combinations with either pembrolizumab or as part of a RAS(ON) inhibitor doublet with daraxonrasib. And as we consider multiple approaches, we plan to share an update on a registrational strategy for eleronrasib this year. The third area of focus, colorectal cancer, remains of high interest and engagement for the company. Approximately 50% of patients with colorectal cancer harbor a RAS mutation. Given the genetically complex and heterogeneous nature of the disease, combinatorial approaches are key to maximizing clinical impact.

We have a range of studies underway, including evaluating RAS(ON) inhibitor doublets, and evaluating RAS(ON) inhibitors with current standards of care and with other novel approaches. We plan to provide visibility into combination data in colorectal cancer this year as we work toward prioritizing registrational opportunities. Our development efforts include several clinical collaborations studying our RAS inhibitors with new targeted therapies in clinical development. Our collaboration with Tango Therapeutics is studying our RAS(ON) inhibitors in combination with vopratelimab, Tango's MTA cooperative PRMT5 inhibitor in patients with tumors carrying both a RAS mutation and MTAP deletion.

We also recently entered into a clinical collaboration with Bristol Myers Squibb to evaluate daraxonrasib in combination with nablimetostat, its MTA cooperative PRMT5 inhibitor, in patients with pancreatic cancer whose tumors carry a RAS mutation and MTAP deletion. This collaboration extends our commitment to evaluating novel targeted agents, such as PRMT5 inhibitors, that may be appropriate to combine with RAS(ON) inhibitors in some settings. Our ongoing collaboration with Summit Therapeutics is evaluating our RAS(ON) inhibitors with Summit’s PD-1/VEGF bispecific antibody ibimesumab across multiple solid tumor settings. The first patient in this trial was recently dosed.

We recently brought our fourth RAS(ON) inhibitor, the RAS(ON) G12V-selective inhibitor RMC-5127, into the clinic and announced that the first patient had been dosed in the first-in-human trial. We expect to identify a recommended monotherapy Phase 2 dose for this compound in 2026. As leaders in developing treatment strategies for patients with RAS-addicted cancers, we recognize the importance of continuing to invest in new approaches that advance the science and have the potential to further transform treatment paradigms. Our discovery team continues pioneering novel new approaches, including an innovative new class of RAS inhibitors from our laboratory designed to overcome RAS-driven drug resistance and thereby extend the clinical benefit of RAS(ON) inhibitors.

As we disclosed in January, in preclinical pancreatic cancer and non-small cell lung cancer models that had developed resistance to daraxonrasib, treatment with a representative compound from this new class, RM055, drove deep and durable regressions. This year, we plan to share more information about this new class of compounds at a scientific meeting and later in the year to begin clinical development of a first compound from this class as our fifth investigational clinical-stage RAS(ON) inhibitor. As late-stage programs, notably daraxonrasib, advance toward possible commercialization, we are committed to building a world-class, end-to-end global oncology enterprise to deliver compelling targeted therapies to patients with RAS-addicted cancers.

We have established a strong operational foundation to move with speed and agility to ensure successful first commercial launch initially focused in the U.S. market. To that end, we have made key strategic hires to form a strong leadership team of professionals who have established track records and launched some of the most impactful oncology products in recent years. In addition to recently onboarding regional field sales leadership to support the U.S. launch, recruitment for our first field sales team is now underway. I would now like to turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance.

Jack Anders: Thank you, Mark. We ended 2025 with $2.03 billion in cash and investments. In 2025, we entered into our innovative and flexible strategic partnership with Royalty Pharma, which provided us access to up to $2.0 billion in committed capital under the terms of the agreement. We received the first royalty monetization tranche of $250 million in June 2025. And there remains an additional $1.75 billion in future committed capital under this arrangement. Turning to expenses, R&D expenses for 2025 were $294.9 million compared to $188.1 million for 2024.

The increase in R&D expenses was primarily due to increases in clinical trial and manufacturing expenses related to our multiple ongoing clinical development programs, and an increase in personnel-related expenses and stock-based compensation expense associated with additional headcount. G&A expenses for 2025 were $66.7 million compared to $28.2 million for 2024. The increase in G&A expenses was primarily due to increases in commercial preparation activities and personnel-related expenses and stock-based compensation expense associated with additional headcount. Net loss for 2025 was $364.9 million compared to $194.6 million for 2024. The increase in net loss was primarily due to higher operating expenses as described earlier.

Net loss for 2025 also included specific noncash charges of $33.7 million in stock-based compensation expense, $12.6 million in noncash warrant expense related to a mark-to-market change in the fair value of warrants we inherited as part of our EQRx acquisition, and $11.9 million in noncash interest expense related to the accounting treatment for our Royalty Pharma arrangement. Full year 2025 financial results are available in our corresponding press release and also included in our Form 10-K that was filed with the SEC this afternoon. Turning to financial guidance, we would like to note that we are switching the forward-looking financial guidance we provide from GAAP net loss to GAAP operating expenses for fiscal year 2026.

The switch to GAAP operating expenses is intended to provide expectations on our anticipated level of spend for 2026 in a more straightforward and easier to follow manner, as GAAP net loss includes certain noncash items within nonoperating income and expense, such as the change in fair value of the warrant liability, and noncash interest expense associated with our Royalty Pharma arrangement. With that said, we expect full year 2026 GAAP operating expenses to be between $1.6 billion and $1.7 billion, which includes estimated noncash stock-based compensation expense of between $180 million and $200 million. The increase in expected GAAP operating expenses for 2026 is a result of the progression and expansion of our clinical development programs.

In particular, the multiple ongoing and planned registrational studies we have outlined as priorities. We also expect higher expenses in 2026 as a result of increased commercial preparation activities as we continue to build and expand our organizational capabilities in preparation for becoming a global commercial-stage company. That concludes the financial portion. I will now turn the call back over to Mark.

Mark A. Goldsmith: Thank you, Jack. 2025 was a pivotal year for Revolution Medicines, Inc., and 2026 is poised to be one of substantial impact as we seek to create the industry-leading global targeted medicines franchise for patients with RAS-addicted cancers. We believe that each asset in our pipeline has the potential to transform the treatment landscape for these difficult-to-treat cancers. With key milestones across our clinical programs, advancing new programs to the clinic, continued investment in innovation, and preparing for our first commercial launch, we are well set up for the future, building on our foundational achievements to date.

Of course, none of the work we do would be possible without the partnership and ongoing support of health care providers, patients and caregivers, and investors, and the remarkable dedication and efforts of Revolution Medicines, Inc. employees. With that, I will turn the call over to the operator for the Q&A portion of today's call.

Operator: Thank you. At this time, we will conduct the 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. Please limit your questions to only one follow-up question when prompted. Please standby while we compile the Q&A roster. Our first question comes from Jonathan Chang of Lyric Partners. Your line is open.

Albert Agustinas: Hi. This is Albert Agustinas on for Jonathan Chang. Thank you for taking our question. I was just wondering, could you please share your thoughts or clarify on your plans to advance the daraxonrasib combination in first-line non-small cell lung cancer this year. Are you still guiding towards the initiation of a registrational trial in this setting? Thank you.

Mark A. Goldsmith: Thanks, Albert, for your question. So I think you are asking about our plans for daraxonrasib in first-line lung cancer. We still have high commitment to continue developing daraxonrasib in lung cancer, particularly in first line. Maybe Dr. Stephen M. Kelsey could comment on a higher resolution answer to that.

Stephen M. Kelsey: The reality is that there are a number of options available to us. We continue to both dose optimize daraxonrasib in combination with the combination partners that you might expect us to use for that indication and also do efficacy testing to get the requisite proof of concept required to invest in a large Phase 3 trial. So as soon as we have that information and a plan to go with it, we will be able to share it with you. And I think we have committed to providing more information on that during the course of this year.

Mark A. Goldsmith: And if I could just add, I think the other element to this, of course, is that we just started dosing patients with ibimesumab, in combination with our RAS(ON) inhibitors. That obviously has a fairly direct impact on how we think about lung care.

Albert Agustinas: Understood. Thank you.

Operator: Thank you. One moment for our next question. Our next question comes from Brian Chang of JPMorgan. Your line is now open.

Brian Chang: Hey, guys. Thanks for taking our questions this afternoon. As we get closer to the top line for the second-line PDAC trial, what is your latest thought on the efficacy that we could get at the time of the top line? And just curious if you can provide a bit more color on the rate of events towards this upcoming top line. Thank you.

Mark A. Goldsmith: Hi, Brian. Thanks for your questions. Of course, we have entered the period in which we indicated we would be providing less detail, so I do not think we will be able to give you higher resolution today. That does not seem like the right time to do that. It is an OS event-driven readout, and the study is powered for OS, but it is, of course, also powered, overpowered then for PFS. So we will have an interim read on that information.

I do not think we will be able to provide any expectations other than that we are directly comparing to standard of care, and that will be the set of benchmarks that will be used in our analyses.

Brian Chang: Got it. Thank you.

Operator: Thank you. One moment for your next question. Our next question comes from Michael Schmidt of Guggenheim. Your line is now open.

Michael Schmidt: Hey, good afternoon. Thanks for taking my questions, and congrats on all the progress. Mark, I had one on your ongoing and planned studies in first-line pancreatic cancer. So, obviously, there is a lot of excitement among physicians and patients in the pancreatic cancer community around daraxonrasib. We have heard from doctors more recently that, if approved, they think that over 90% of their second-line indications could go on daraxonrasib within months of approval. And so when you think about that, to what degree do you think daraxonrasib use in your first-line studies post-progression in the control arm could potentially impact OS outcomes in RESOLUTE-303 and RESOLUTE-305?

And how important is it to demonstrate OS in these studies in the first place? Thank you.

Mark A. Goldsmith: Okay. Thanks, Michael. I think I understand the question. To what extent does the availability of an approved daraxonrasib with a second-line label potentially provide a complication with some form of crossover for patients from the chemo arm in the second-line study, in the 302 study. There is some potential risk for that. Of course, the label would not necessarily indicate ability to crossover unless somebody was declared that they were now formally a second-line patient. We would not be able to speak to what somebody might do off label. But there is some risk associated with that.

We have the ability to address that, both through timing—we are moving forward with that first-line trial, and it will be some period of time before FDA would review and potentially approve the product. So I think during that period, we can probably establish some significant momentum and buffer against that concern. And the other contribution to solving that is geography, and we do expect that outside the United States, patients will enroll in the trial and contribute significantly, and in those settings, it is not likely that the product would be approved yet during the early course of the study.

Michael Schmidt: Makes sense. Thank you.

Operator: Thank you. Our next question comes from Charles Xu of LifeSci Capital. Your line is open.

Charles Xu: Hey. Good afternoon, everyone. Congrats on all the progress, and thanks for taking the questions. I have a couple regarding some of your ongoing partnered collaborations. First, can you talk about your decision to also combine your pipeline assets with Bristol's PRMT5 inhibitor and how this fits in context with your ongoing collaboration with Tango. And second, your collaboration with ibimesumab. At what point might you make go/no-go decisions on later stage clinical development with your pipeline assets? And how do you weigh not only the emerging combination data that you are generating, but also the broader landscape of the various HARMONY trials shaping up. Thank you.

Mark A. Goldsmith: Thanks, Charles. I appreciate those questions. Really two different topics. One is PRMT5 inhibitors and why assess, or support assessment of RAS inhibitors in combination with more than one PRMT5 inhibitor. To some extent, we had already established that precedence because we have an ongoing collaboration with both Amgen and Tango, and the PRMT5 inhibitors appear to be emerging as a potentially important new targeted class of therapies for patients with MTAP gene deletion. So it makes sense for us to make our compounds, which are differentiated and compelling, available to others who have PRMT5 inhibitors. This is not really a signal or a vote on our part about any particular inhibitor.

It does not speak at all to the work that is ongoing with Tango or Amgen. It is rather more of an inclusive approach, and to allow for compounds to be considered in other contexts as well. With regard to the second question, which is ibimesumab and how we will make decisions about when to advance into a late-stage trial, probably the same way we make all such decisions. It will be data-driven. It will depend on the context. Potentially this class of inhibitors could offer a significant advantage over the first-generation PD-1 inhibitors. There is a growing body of evidence to support that.

We do not have the definitive data yet, and we are staying very much on the front lines of combination strategies involving ibimesumab with our RAS(ON) inhibitors. I think we will be in a great position to make the decision with data in hand.

Charles Xu: Understood. Thanks for taking the questions.

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

Marc Frahm: Hi. Thanks for taking my question and congrats on all the progress. Maybe just first off on a bit of a housekeeping thing. Can you just confirm whether any event thresholds have been reached in 302 to trigger yet, or if just none of those have been hit yet. And then thinking more broadly about pancreatic cancer, you now have several first-line trials either ongoing or getting started in the next handful of months. Just what is the kind of long-term vision you have for what the treatment paradigm in pancreatic cancer looks like in four or five years? How do daraxonrasib, zoldonrasib, and chemo all get sequenced, for maybe the typical patient?

Mark A. Goldsmith: Thanks for your question, Marc. I think I will comment on the first one, and then maybe Alan Sandler can comment on your question about sort of future landscape and future expectations for treatment paradigms. My comment is I do not really have any answer to your question. When the data are unblinded, that causes us to do an analysis, which then leads to a disclosure. That is about all I can say today. On your question about how pancreatic cancer looks a few years from now, Alan?

Alan Bart Sandler: Thanks for the question. I think we have set up very nicely with multiple studies to have a major say as to what pancreatic cancer will look like in the next three to five years. With our early studies looking at second-line therapy with daraxonrasib, moving into the first-line setting also with daraxonrasib, looking at it both with respect to as a monotherapy but also potentially in combination with chemotherapy. And then we are doing that with a more specific agent such as zoldonrasib for D, and looking at that as well in combination with chemotherapy versus chemotherapy in the frontline setting, but also the novel ability to combine it with daraxonrasib also in that first-line setting.

This will provide patients with the optionality in first-line setting to actually potentially have a chemotherapy-free opportunity as well as building upon the results that have been seen with chemotherapy alone. In addition, and potentially even more important, we have the opportunity to impact patients who have potentially curable pancreatic cancer by conducting 304, which is our adjuvant study for those patients who have had resected cancer and perioperative therapy. So we really are covering the gamut of patients with pancreatic cancer from second-line therapy all the way to resectable and potentially curable pancreatic cancer. And I think that covers probably three to five years and maybe even a year or two beyond that as well.

And then in addition, of course, as Mark mentioned earlier, there are other agents in our pipeline that we will be looking at as well that will also potentially have an impact.

Marc Frahm: Okay. Thank you.

Operator: Thank you. Our next question comes from Alec Stranahan of Bank of America. Your line is open.

Alec Stranahan: With the ibimesumab study now dosing patients, could you maybe speak a bit about the study design and which tumor types and lines of therapy you expect might enrich the study as it enrolls? Longer term, how is this combo maybe emblematic of how you are hedging your RAS therapies alongside potential shifts in standard of care? Thank you.

Mark A. Goldsmith: Thanks, Alec. I think Dr. Wei Lin, our Chief Medical Officer, can comment on our approach to ibimesumab in the initial Phase 1 context.

Wei Lin: Thanks for the question. So the trial, as has been pointed out, has been initiated, and that is the AUPEX study. It involves all three stage RAS(ON) inhibitors—that is zoldonrasib as well as eleronrasib and daraxonrasib that cover RAS, the G12D, as well as the G12C population. There is a standard dose escalation involving ibimesumab in combination with daraxonrasib, in combination with zoldonrasib, and in combination with eleronrasib. And the dose escalation is standard all solid tumors, and it will help to define the safety and preliminary activity across some of the major solid tumors that are going to be seen.

And then once the doses have been defined and safety has been cleared, there are dedicated expansion cohorts across the three major diseases of interest on both Summit as well as Revolution Medicines, Inc.’s side. It really is focusing on the three diseases that we have focused on today that include pancreatic cancer, non-small cell lung cancer, and colorectal cancer.

Mark A. Goldsmith: And would you like to repeat your second question, which had to do with, I guess, hedging how treatment landscape may evolve in the context of ibimesumab?

Alec Stranahan: Yes. Just broadly, how you are thinking about combos as standard of care evolves across these treatment settings?

Mark A. Goldsmith: Yeah. Well, I think we are not holding anything up. We are certainly developing things in combination with pembrolizumab to the extent that makes sense to do. But we also have to recognize that the field is evolving, and so we are right on the leading edge of it in collaboration with Summit to make sure that we are the first to evaluate RAS inhibitors, and particularly class-leading RAS inhibitors, in combination with ibimesumab. And we will learn a lot. With regard to non-small cell lung cancer where pembrolizumab really is dominant standard of care in most parts of the world, it will take more to knock that off and for there to be a real change.

And that will be up to ibimesumab to prove itself, which is currently, you know, work is underway. In the GI tumors, there is much less of a precedent here, and the combination of a PD-1 and a VEGF inhibitor in the same molecule really opens up a real significant opportunity there, and again, to be the first RAS inhibitors for the RAS versions of those tumors. In combination with ibimesumab is an exciting thing to do. So we are playing all of it all the time, sort of like our overall strategy: everything, everywhere, all at once. And that is pretty much what we have to do in a rapidly evolving environment.

Alec Stranahan: That makes sense. Thanks so much for the color.

Mark A. Goldsmith: Thank you.

Operator: Our next question comes from Asthika Goonewardene from Truist. Your line is open.

Asthika Goonewardene: Hey, guys. Thanks for taking my question. I want to kind of go back to Albert's question at the beginning. Specifically on daraxonrasib in frontline non-small cell lung. I guess in previous earnings calls, we have talked about and you pointed out how pembrolizumab plus chemo is a backbone therapy and how it makes a lot of sense to consider that combination with daraxonrasib. When you talked about other options today, I wanted to just get a little clarity here. When you talk about other options, do you mean other PD-1s in combination with chemo?

Other mechanisms, like maybe involving PD-1 and CTLA-4, or are you considering chemo-free options here for the ideal regimen you want to take daraxonrasib into frontline non-small cell lung?

Mark A. Goldsmith: I think that was really in reference to first-line lung, daraxonrasib, and whether it should be combined with pembrolizumab and chemo or whether potentially ibimesumab emerges during that period of time. I think that was the context for that narrow answer—that we are now evaluating ibimesumab, and so we will have some of that information. But in the meantime, as Steve had articulated, we are continuing the dose optimization and efficacy analysis of daraxonrasib plus pembrolizumab plus chemo from the KEYNOTE-189 context. So those are running in parallel, and that will put us in a good position to make the best decisions.

Asthika Goonewardene: Got it. Thank you.

Asthika Goonewardene: If I can just take a quick one, any thoughts on whether you will use your Commissioner’s priority review voucher for second-line PDAC once you have the RESOLUTE-302 data in hand?

Mark A. Goldsmith: Yeah, I think that has been made clear that it would not really make sense to hold back. The CNPV was awarded on the basis of largely second-line and third-line data that we have shown publicly and shared with the FDA. And so I cannot really see a scenario in which we would not be operating under the CNPV in that second-line 302 data readout context.

Operator: Thank you. One moment for our next question. Our next question comes from Laura Prendergast at Stifel. Your line is open.

Laura Prendergast: Hey, guys. Thanks for taking the question. In a recent public appearance, Mark, you brought up the concept of treating beyond progression in PDAC. From the angle of patients progressing under daraxonrasib. The first part, the amplification of the RAS target. It would be a pretty unique consideration in oncology, where perhaps you are leaving the RAS up on progression of the patient. I am going to raise a few important questions on our end. First, are investigators on the Phase 3 trials in first and second line PDAC being encouraged to treat beyond progression? Is this allowed through study protocols, and you—

Mark A. Goldsmith: Since I could only hear every other word of what you are saying, I am going to have to sort of infer. The question was about treatment beyond progression. We have made the comment that we have heard a number of anecdotes from investigators who have chosen to continue treating patients based on clinical criteria, even in the face of some sort of radiographic progression. And in that context, they have observed a number of patients who continued to do quite well on daraxonrasib for even long periods of time. And the biological context for that is that RAS does not disappear as a driver. It is the driver before we treat with the RAS inhibitor.

It is the driver while we are treating with the RAS inhibitor. It is the driver after you stop treating with the RAS inhibitor. And so in reality, it probably does not make much sense to discontinue if a patient is continuing to benefit. And that set of observations that we have heard syncs up nicely with that underlying biology. But we do not have enough quantitative data to really say anything definitively. We are really giving you anecdotal comments here, and theoretical comments. But now we would like to collect some more data to determine if that really does establish an additional benefit over and above the benefit they have already received at that point in time.

That is my general comments, but I do not know what the actual question was. Can you clarify what you were specifically asking beyond that?

Operator: Yeah. So specifically, as it relates to study protocols, was there any guidance on how much on whether or not this is a possibility on the first-line or second-line Phase 3? Then how you guys think this could impact overall survival of those studies.

Mark A. Goldsmith: Yeah. Okay. I do understand the question now. So did we formalize this in the 302 study versus other studies? It is not in the 302 study because that study was already too far underway to make that modification. That would be difficult to do in the middle of a study. And so treatment beyond progression was not permitted and is not permitted in the 302 study. But as other studies come online, we have encouraged investigators to evaluate that possibility and, where it makes sense, to continue treatment beyond progression, particularly in the earlier-line studies. And so we will be able to generate a lot more information in those contexts.

Operator: Got it. Thank you. Thank you. Our next question comes from Jay Olson of Oppenheimer. Your line is open.

Jay Olson: Congrats on all the progress. Since you are making a lot of headway in PDAC and non-small cell lung cancer, can you talk about your vision and strategy in colorectal cancer? And how are you prioritizing the CRC opportunity for Revolution Medicines, Inc.? Is CRC an area that you would prefer to focus on with partnerships—for example, in combination with ibimesumab—or is CRC something that you plan to pursue independently? And from a BD perspective, would you consider in-licensing some molecules that have synergy with your RAS portfolio so you would not need to rely on partnerships in CRC? Thank you.

Mark A. Goldsmith: Yeah, Jay, thanks for your question. Maybe Steve Kelsey can just comment in general on our approach to CRC, and then if there is anything left on BD at the end, I can come back and comment on it.

Stephen M. Kelsey: Yes. I mean, colorectal cancer has never been deprioritized. Right from the very start of the daraxonrasib and zoldonrasib dose-escalation studies, we included patients with colorectal cancer. I think what we found, which was hardly surprising because a number of other people have also found this both before and since, is that colorectal cancer is an incredibly complex and heterogeneous disease, with multiple subclones, each of those clones often containing multiple genetic abnormalities. And as a result, two things happen, really. One is that overall response rates are lower than they are traditionally in the other RAS-driven diseases, which makes rapid decision-making about future clinical development more complicated because you now have to wait for somewhat longer-term readouts like PFS.

And secondly, it becomes an obligate combination play. There really are no opportunities for developing a single agent in advanced colorectal cancer in the late stage, after chemotherapies have failed. It is such a heterogeneous and genomically complex disease. You need combinations. And in earlier lines of therapy, you really need to combine with combination chemotherapy, which is standard of care. So it becomes more difficult and more time consuming to reach a point where there is a clear path forward into pivotal trials. And I think that is what we have found. It has got nothing to do with prioritization. It is really down to the biology of the disease and how that translates into early-stage clinical trials.

And with regards to methodology, our philosophy as a company is that we have made the decision to be a standalone global organization, and we are not looking to change that purely based on a disease or histotype. There may be opportunities for doing studies in collaboration with partners if we believe that is the right combination and we have the right partner. We may choose to do it as part of a clinical collaboration or maybe even as some other type of business arrangement. But right now, that is not the preferred or even the base case plan.

Our plan is to figure out combinations involving a RAS(ON) inhibitor that are going to make the biggest impact in colorectal cancer and prosecute those to registration.

Mark A. Goldsmith: I think your answer covered it pretty darn well. Maybe the one last little piece is would we bring in additional compounds into our pipeline? That is always possible. We have a very robust process by which we evaluate other people's assets. We receive a lot of inbound proposals, and occasionally, we reach out to somebody else to learn more. So that is all just practical considerations. The fundamental points I think Steve made are the fundamental points.

Jay Olson: Thank you.

Operator: Our next question comes from Leonid Timashev from RBC.

Leonid Timashev: Thanks for taking my question. I wanted to ask a little bit on RM055 and that class of molecules. I guess, does this address secondary mutations, or does it really only work directly on RAS mutations themselves? And I guess, said another way, do you think you will ultimately need to be selecting patients that might be amenable to this? And then, just based on some of the preclinical work you have shown, it looks like it drives very deep responses even relative to daraxonrasib. So are you seeing this ultimately be positioned as a next-line option, or can this be something that ultimately replaces and is a better daraxonrasib? Thanks. Yeah. Thanks, Leonid. Appreciate the question.

Mark A. Goldsmith: All interesting ideas. I think that will become a little bit clearer when our scientific team has a chance to present more formally and in a more fulsome way at an upcoming scientific meeting. The one thing I will say biologically is that point mutations have not emerged as the major form of resistance for daraxonrasib. What has emerged is reactivation of the RAS pathway through other means, typically amplification of the original mutant allele, through increased signaling, for example, through RTKs to increase flux through the pathway, and so on. And so daraxonrasib seems to do generally a very good job of suppressing new oncogenic mutations that might have otherwise emerged in the setting of a selective mutant-selective inhibitor.

So that really is not the primary problem that we are trying to address, or that the team had as its mission in developing this new class of inhibitors. But more to come. Stay tuned. Thanks for the question.

Leonid Timashev: Thank you.

Operator: Our next question comes from Ami Fadia from Needham & Company. Your line is open.

Poorna Kannan: Hi. This is Poorna on for Ami. Thank you for taking our question. Just want to understand how soon can you get to commercialization of daraxonrasib in case the first interim is positive? What are some of the aspects within the commercialization preparations that you still need to work through? Thank you.

Mark A. Goldsmith: Thank you for those questions. So I think you are asking about what have we done to prepare, and what does the timeline look like? I think Anthony can step into that.

Anthony Mancini: Yeah. Thanks for the question. I think we are really pleased with how our launch readiness plan is advancing, and we continue to add highly experienced and talented members of the team, and we are really achieving broad organizational readiness, led by the U.S., but also in Europe and in Japan. So we are really pleased with the launch readiness across the board. As Mark alluded to in his prepared remarks, that launch readiness in terms of the U.S., the first launch, is actually proceeding quite well with leadership teams in place across commercialization and across functions. So field-based leaders across medical affairs, market access, marketing, and sales.

And as Mark mentioned as well, we have now initiated the posting of our further extension of our field-based teams, our sales team. So we are really, really pleased with how the launch readiness overall is coming together. And certainly, as we get closer to filing and launch, we will provide some more color there.

Operator: Thank you. Got it. Thank you. Our next question comes from Kalbat Patel of Wolfe Research. Your line is open.

Kalbat Patel: I guess how should we think about the disclosure of the pivotal update here in second-line pancreatic? If for any reason you missed the interim PFS analysis, and that does not cross the prespecified boundary, would you expect to provide an update at that point, or would you just wait for the OS-driven readout after?

Mark A. Goldsmith: Well, thanks for your question. I do not think we can give you much of an answer to that question right now. We will see what the data show and decide what we consider as appropriate disclosure at that time. Just a reminder, it is an OS event-driven study. It is powered for OS, which means it is more powered for PFS. So the possibility that it does not cross PFS is less likely than not crossing OS at that interim analysis. So if there is a split result, it could be PFS is crossing, OS has not reached statistical significance yet. That is conceivable. Not emphasizing that particularly, but it is one of the possible scenarios.

And we will just have to see what that looks like at that point in time and make an appropriate disclosure decision.

Kalbat Patel: Thank you.

Operator: Thank you. Our next question comes from Sean McCutcheon of Raymond James. Your line is open.

Sean McCutcheon: Hey, guys. Thanks for the questions. Can you speak to the staggering of enrollment for 302, 305, 309, and the 303 protocol components to ensure a representative sample of mutations in 303, and avoid an enrichment of non-G12D patients? And perhaps germane to that as well, can you speak to your expectation for the G12D versus the G12V and G12R patients in the gemcitabine + nab-paclitaxel arm given G12D tends to be a bit more aggressive and chemo resistant?

Mark A. Goldsmith: Okay. Got the general idea. There were a lot of specifics in that. Maybe just the staggering of enrollment—just to make sure we understood your question—were you linking the staggering of enrollment to the mutation representation, or was that more of a broad question about getting access to patients and enrolling patients? I did not quite follow that.

Sean McCutcheon: Yeah. Linking. So, obviously, 303 is all-comers there versus 305 and 309 being G12D. So the staggering as it relates to kind of shuttling the patients, avoiding shuttling the G12D patients to the 305 and 309 studies?

Wei Lin: Sure. I think some of this will be managed by the site selection. All three are global trials. We are certainly mindful that we want to have a fair and equitable representation of all RAS mutants in the all-comer population in the 303 study, and the G12D mutant population in 305 as well as 309. And the control arms do vary among these three trials, so 305 specifically does offer both gemcitabine + nab-paclitaxel as well as FOLFIRINOX. 309 and 303 offer gemcitabine + nab-paclitaxel as a control. And as you know, there are local regional practices as well as institutional practices when it comes to preference for gemcitabine + nab-paclitaxel and FOLFIRINOX.

So we have a variety of sites, regions, and countries to select from. The PDAC patients are certainly very common. As you know, there are nearly 60,000 Americans who are newly diagnosed with PDAC every year. Half of those are probably first-line metastatic patients. The U.S. alone would account for about 30,000 in a year, and globally, certainly many more. So I do not think there would be a lack of patients to be selecting from. It is really trying to identify sites based on their local practice and investigator interest in these trials, and then offering these trials as an option to their patients.

And we are still being mindful about the site footprint overlap around these three studies to ensure that the competition across these three studies is not going to be at the individual site level.

Mark A. Goldsmith: Maybe back to mutations and their representation. Eighty-five percent of PDAC cases have a G12 mutation. It would be hard to bias that dramatically just from the few ongoing trials. And so there should be fairly similar representation across any of the multi-RAS inhibitor trials. And then in a G12D trial, it is going to be G12D mutation. It is going to be very specific for that. And then within any given trial, there should be balance between the control groups and the treatment groups because there will be randomization. After patients are designated for a particular chemo type, if it is a chemo-bearing trial, they would be randomized to treatment arm versus chemo.

So this should be balanced throughout these. I am not sure that there is any inherent bias that would lead towards anything unusual.

Sean McCutcheon: Understood. Thanks. And just on the expectation for the 303 study for G12D performance relative to G12V and G12R, given the respective expectations for each of those mutations being treated with gemcitabine + nab-paclitaxel.

Mark A. Goldsmith: Well, you are asking a question that, as posed, presupposed that there are very well-established differences amongst these mutations and how patients perform in a given treatment. I do not think that is so well established. In fact, if you look at multiple studies, you can find very conflicting results. It is just not particularly well established. So, again, whatever it is, whatever the underlying biology is, will be randomized and balanced in a given trial. So whatever that representation is should not put a finger on the scale on control arm versus experimental.

Sean McCutcheon: Understood. Thanks.

Operator: Thank you. Our next question comes from Faisal Khurzid of Jefferies. Your line is now open.

Faisal Khurzid: Hey, guys. Thanks for taking the question. Just wanted to ask, now that you have had the Commissioner’s priority review voucher for a little bit, can you speak to what benefits you are either seeing now or expect to receive from that above and beyond what you would otherwise get from programs like breakthrough designation and the real-time oncology review. Thank you.

Mark A. Goldsmith: Yeah. Thanks for your question. We do not have much to offer on this particular point. We do not generally disclose a great deal about our interactions with the FDA other than to say we do have a constructive interaction with the review team at the FDA, with the division that is handling this. It is the same group that has been handling it all along. They just now have a CNPV to manage. And we have found them to be very communicative, and we have a good constructive dialogue underway. You know, the main advantage that has been described to go with this would be a faster review process. That is really what it is all about.

That is really a question for the FDA and not for us. What we will do is we will provide the data in the sequence that they are requesting it and as quickly as we can. And then their clock, as they see it, starts ticking once they accept a submission, which means after everything is in, they have reviewed it and decide that it is an adequate submission, then they can accept it. Then they have given a suggested time frame for how quickly they would review it. But that is not in our hands. So we do not really have any comments to make on that.

Faisal Khurzid: Great. Thank you.

Operator: Thank you. I am showing no further questions at this time. I would now like to turn it back to the Chairman and CEO, Mark A. Goldsmith, for closing remarks.

Mark A. Goldsmith: Thank you, operator, and thanks to everyone else for participating today and for your continued support of Revolution Medicines, Inc.

Operator: Thank you for your participation in today's conference. This does conclude the program, and you may now disconnect.

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