管理層發言
Thank you, and welcome, everyone, to our fourth quarter and full year 2025 earnings call. Joining me on today's call are Dr. Mark Goldsmith, our Chairman and Chief Executive Officer; and Jack Anders, our Chief Financial Officer; Dr. Steve Kelsey, our President of Research and Development; Dr. Alan 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'd 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 December 31, 2025, and recent corporate updates. The press release is available on the Investors section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer. Mark?
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, 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, a groundbreaking RAS(ON) multi-selective inhibitor; elironrasib, a differentiated, highly active and well-tolerated RAS(ON) G12C selective inhibitor; zoldonrasib, an innovative, highly active and well-tolerated RAS(ON) G12C selective inhibitor; and our newest clinical compound, RMC-5127, a promising RAS(ON) G12V selective inhibitor. We have 8 ongoing or planned Phase III 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 has 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'll provide an update on our clinical activities in pancreatic cancer, our most advanced clinical program. With more than 90% of pancreatic cancer being RAS driven, there's 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 commissioners 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. RASolute 302, a randomized registrational trial evaluating daraxonrasib monotherapy in second-line metastatic disease. As a reminder, RASolute 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 the first half of 2026. In earlier lines of therapy, two randomized registrational studies were recently initiated. RASolute 303 is evaluating both daraxonrasib monotherapy and daraxonrasib in combination chemotherapy in first-line metastatic disease, evaluating both monotherapy and combination approaches may enable treatment optionality for physicians and patients.
RASolute 304 is evaluating daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease after receiving conventional surgery and perioperative chemotherapy. The data we've 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 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're pleased to announce that RASolute 305 has been initiated. RASolute 305 is a randomized, double-blind, placebo-controlled trial that is evaluating zoldonrasib in combination with investigators' choice of either gemcitabine, nab-paclitaxel, or modified FOLFIRINOX chemotherapy compared to investigators' choice of chemotherapy with placebo. RASolute 309 will evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib plus daraxonrasib, and we plan to initiate this trial in the second half of 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 doublet combination in PDAC at one or more medical meetings this year.
A second area of focus in which we've shown continued clinical advancement is non-small cell lung cancer. With approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, this tumor type remains a key priority. To date, we've shown encouraging initial safety, tolerability, and antitumor activity in patients with RAS mutant lung cancers across our three lead compounds that supports their potential to establish new standards of care, and we are building a set of registrational trials accordingly. RASolve 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 therapy in first-line non-small cell lung cancer this year.
With zoldonrasib and elironrasib, we've reported highly encouraging safety, tolerability, and antitumor activity data from previously treated patients with lung tumors harboring RAS G12D or G12C mutations, respectively. The 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 RASolve 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 elironrasib, we continue to evaluate this compelling G12C selective inhibitor that has demonstrated a differentiated clinical profile in both G12C inhibitor naive and G12C inhibitor experienced lung cancer patients.
We've 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 our registrational strategy for elironrasib 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(ON) inhibitors with new targeted therapies in clinical development. Our collaboration with Tango Therapeutics is studying our RAS(ON) inhibitors in combination with Vopimetostat, 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 Navlimetostat, an MTA cooperative PRMT5 inhibitor in patients with pancreatic cancer whose tumors carry both 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) inhibitor with Summit's PD-1 VEGF bispecific antibody, Ivonescimab, 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 II dose for this compound in the second half of 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 approaches including an innovative new class of RAS(ON) 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, RM-055, 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 a 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'd now like to turn the call over to Jack Anders, our CFO, to summarize our fourth quarter financial results and forward-looking guidance. Jack?
Thank you, Mark. We ended the fourth quarter of 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 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 the fourth quarter of 2025 were $294.9 million compared to $188.1 million for the fourth quarter of 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 the fourth quarter of 2025 were $66.7 million compared to $28.2 million for the fourth quarter of 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 the fourth quarter of 2025 was $364.9 million compared to $194.6 million for the fourth quarter of 2024. The increase in net loss was primarily due to higher operating expenses as described earlier. Net loss for the fourth quarter of 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. This 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.
Thank you, Jack. 2025 was a pivotal year for RevMed, 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 RevMed employees. With that, I'll turn the call over to the operator for the Q&A portion of today's call.
分析師問答
Our first question comes from Jonathan Chang of Leerink Partners.
This is Albert Agustinus on for Jonathan Chang. 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 for in this setting?
Thanks, Albert, for your question. So I think you're asking about our plans for daraxonrasib in first-line lung cancer. We still have a high commitment to continue developing daraxonrasib in lung cancer, particularly in first line. Maybe Dr. Kelsey could comment on prior resolution answer to that.
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 base through trial. So as soon as we have that information and a plan to go with it, we'll be able to share it with you. And I think we've committed to providing more information on that during the course of this year.
Yes. And if I could just add, I think the other element to this, of course, is that we just started dosing patients with Ivonescimab in combination with our RAS(ON) inhibitors that obviously has a fairly act on how we think about lung cancer.
Our next question comes from Brian Cheng of JPMorgan.
As we get closer to the top line for the second-line PDAC trial, what is your latest thought on the efficacy measure 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.
Brian, thanks for your questions. Of course, we've entered the period in which we indicated we'd be providing a disclosure. So I don't think we'll be able to give you higher resolution today, that doesn't seem like the right time to do that. It is an OS event-driven readout. And the study is powered for OS, but it's, of course, also overpowered for PFS. So we'll have an interim read on that information. I don't think we'll 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.
Our next question comes from Michael Schmidt of Guggenheim.
Congrats on all the progress. Mark, I had one on your ongoing trials in first-line pancreatic cancer. So obviously, there's a lot of excitement among physicians and patients in the pancreatic cancer community around daraxonrasib. We've heard from docs 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 outcomes in RASolute 303 and 305? And how important is it to demonstrate OS in these studies in the first place?
Okay. I think I understand the question. To what extent does the availability of an approved daraxonrasib with a second-line label potentially provide 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 the ability to cross over unless somebody was declared that they were now formally a second-line patient. We wouldn't 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're moving forward with that first-line trial, and it will be some period of time before the FDA will review and potentially approve the product. So I think during that period, we can probably establish some significant momentum and buffer against that concern. 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's not likely that the product would be approved yet during the early course of the study.
Our next question comes from Charles Zhu of LifeSci Capital.
Congrats on the progress. 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 kind of fits in context with your ongoing collaboration with Tango? And second, your collaboration with Ivonescimab, 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're generating, but also the broader landscape among the various HARMONY trials shaping out?
Thanks, Charles. I appreciate those questions. We have two different topics to discuss. The first is about PRMT5 inhibitors and how they relate to the assessment of RAS(ON) inhibitors when used in combination with multiple PRMT5 inhibitors. We have already set a precedent with our ongoing collaboration with Amgen and Tango, and PRMT5 inhibitors are becoming an important new target class of therapies for patients with MTAP gene deletion. Therefore, it makes sense for us to make our differentiated and compelling compounds available to others who are developing PRMT5 inhibitors. This decision isn't specifically an endorsement of any particular inhibitor and does not reflect on the work that is ongoing with Tango or Amgen. It is more about taking an inclusive approach to allow our compounds to be evaluated in various contexts. Regarding the second question about Ivonescimab and how we determine when to advance to late-stage trials, our decision-making process is likely to remain data-driven and context-dependent.
This class of inhibitors may offer significant advantages over first-generation PD-1 inhibitors, and we have emerging data to support this. Although we do not have definitive results yet, we are actively involved in a combination strategy that includes IVO and our RAS(ON) inhibitors. We expect to be well-positioned to make informed decisions once we have some data available.
Our next question comes from Marc Frahm of TD Cowen.
Congrats on all the progress. Maybe just first off on more of a bit of a housekeeping. Can you just confirm whether any event thresholds have been reached in 302 to trigger interim analyses yet or if just none of those have been hit yet? And then thinking more broadly about pancreatic cancer, now you have several first-line trials either underway 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 patients?
Thanks for your question, Marc. I think I'll 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 don't 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. And that's about all I can say to that. On your question about how does pancreatic cancer look a few years from now, Alan?
Thank you for your question. I believe we are well positioned with multiple studies to understand what pancreatic cancer treatment might look like in the next three to five years. Our early studies are examining second-line therapy with daraxonrasib as we look to move into first-line treatment. We're also investigating daraxonrasib as a monotherapy and in combination with chemotherapy. Additionally, we are exploring the specific agent zoldonrasib in combination with chemotherapy versus chemotherapy alone in the frontline setting, and also considering combining it with daraxonrasib in first-line treatment. This approach aims to provide patients with a chemotherapy-free option in first-line treatment while building on the results seen with chemotherapy alone. Furthermore, we have the opportunity to help patients with potentially curable pancreatic cancer through our adjuvant study, 304, for those who have undergone surgery. Therefore, we are addressing a broad range of pancreatic cancer patients, from those receiving second-line therapy to those with resectable and potentially curable cancer. This strategy may extend beyond three to five years. Moreover, as Mark mentioned earlier, there are additional agents in our pipeline that we will also be evaluating for potential impact.
Our next question comes from Alec Stranahan of Bank of America.
With the Ivonescimab study now dosing patients, I guess could you maybe speak a bit about the study design and which tumor types and lines of therapy you expect might enrich in the study as it enrolls and longer term, how is this combo maybe emblematic of how you're hedging your RAS therapies alongside potential shifts in standard of care?
I think Dr. Lin, our Chief Medical Officer, can comment on what's our approach to ivo and the initial Phase I context.
Thanks for the question. So like before, the Ivonescimab trial has been initiated, and that's the study that involves all three of our kind of stage RAS(ON) inhibitors, that's daraxonrasib, zoldonrasib, as well as elironrasib that covers all RAS, the G12D as well as the G12C population. There's a standard dose escalation involving Ivonescimab in combination with daraxonrasib, in combination with zoldonrasib, and in combination with elironrasib, and the dose escalation is standard in all solid tumors and will be helped to define the safety and preliminary activity across some major solid tumors that's going to be seen. And then once the dose has been defined and safety has been cleared, there will be dedicated expansion cohorts across the three major diseases of interest for both Summit and Revolution Medicines. And 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.
Do you want to repeat your second question, which relates to how the treatment landscape may evolve in the context of Ivo?
Yes, just broadly, how you're thinking about combos as standard of care across these treatment settings.
Yes. Well, I think we're not holding anything up. We're certainly developing things in combination with pembro to the extent that that makes sense to do, but we also have to recognize that field is evolving. And so we're right on the leading edge of it in collaboration with Summit to make sure that we're the first to evaluate RAS inhibitors and particularly class-leading RAS(ON) inhibitors in combination with IVO, and we'll learn a lot. With regard to non-small cell lung cancer, where pembro really is a 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, go to prove itself, which is currently work that's underway. In the GI tumors, there's 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 IVO is an exciting thing to do. So we're playing all the time sort of like our overall strategy, everything everywhere all at once. And that's pretty much what we have to do in a rapidly evolving environment.
Our next question comes from Asthika Goonewardene from Truist.
I want to revisit Albert's question from earlier. Specifically, regarding daraxonrasib and frontline non-small cell lung cancer, we've mentioned in past earnings calls how pembrolizumab combined with chemotherapy serves as a foundational therapy, and it makes sense to consider it alongside daraxonrasib. However, when you discussed other options today, I would like some clarification. Are you referring to other PD-1 inhibitors in combination with chemotherapy, mechanisms that might involve both PD-1 and CTLA-4, or are you exploring options that do not include chemotherapy for the ideal regimen you have in mind for daraxonrasib in frontline non-small cell lung cancer?
I believe the reference was specifically about the first-line lung treatment with daraxonrasib and whether it should be used alongside pembro and chemotherapy, or if ivo might become a consideration during that timeframe. That context explains the focused answer regarding our ongoing evaluation of ivo. We will gather more information on that. In the meantime, as Steve mentioned, we are continuing to optimize the dosing and analyze the efficacy of daraxon in combination with pembro and chemotherapy within the KEYNOTE-189 framework. Both studies are progressing simultaneously, which will help us make the most informed decision.
Got it. If you can speak a quick one in. Any thoughts on whether you would use your commissioner's priority review voucher for second-line PDAC when we had the RASolute 302 data in hand?
What's the question?
Will the priority review voucher be used for second-line PDAC?
I see. Yes, I think that's been made clear that it wouldn't really make sense to hold back. The CMPV 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 can't really see a scenario in which we wouldn't be operating under the CMPV in that second-line 302 data readout context.
Our next question comes from Laura Prendergast at Stifel.
In a recent public appearance, Mark, you mentioned the idea of addressing treatment beyond progression in PDAC by looking at patients who progress while on daraxonrasib and the amplification of the RAS target. This is a rather unique consideration in oncology, as it involves evaluating the drug after progression of PDAC in patients. Now, I have a few questions for you. First, our investigators in the Phase III studies for first and second-line PDAC have been encouraged to allow for any protocols, and you...
I could only catch every other word, so I'll infer that your question was about treatment beyond progression. We've noted several anecdotes from investigators who opted to continue treating patients based on clinical criteria, even when facing radiographic progression. They've seen a number of patients who still respond well to daraxonrasib for extended periods. Biologically, RAS remains a driver; it doesn't vanish when we use a RAS inhibitor. It continues to be the driver during treatment and even after stopping the inhibitor. Therefore, it may not make sense to discontinue treatment if a patient continues to show benefits, and these observations align with the biology behind it. However, we currently lack sufficient quantitative data to draw any firm conclusions. What I am sharing is mostly anecdotal and theoretical, but we aim to gather more data to see if there is an additional benefit beyond what patients have already gained by that time. Those are my general thoughts, but I'm unclear about the specific question you were asking. Could you please clarify?
Yes. Specifically, regarding study protocols, were there any limitations on the possibility of this being applied in first line or second line Phase III? Additionally, how do you anticipate this could affect the overall survival in those studies?
Yes, I understand the question now. We did not include this in the 302 study because it was already too advanced to make that adjustment, which would have been challenging to implement mid-study. Therefore, continuing treatment beyond progression was not allowed in the 302 study. However, as new studies are initiated, we have encouraged investigators to explore this possibility and where appropriate, to continue treatment beyond progression, especially in earlier line studies. This will allow us to gather much more information in these situations.
Our next question comes from Jay Olson of Oppenheimer.
Congrats on all the progress. Since you're 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 RevMed? Is CRC an area that you would prefer to focus on with partnerships, for example, in combination with Ivonescimab? 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 wouldn't need to rely on partnerships in CRC?
Yes, Jay, thank you for your question. Perhaps Steve Kelsey can share some insights on our approach to colorectal cancer, and if there are any additional points to address later, I can follow up on those.
Colorectal cancer has always remained a priority for us. Since the beginning of the daraxonrasib dose escalation studies, we have included patients with colorectal cancer. Our findings, which align with those of others, indicate that colorectal cancer is a highly complex and varied disease, characterized by multiple subclones, each harboring various genetic abnormalities. Consequently, two main issues arise. First, the overall response rates are lower compared to other RAS-driven diseases, complicating our ability to make swift decisions regarding future clinical developments since we need to wait for longer-term readouts such as progression-free survival. Second, in advanced colorectal cancer, particularly after chemotherapy has failed, the disease's heterogeneity and genetic complexity necessitate unique combinations. In earlier therapeutic lines, we must combine treatments with standard chemotherapy.
This adds difficulty and time to finding a clear path forward for pivotal trials. Our findings reflect the underlying biology of the disease rather than any prioritization issues. Our company's philosophy is to operate as a stand-alone global organization, without changing our strategy based on disease type or histotype. While there may be opportunities for collaborations with partners if we find the right combination and partner, currently, that is not our main focus. Our objective is to determine which combinations involving a RAS(ON) inhibitor can make a significant impact on colorectal cancer and to advance those toward registration.
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? And that's 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 look to learn more. So that's all just the practical considerations. The fundamental points, I think Steve made are the fundamental points.
Our next question comes from Leo Timashev from RBC.
I wanted to ask a little bit on RM-055 in 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'll ultimately need to be selecting patients that might be amenable to this? And then just based on some of the preclinical work you've shown, it looks like it drives a 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?
Yes. Thanks, Leo. Appreciate the question. 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'll 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. Daraxonrasib seems to do generally a very good job of suppressing new oncogenic mutations that might have otherwise emerged in the sending of a selective mutant selective inhibitor. So that really isn't the primary problem that we're 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.
Our next question comes from Ami Fadia from Needham & Company.
This is Poorna on for Ami. Just wanted to understand how soon can you get to commercialization of data 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 for those questions. So I think you're asking about what if we don't repair and what does the timeline look like? I think Anthony can step into that.
Yes. Thanks for the question. I think we're really pleased with how our launch readiness is planned. We are advancing, and we continue to add highly experienced and talented members of the team, and we're really achieving broad organizational readiness led by the U.S., but also in Europe and in Japan. So we're 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 cross functions field-based leaders across med affairs, market access, marketing, and sales. And as Mark mentioned as well, we've now initiated the posting of our further extension of our field-based teams, our sales team. So we're really going to be pleased with how the launch readiness overall is coming together. And certainly, as we get closer to filing and launch, we'll provide some more color there.
Our next question comes from Kalpit Patel of Wolfe Research.
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 thereafter?
Well, thanks for your question. I don't think we can give you much of an answer to that question right now. We'll see what the data show and decide what we consider as appropriate disclosure at that time. Just a reminder, it's OS event driven. It's powered for OS, which means it's more powered for PFS. So the possibility that it doesn't cross PFS is less likely than not crossing OS at that interim analysis. So if there's a split result, it could be PFS crosses an OS that has not reached statistical significance yet. That's conceivable, not emphasizing that particularly, but it is one of the possible scenarios. And we'll just have to see what that looks like at that point in time and make an appropriate disclosure decision.
Our next question comes from Sean McCutcheon of Raymond James.
Can you speak to the staggering of enrollment for RASolute 302, 305, and 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 G12V and G12R patients in the GNP arm given G12D tends to be a bit more aggressive in chemo-resistant?
Okay. I 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 didn't quite follow that.
Yes. Linking study 303 includes all patients, whereas studies 305 and 309 focus on G12D. How does the staggering of enrollment relate to managing the flow of patients, particularly in ensuring that we avoid enrolling difficult G12D patients into studies 305 and 309?
Do you want to comment on that?
Sure. Some of this will be managed by the selection of sites for all three global trials. We are mindful of ensuring a fair representation of RAS mutant patients in the RAS all-comer population for the 303 study and the G12D mutant population for both the 305 and 309 studies, as the control arms differ among these trials. Specifically, the 305 trial offers both GMP and FOLFIRINOX, while the 303 and 309 studies use GMP as the control. There are also regional practices influencing preferences for GMP and FOLFIRINOX. We have a variety of sites to choose from across different regions and countries. PDAC patients are quite prevalent; nearly 60,000 Americans are diagnosed with PDAC each year, with about half being first-line metastatic patients, which accounts for approximately 30,000 annually in the U.S. alone, and significantly more worldwide. Therefore, I don't anticipate any shortage of patients to select from. The focus is really on identifying sites based on local factors and interest from investors in these trials, and then presenting these trials as options to patients. We are also very conscious of the overlap in site footprints among these studies to ensure that there won't be competition at individual site levels.
Maybe mutations in their representation, 85% of PDAC cases have a G12 mutation. Things could be hard to bias that dramatically just from a 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's going to be G12D mutation is going to be very specific for that. And then within any given trial, there should be balanced between the control groups and the treatment groups because there will be randomization after patients designated for a particular chemo type, if it's a chemo bearing the trial, then they would be randomized to treatment arm versus chemo. So this should be balanced throughout these. I'm not sure that there's any inherent bias that would lead towards anything unusual.
Our next question comes from Faisal Khurshid of Jefferies.
I just want to ask now that you've had the commissioner 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'd otherwise get from programs like breakthrough designation in the real-time oncology review?
Thank you for your question. We don't have much to share on this topic. We typically don’t reveal a lot about our interactions with the FDA, but I can say that we have a positive relationship with the review team handling this case. They are the same team that's been involved from the start, and they now have a CNP to manage. We have found them to be very communicative, and we are engaged in constructive dialogue. The main benefit described is a faster review process. Ultimately, this question is for the FDA rather than for us. We will provide the data in the sequence they request and as swiftly as possible. Their review period begins once they accept a submission, which occurs after they have reviewed everything and determined the submission is adequate. They have suggested a timeline for their review process, but that is not something we control, so we don’t have further comments on that.
I am showing no further questions at this time. I would now like to turn it back to the Chairman and CEO, Mark Goldsmith, for closing remarks.
Thank you, operator, and thanks to everyone else for participating today and for your continued support of Revolution Medicines.
Thank you for your participation in today's conference. This does conclude the program, and you may now disconnect.