Revolution Medicines, Inc. ($RVMD)

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

Thank you, and welcome, everyone, to the webcast. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; and Dr. Roy Lin, our Chief Medical Officer; Dr. Steve Kelsey, our President of R&D; Dr. Alan Sandler, our Chief Development Officer; Anthony Mancini, our Chief Global Commercialization Officer; and Jack Anders, our Chief Financial Officer, who will join us for the Q&A portion of today's call. As we begin our presentation, I would ask that you review our legal disclaimer on Slide 2. And with that, I'll turn the call over to Dr. Mark Goldsmith, our Chairman and Chief Executive Officer. Mark?

Thank you, Ryan, and thank you, everyone, for joining us. Today marks an important landmark for patients living with metastatic pancreatic cancer and a major milestone for Revolution Medicines. This afternoon in the ASCO plenary session, Dr. Brian Wilton from the Dana Farber Cancer Institute and the study's lead investigator presented results from Resolute 302, the first Phase III study of Draxon/RaSIb, demonstrating an unprecedented survival benefit in patients with previously treated metastatic pancreatic cancer. These results represent a potential turning point in treatment for a disease that has seen limited therapeutic progress until now. These findings also reinforce our conviction that RAS on inhibition can fundamentally change treatment paradigms across multiple cancers that are driven by RAS. Based on these data, we are working with great intensity to prepare a new drug application for the U.S. FDA as the first step towards bringing Duraxon/Rasib to patients globally. At the same time, we are executing or preparing to conduct multiple registration studies across tumor types, treatment settings and combination approaches. We have significant momentum with a robust pipeline and aim to build the leading targeted oncology company serving patients with RAS-addicted cancers, supported by a differentiated discovery platform, multiple pioneering investigational medicines and a broad pipeline designed for long-term impact. Powered by a highly productive innovation engine, deep sustainable asset portfolio, including groundbreaking investigational medicines and a strong patient-focused and science-driven organization, we are well positioned to achieve our ambitions. We are not pursuing RAS opportunistically, we are systematically building coverage across the RAS landscape through our clinically validated discovery platform. spanning oncogenic mutations, tumor types and treatment settings. Our strategy is designed to create long-term value through differentiated medicines, rational combinations and a sustainable multiproduct oncology franchise built on continuous innovation. Our mission is bold, to revolutionize treatment globally for patients living with RAS-addicted cancers through the discovery, development and delivery of innovative targeted medicines. As pioneers in the RAS targeting field, we operate as a late-stage clinical oncology company, pushing the boundaries in 3 of the most common and difficult-to-treat segments in oncology, pancreatic, non-small cell lung and colorectal cancer both targeting areas of clinical unmet need today and creating a significant long-term opportunity. We have 8 completed ongoing or announced registrational Phase III studies an extensive aggregate clinical experience to date with more than 2,500 patients having received 1 or more of our RAS ON inhibitors. These include 4 RAS ON inhibitors in the clinic and a deep pipeline behind them. including a fifth on track to initiate clinical study this year and a rich set of innovative preclinical and discovery stage programs. Allow me now to briefly frame the RESOLUTE 302 study, and then Dr. Wallin will walk you through the Resolute 302 results. Pancreatic ductal adenocarcinoma or PDAC remains 1 of the most aggressive and lethal cancers. Most patients are diagnosed with advanced disease and current outcomes in the metastatic setting call for significant improvement. For patients whose disease has progressed following initial treatment, current chemotherapy options provide limited benefit with median overall survival generally measured in months. Mechanistically, pancreatic cancer is driven by and highly dependent on RAS signaling within the tumor. More than 90% of PDAC tumors harbor oncogenic RAS mutations. -- and tumors without an identified rasputation, often harbor an undetected RAS mutation and/or are dependent on RAS pathway signaling even in the absence of the mutation. Pancreatic cancer calls for RAS targeted medicines, but there are currently no approved draft targeted drugs for pancreatic cancer, representing 1 of the most significant unmet needs in oncology. Traxon Rasib is an oral once-daily RAS ON multi-selective inhibitor designed to target the active GTP-bound or RAS ON form of both mutant and wild-type gas. Mechanistically, direxonrasid acts as a synthetic molecular glue binding to intracellular cyclophilin A to form a binary complex that selectively engages Raton proteins and suppresses signaling by sterically blocking engagement of downstream as effectors. This resulted in broad inhibition of RAS-driven tumor growth. Importantly, data from a prior Phase I/II study recently published in the New England Journal of Medicine demonstrated encouraging clinical activity together with a manageable safety profile in previously treated advanced pancreatic cancer. RAS olute 302 was designed to rigorously evaluate whether these early signals would translate into a clinically meaningful survival benefit in a global randomized Phase III study. Wei, please take it from here.

Resolute 302 is a global randomized open-label Phase III study that enrolled patients with previously treated metastatic PDAC. Patients were randomized 1:1 to receive either direction acid 300 milligrams orally, once daily or investigator's choice of standard care chemotherapy. The primary analysis population included patients with RAS G12 mutant tumors. The broader overall population included patients both with and without identified RAS mutations. -- dual primary end points were overall survival and progression-free survival measured by blinded independent central review in patients with DraG12-mucent tumors. Key secondary endpoints included overall survival and progression-free survival in the overall population, objective response rate and patient-reported outcomes. The study design included 2 planned interim analysis for overall survival. The results we are presenting today are from the first interim analysis. Importantly, this prespecified analysis crossed the protocol defined boundaries force to scope significance and therefore, constitute the final analysis for all outcomes. A total of 500 patients were randomized. 248 patients were assigned to Daraxonrasib and 252 to chemotherapy. Notably, substantially more patients remained on treatment with Daraxonrasib at data cutoff compared with chemotherapy. In addition, fewer Daraxonrasib patients discontinued treatment due to toxicity or symptomatic deterioration. These operations are consistent with both meaningful clinical benefit and a manageable tolerability profile. Based on characteristics, we're well balanced across treatment arms and representative of patients typically seen with previously treated metastatic pancreatic cancer. Importantly, the study population reflected the expected distribution in pancreatic cancer with the majority of tumors harboring RAS G12D or G12B mutations. Turning to efficacy. The dual primary end point of overall survival in the RAS G12 population was met. Daraxonrasib reduced the risk of death by 60% compared with chemotherapy. At a median follow-up time of 8.5 months, median overall survival was 13.2 months. with Daraxonrasib versus 6.6 months with chemotherapy, with has ratio of 0.40 and a highly statistically significant p-value. To our knowledge, no prior Phase III study in metastatic pancreatic cancer has demonstrated median overall survival exceeding 1 year in any line of therapy. These are unprecedented outcomes for patients with a devastating disease. The overall survival benefit was nearly identical in the overall intent-to-treat population, which included both the RAS G12 population and patients carrying the tumors harboring other RAS mutations as well as tumors without an identified RAS mutation. The risk redev was reduced by 60%. Median overall survival, again reached 13.2 months with Daraxonrasib compared with 6.7 months for chemotherapy with has ratio of 0.40. These clinical findings firmly established the biological relevance of RAS pathway inhibition in pancreatic cancer broadly and the survival benefit of targeting RAS in patients living with pancreatic cancer with or without an identified RAS mutation. Collectively, we believe these results establish a new benchmark for survival outcomes in briefly treated metastatic pancreatic cancer. The observed OS benefit of grain acid versus chemotherapy was consistent across prespecified subgroups, including tumor RAS mutational status. These findings support the robustness and consistency of the survival benefit observed with droximracid. The second dual primary end point progression-free survival was also met. Daraxonrasib reduced the risk of progression or death by 55% versus chemotherapy in the RAS G12 population. Median progression-free survival was 7.3 months compared with 3.5 months for chemotherapy. Results were consistent in the overall population. Taken together, the PFS findings complement the overall survival benefit and further demonstrate meaningful disease control observed with racinrastib treatment. Objective response rates were also substantially improved with ORR in the director acid arm approximately 3x higher than in the chemotherapy arm. In the overall population, gibjectriv response rate was 31.6% with Daraxonrasib compared with 11.2% for chemotherapy. These response data further support the broad antitumor activity of doctorasid in metastatic pancreatic cancer. Turning to safety. Daraxonrasib showed a manageable safety profile with no unexpected safety findings. Importantly, treatment discomuniation due to treatment-related adverse events were very rare at 1.2%. Grade 3 or higher treatment-related adverse events were also less frequent with Daraxonrasib compared with chemotherapy. One patient in the Daraxonrasib 5 pneumonitis, which was considered possibly related by the investigator median dose intensity for directional asset remained high at over 93%, supporting the feasibility of sustained treatment delivery. Overall, we believe dramas tolerability profile is particularly notable in the context of the substantial efficacy benefit observed. The most common treatment-related adverse events with Daraxonrasib were primarily low-grade dermatologic and gastrointestinal events. Importantly, severe events or infrequent and generally manageable through supportive care and dose modifications. Chemotherapy demonstrated the expected pattern of hematologic toxicity and peripheral neuropathy that are associated with these agents. We also observed meaningful improvements in patient-reported outcomes for patients receiving Daraxonrasib. In particular, Daraxonrasib delayed deterioration both in pain symptoms and in overall quality of life compared with chemotherapy, leading time to worsening of pain was more than doubled on Daraxonrasib versus chemotherapy. And patients receiving Daraxonrasib experienced longer preservation of global health status and quality of life. These findings are especially important in pancreatic cancer, where symptom burden is typically profound and sustained. Importantly, improvements in patient-reported quality of life with Daraxonrasib were consistent with a meaningful overall survival and progression-free survival benefits observed in the study. In summary, Daraxonrasib demonstrated unprecedented statistically significant and clinically meaningful improvements across every major efficacy endpoint evaluated in Resolute 302. The study showed a 60% reduction in the risk of death and approximately doubling of meeting overall survival to greater than 1 year, doubling our progression-free survival and near tripling of response rate, superior patient report outcomes and a manageable safety and tolerability profile, along sustained treatment. We believe these results redefine treatment expectations in patients with previously treated metastatic pancreatic cancer support Daraxonrasib as a potential new standard care and firmly validate the clinical benefit of RAS ON inhibition in pancreatic cancer. Furthermore, these patient outcomes increase our confidence in the work we're doing to extend targeted therapy to other RAS dictate cancers. With that, I'll hand the call back to Mark.

Thank you, Wei. The implications of Resolute 302 extend well beyond this important individual study. These results established the first targeted therapy to demonstrate a transformative survival benefit in patients with metastatic pancreatic cancer, offering a compelling basis for becoming the new standard of care in a disease clinically proven to be primarily driven by RAS. These results also clinically validate our broader RAS ON inhibition strategy in pancreatic cancer and increased confidence in the studies we are conducting related to expansion into earlier lines of therapy, rational combination regimens and additional tumor types. And finally, these results reinforce the value of the scientific and strategic foundation we've built at Revolution Medicines. What began as a differentiated discovery platform has evolved into what we believe can become a global franchise in targeted oncology medicines with what we believe is a significant opportunity to reshape treatment paradigms across rasentictede cancers. Given the compelling and consistent benefit for patients observed in Resolute 302 -- we at Rev Med feel a deep sense of responsibility to deliver this benefit more broadly to patients and are moving with urgency to enable potential commercialization. We are offering treatment crossover to patients in the chemotherapy arm of the RESOLUTE 302 study and have operationalized an FDA-authorized early access program in the United States. Many U.S. prescribers and institutions are now registered in the expanded access program, and drug is being shipped on behalf of their approved patients. We are also actively preparing regulatory submissions globally focused initially on a planned U.S. FDA submission under a breakthrough therapy designation and a commissioner's national priority voucher. Multiple components of the NDA and are advancing through a rolling submission process and the clinical data and analyses will be incorporated as soon as possible, recognizing the need for improved options globally, sequential filings are also planned across international regulatory authorities. Operationally, we are well prepared to provide broader access. Over the past several years, we have built a strong commercialization organization with highly experienced leaders and staff with valuable collective oncology launch expertise. We have established core U.S. market infrastructure. and our U.S. field teams are in place, including having onboarded and experienced U.S. account manager team. We also continue to grow our international teams. Taken together, we believe we are positioned to execute a successful global launch pending regulatory approvals. Before concluding, I want to briefly step back and frame what we believe investors should take away from today. Resolute 302 is not simply a compelling positive Phase III study in previously treated pancreatic cancer. We believe it represents validation of our productive bold and differentiated scientific platform, proof that RAS ON inhibition can deliver transformational outcomes for patients with RAS-addicted cancers and a catalytic step for creating an industry-leading global targeted medicines franchise for patients with RAS addictive cancers. We have a broad and innovative clinical stage pipeline focused on RAS ON inhibitors, including 4 groundbreaking and differentiated clinical programs. to RAS ON rated, the RAS multi-selective inhibitor, Zolonrasib, the RASM-G12D-selectiv inhibitor, Leronrasib, ArasG12C-selective inhibitor RMC-5127, Orason-G12V selective inhibitor and a fifth compound, a true catalytic restaurant inhibitor poised for initiating clinical study. Our development strategy for these assets is deliberately broad to maximize the clinical impact across tumor types and lines of therapy through both monotherapy and combination approaches. Importantly, this strategy creates rich opportunities for continuing value creation over time while reinforcing our leadership position in RAS-targeted oncology. Our capabilities extend beyond individual molecules -- we have built an integrated organization that connects discovery science, translational medicine, clinical development and commercial execution, insights generated from each stage continuously strengthen the next and fuel a virtuous cycle of innovation capable of producing differentiated medicines over many years. I'll conclude with our core purpose. Everything we do at Revolution Medicines is centered around patients and our impact is measured by patients experience. Rasadictive cancers, including, but not limited pancreatic cancer, remain among the most devastating diseases in oncology. For many patients, treatment options remain limited and outcomes remain poor. We believe the work we are doing has the potential to fundamentally improve those outcomes. Today's Resolute 302 results represent an important step towards realizing that vision. At the same time, we are investing at scale to build a durable industry-leading global oncology company aiming to provide exceptional long-term value for patients, physicians, caregivers, employees and shareholders. With that, I'll now turn the call over to the operator for the Q&A portion of the call.

[Operator Instructions] Our first question comes from the line of Marc Frahm from TD Cowen.

This is Ellen on for Mark. Congratulations on the fantastic data. That was a really powerful finery. I guess 1 question. We noticed that 57% of the patients in the control arm were treated with [indiscernible]. Have you compared Daraxonrasib to the subgroup specifically? And is there any reason to expect that the hazard ratio might differ in the patients treated that we're acting versus other regimens, it's almost like directors because it's already beaten gemabraxane, in a second-line trial, and so this just kind of would further support potential success in the front line .

Thanks very much for your question. I think Lynn can answer those comments about whether or not there's any more information relative to alternatives but as you pointed out, about 60% of patients received Daraxonrasib a 50% in the area 10% or base therapy including other clearly representative of the global usage in second line. So I think the trial certainly fair percentage with regard to specific chemo regimens and certainly given the high proportion anthrax efficacy conversion is very overall also houses a and with the economy

And I show our next question in the queue comes from the line of Charles Zhu from LifeSci Capital. .

This is Sue on for Charles. Congrats on the data. Obviously, this is the first innovative drug in pancreatic cancer in a really long time. How well do you think prophylaxis type measures on rash worked 432. And do you think rashevents, either any grade or grade 3 could be further optimized beyond what is presented today as physicians get more used to using direction asset? And can you talk about your plans regarding physician and patient education on implementing preventative measures .

Sue, thanks for your questions. I think back to Wayne who can comment on measures that we can take to help physicians and also their own experience and how that changes over time. Right Yes. So Certainly, it was recommended Daraxonrasib that are typical for each inhibitors, such as oral antibiotics. -- sun block as well as skin motions. Those were recommended. They were applied on throughout the trial. I think as we try to launch a product and making it hopefully available, those recommendations probably be put into clinical practice I think the -- we have -- we're certainly doing studies and generate data demonstrating the effectiveness of these prophylaxis. And there's wealth experience within the GI community, especially with F antibodies. -- with effective of these prophylaxis for patients. And I think we hope this becomes a common use for patients using Daraxonrasib as well. .

This is Alexandre. I just want to add to exactly what Wan said and just to emphasize that the point that you had made that the more experienced physicians have with direct unrated, the better they are in terms of anticipating and treating the rash. In addition, our medical affairs group will be coming up with standardized opts for the prophylaxis folks, particularly for those doctors who may be utilizing Draxton assets for the first time. And I think all of this will be an effort to ensure that patients are treated appropriately.

Yes. I might add 1 more thing to Alan's comment, which is that any or most of these investigators were not part of the Phase I/II experience. And so their first few patients on trial would be their learning experience. And that comes from expanding to 59 sites across 6 countries. So that reinforces the point that Alan just made. .

And I show our next question comes from the line of Fei Keshet from Jefferies.

This is Anantha for Fazal. Do you think you can get the first-line therapy on the label along with the initial approval in second line, maybe leveraging the Phase I data without having to wait for the Phase IIIs to read out. and maybe even something innovative where they give you a full approval in second line and accelerated approval for first line with the ongoing Phase III serving as confirmatory evidence. Just wondering about the possibility of that. .

Yes. We appreciate the point that you're raising here. Given that RAS biology underlies first-line disease, just as it does second line and later lines there's some logic to that. The fact that the -- in the 302 study, the second-line patients outcomes outperformed at least numerically outperformed the historical experience in first line. And then, of course, as you point out, also, the preliminary data we've shown in first line and single-arm studies that all adds up to a picture -- it's really up to the FDA. Our primary objective right now has to be to make sure that we get the 302 study to them in a way that's clear and supportive of a robust label but we understand the point that you're raising, and let's just let this all play out. And in the meantime, we are running, of course, a first-line trial, as you know, 3R trial, and we'll continue to have dialogue with the.

Thank you -- and our next question comes from the line of Laura Prendergast from Stifel. .

Congrats on a very exciting data today. Can you speak to the inclusion of some first-line patients in RASL302 who didn't seem to do well in their adjuvant setting therapy. -- their disposition of baseline, how they performed versus the second-line patients enrolled? And to follow up on the last question, any implications this could have for an FDA label -- we do you want to comment on that? .

Yes. So the patient referring to our patients who have received athlete therapy and then have progressed within 6 months and therefore, they're considered to be second-line patients. Now those patients in term prognosis are fleet the same the patients for uninitiated received a better treatment. So there is a -- we haven't done a detailed analysis in terms of product or experiences -- those patients are always treated as the same and they're prognostic for about the same. So .

So we don't think it represents much of an issue and it's a relatively small number of patients .

And just to add again that those patients who received the neoadjuvant or adjuvant setting and then failed to be able to go on study. They had to do that within a time period of less than 6 months. again, which sort of mirrors what the first line came out therapy would have been. .

And I show a next question comes from the line of Corey Kasimov from Evercore ISI.. .

This is Noah on for Cory. Congrats on the fantastic data. Just a bigger picture question for us. Given the discussing commentary on the call to action, into you Resolute 302 as a starting point for ongoing development in pancreatic cancer. I guess just like how public can you guys be about your future development plans for both the racks and acid and the broader pipeline to stay ahead of the growing competitive field. .

Yes, thanks for your question. We have a pretty expansive registrational program around Daraxonrasib both in pancreatic cancer and outside pancreatic cancer, we're covering most lines of therapy, and we're covering them in multiple ways. In some cases, including in first-line Daraxonrasib alongwith Daraxonrasib with [indiscernible]. So I think we have quite an extensive program and we'll continue to do that. I found the comment to be supportive of exactly what we were doing. I didn't think that there was much that we're leaving on the table. But we're, of course, scrubbing that every day and looking for other opportunities to expand even further. And then with the pipeline behind it, [indiscernible] our RMC5127, or G12D-slective inhibitor, we have opportunities to move and are moving to metselective inhibitors into pancreatic cancer studies as well. And then, of course, outside of pancreatic cancer, lung cancer and colorectal cancer. So I think we have a pretty extensive program in the pipeline chart outlined some of that. In some cases, I mean the chart so full that we had to compress a number of different things into a single line, but that information is all available on clinical trial staff go. It shows the many different things that we're doing, either preregistrational or as part of the registration strategy. .

Our next question comes from the line of Michael Schmidt from Guggenheim Securities.

This is Sara on for Michael. Congrats on today's data. Continuing on the theme of potential expansion opportunities for Daraxonrasib, I guess, wanted to ask if you had any updated comments on plans in frontline lung. We saw some data this weekend on D12Cs in the frontline setting. So I guess how does the evolving frontline landscape sort of impact how you're thinking about the opportunity for Daraxonrasib.

Yes. Thanks, Sarah, for the question. I'll just make a high-level comment. I don't know if anybody would want to add something to it here, which is that lung cancer is really the tumor type in which mutant identification of specific forms of forms of gas have already caused the stratification of disease types. There's a G12C lung cancer is a thing now. and G12D lung cancer will become a thing pretty quickly in G12D and probably beyond that as well. And so we are definitely paying attention to that. We want to be both drivers of it and also be compatible with how physicians think about things. So stay tuned as we continue to update our first-line strategy. But clearly, we -- it's a high priority for us in in non-small cell lung cancer justice. It is in pancreatic cancer and in dated colorectal cancer as well. So we'll continue to take that into account and clarify things over time. .

And your next question comes from the line of Brian Chang from JPMorgan.

This is Sarah on for Brian. Could you provide some color on the demand coming from the compassionate use program -- how many centers are now offering Dara in this program? And how should we think about the number of patients that can be in this program by the time that you get the approval? .

Yes. Thanks for your question, Sarah. We can't quantitate it for you at the moment is that it's constantly moving. But the demand has been very, very high, our call center and our Medipole receive a very large volume of inquiries, both from within the U.S. and outside the U.S. to acquirers come from individual patients. They come from doctors. They come from institutions. And we have field of those. We're very much on top of it. It's a fully operational program now. There are many registered institutions and physicians within those institutions within our expanded access program, and we're now shipping to exon rated to the individual doctors who have approved patients and who are coming from an approved certified institution. So we're well on our way to serve patients. In terms of what the spoke will end up being -- that's hard to say. It's really hard to predict exactly as to the timing -- well, that's hard to predict, too. That depends also on when the FDA receives and then reviews and makes a decision about approval because that will have an impact also. There's not really -- if you're asking about whether there's sort of a cap on the number of people being served, there is not -- there is not ranking of individuals, anybody who is eligible and who is supported by an application from a U.S. license physician that has to be eligible themselves to their institution, they will -- they'll be served by our expanded access program. And I think that's clearly ramping up. But here we are, we're still in the month of May. This program was just cleared by the FDA earlier in this month, and we're already operational and delivering drug on behalf of patients.

And so our next question comes from the line of Michael Yee from UBS.

This is Matalan on for Michael. Congratulations on the data today. Just wanted to ask quickly about the duration of treatment, 6.2 months. Comparing that to the PFS number and just sort of thinking about that in the real world, -- could the difference between PFS and the duration of treatment be related to scan frequency. How do you think about the limiting factor in terms of 8.5 months median follow-up as well as what are you hearing from physicians in terms of treating past progression in the real world?

Madeline, thanks for your question. Those are 2 very important questions, and we'll be happy to comment on it, Wei. .

Yes, sure. The the treatment duration and the rev survival are analyzed by different school methodology. So they don't always correlate perfectly. And the progression is actually assessed by a true progression progression versus the treatment is really how long the patient is on the treatment cloud. And sometimes they may discontinue for reasons such as average spend on our other decisions. And so therefore, the treatment duration may be actually a different number than merchant pricing. We just had a train go by. So we'll pick up the there. Yes. So the -- I think -- so that's -- I think that's largely kind of explain the difference between the 2 numbers.

But there certainly are differences in duration of follow-up in this study compared to our earlier study if you're wondering about the median PFS values and how they may be a little bit different. And there are differences as well in the frequency of scanning under this protocol versus the other at least after a certain amount of time. So there are a variety of factors that go into that. This was statistically significant. It's the final read, but it doesn't mean it's the final ever looked at. It is the 1 that will be -- that's provided to the FDA, but we don't note today that it's actually representative of the true duration of treatment, which I'm sure you're trying to use to project things. As to treatment beyond progression, Alan, do you want to comment on that? .

Yes, yes. So there -- I think a couple of important points. So the treatment beyond progression was not part of the protocol for 302. However, it is formerly allowed in all of our subsequent protocols. And in terms of physicians who -- and what they're thinking there is certainly interest in the concept doing that, and we have anecdotal evidence of patients who seem to drive some benefit for it, which is why we're looking at it prospective manner in our clinical trials. It will be interesting to see what happens after the Daraxonrasib is approved and how physicians will do that. It's not -- certainly not unprecedented with other forms of therapy in oncology. So we'll see how that enplays out. But this dividend that we have prospectively may provide further evidence in order to support that use.

And if I may just add to that, back to the biology I think I said it earlier, RAS the cancer driver in pancreatic cancer, whether you're in first line, second line or third line of treatment and whether or not you progressed on a RAS inhibitor in all likelihood, you progress because the tumor has increased its RAS signaling. And so taking your foot off the brake seems like exactly the wrong thing to do from a biological perspective, I'm not speaking to the clinical outcomes yet is we don't really have that rigorously assessed. But from a biological perspective, it really doesn't make sense. -- to try to defeat a cancer that's hungry for RAS and to withdraw on the RAS treatment, but that has to be established through a collection of data. and huge congratulations.

And I show our next question comes from the line of Jay Olson from Oppenheimer.

Congratulations on this major accomplishment for cancer patients. And thanks for providing this update on a super busy day. The discussion spoke about the opportunity to expand the use of Daraxonrasib into combinations in earlier lines of PDAC therapy, including adjuvant and neoadjuvant -- and do you share a list of all the studies you're running, can you just talk about the read across from 302 study results to your other PDAC studies? And I think you suggested that your mutant specific RAS inhibitors could offer improved tolerability. Is that something that you'll be looking for? And then if you could talk about the time line of you would -- when you would anticipate having the G12 mutant level subgroup analyses such as TV and wild-type subgroups from RAS302 that was discussed I think someone said it could be shared later this year. Is that correct? .

Let's come back to that second point, but Steve Kelsey can comment on the first point, the main part of your question. .

Yes. So -- well, I think there were 2 parts, 2 questions. The first was how confident are we like a paragon confident are we in the other studies we're running with Repsol asset based on the readout from the 302 study SP1 I mean we generated a fairly substantial volume of Phase I/II data before we started most of our Phase III studies with the possible exception of the 304 study, which we inferred from the Phase I/II data that we already had in both second line plus and first-line pancreatic cancer I think the thing that's most trading is that the data that we made public maybe 8 months ago or so from the Phase I/II cohort of patients with second-line pancratic cancer was almost exactly reproduced in this randomized Phase III study that we did. And so I think we can then infer the A lot of our earlier data may be reasonably predictable what's going to happen in the other Phase III studies. And I think that does give us at least reinforces the confidence that we had in those studies when we started the diesel line and a very expensive study. So you have to have a reasonable degree of confidence they're going to work before you you starting off, but I think that that's been reinforced by the outcome from the 302 study. With regards to mutant selective inhibitor -- not all mutant selective inhibitors are created equal. It is still a matter of -- there's a big -- it's a conundrum to us why so many of the mutant selective inhibitors of G12C seem to demonstrate gastrointestinal toxicity that is at least as bad and not worse than the exon Reed, which is a RAS-muteinhibitor. -- when they are supposed to be absolutely selective for Golf -- having said that, our net Selecta G12D inhibitor is extremely well tolerated. And we're currently exploring that of all its with standard of care in pancreatic cancer and first-line pancreatic cancer, but also in combination with Daraxonrasib first-line penetrance. So I think the the place of the mutant selective inhibitors will fall out based on their own individual efficacy and tolerability profiles. But we believe that the rate real inhibitors that we have, which now include Eleanor G2C, solar rate and 5127 for G12V are pretty good with regards to tolerability and gives us a lot of flexibility. With regards to subgroup analysis, I think Wei Lin commented earlier in the call that we do intend to do exploratory subgroup analyses of the data I wouldn't expect too much definitive to come out of that because probably the only 2 mutant subgroups that are going to be sufficiently large to had anything determine on the G12D subrent subgroup. But those exploratory analyses will be performed now that the main analysis has been performed in a public.

It's hard to have much to what Steve said, but I'm still going to add something, which is pancreatic cancer is caused by RAS, first line, second line, third line, whether it's local disease, local resectable they're slowly advanced or where there's been static. And so the underlying biology is the same there, and so I'll take an even more bullish position on it, inhibiting RAS is going to make a difference across these. We just have to design trials and execute trials that will assess that normally, and that's what's being done now. Those trials are underway, and we'll learn the answers from them.

And I show our next question comes from the line of Sean McCutchen from Raymond James. .

Congrats again on stellar data. Maybe could you speak to the rate of high-grade stomatitis, how stomatitis is managed on the study and expectation for real-world mitigation strategies. .

Sure. Thanks for your question, Wei.

Yes. stomatitis it's actually also a part of the Rasmisin because -- the -- in addition to RAS, they became our kinase pathway is also effective with brass and vision and. So this is so much ideation revenues in Dampinhibitors. So on the study, we have implemented a management guideline very similar to the mTOR inhibitor, which is involving oral mouthwash with steroids, and that's been fairly effective. And so there's also -- as Alan mentioned, along with the rash management, our medical affair team will also be promoting additional management when it comes to stomatitis, which include not only management on stomatitis is after onset, but also there's operating potential to prophylax because that's another opportunity for improving the safe and tolerability of long-term use is is to use the store malware team to cover the onset in addition to growth by managing the stomatitis.

And our next question comes from the line of Jonathan Chang from Leerink Partners.

This is Sean on for Jonathan. Congrats on the data. SP1 Just 2 small questions on the non-G12V population. Can you provide more color on why these patients seem to the rabi benefit but not a PFS benefit from direct are -- and also, can you frame color resistance mechanisms to terexresib in this study? And how might that inform strategies for next-generation inhibitors and combinations.

Thanks for your question. I'm going to take the second question, which is resistance from this study. We don't have any data on resistance from this study. We have data that we've recorded now on several different venues, I think, on resistance mechanisms, and they typically involve the cell finding ways to increase RAS signaling that works around the initiator either amplifying the underlying oncogene and expressing more protein that can signal more that sort of thing. So we think the main thing to do for RAS inhibitor resistance in pancreatic cancer is to increase your inhibition of RAS and we have several strategies for doing that, including combining a second RAS inhibitor. We also, of course, have our newest innovative class of compounds that is catalytic in its activity represented by RM55. So there are various strategies for dealing with that, but we do not have any data today from the resl302non-G12X. Why did it appear to show that is not as compelling yet the OS value pine.

Yes. So I think there's a number of potential questions and issues, I guess, that's supposed with this. one, of course, overall survival is the most definitive evaluation of treatment effect. The second would be the fact that they are, of course, small numbers. And when you have small subgroups such as this, you can have treatment effects that very are certainly less precise because we just don't have the number of patients to look at that. And so the confidence intervals as a result, are quite wide. -- showing encompassing both effect and greater than 1. So I think that that's basically sort of the summary of it at this particular point. Numbers are quite small and variable. But let's not forget OS and the consistent benefit that we've seen across all of the subgroups throughout overall survival of the study.

And I show our next question comes from the line of Kalpit Patel from Wolfe Research.

This is Gugino for Culp. Today's 33% ORR in 2Pacess benchmark. What ORR would you need to see in the MTAP-deleted subgroup to feel confident loping metastatic are adding a signal over deroxanrasib monotherapy.

To see a benefit of adding what to Daraxonrasib rated, I couldn't wear that will be here that will be I see. Yes, I'm not going to answer that question. I think the underlying question really here is to what degree is response rate predictive of durability -- and we don't really have an answer to that question today. Certainly, we have some level of relationship between a higher response rate here in this study, as we saw in the Phase I/II study and and durability, but we don't know what that relationship really is since we only have 2 points on the line. We have everything else, and we have Daraxonrasib we nothing in between or on either side of that. So we don't know the answer I get why you're asking it, but we can't -- if we can't help you enter that today.

And our next question comes from the line of Kelsey Goodwin from Piper Sandler.

This is Brittany Stop on for Kelsey. Congratulations on the strength of the data and the powerful response from the audience during the plenary session. there's not much to poke out in the data, but just 1 small question from us. Given the median follow-up of 8.5 months at this analysis, do you have any thoughts on how PFS and OS benefit might evolve with more mature follow-up. And do you plan to provide additional analysis at any time in the future?

Thanks very much for your comments and for your question. Alan, do you want to comment on follow-up and could the survival parameters move? And if so, were you particularly would move to.

So obviously, it's not possible to predict. However, what we would say is with the results of the hazard ratio of 0.4 and that highly statistically significant finding, we anticipate that with additional follow-up, we'll continue to see the broad benefit that we have seen, particularly for the PFS, which is more mature than the OS. But we do believe that both are strong enough that will continue to be seen -- and although this is the final analysis as has been stated, we will be looking at a subsequent follow-up, although not with more in a descriptive p-value approach and not with an alpha spend. but we look forward to doing that as well.

I might add, though, we are now allowing crossover for patients who progress in the chemotherapy through for those patients who are still on study. And so that could have some impact on looking at overall survival, but shouldn't affect progression-free survival. Thanks for your question.

And so we have time for 1 more question. Our last question comes from the line from Ami Fadia from Needham.

Firstly, congratulations for this really strong data and the achievement. My question was really around the expanded access -- can you elaborate on the expanded access and if there is potential for that outside the U.S. And then within the U.S., do you think patients that are in third line could get access to Dara at this stage? And then just more broadly, given all the data that you've generated in PDAC and lung, -- can you give us some comments on how you're exploring colorectal cancer and what we might expect to see in the foreseeable future? .

You've asked 3 of your permitted 2 questions. So we'll do what we can. With regard to the expanded access program, right now, it's an FDA-authorized U.S. program that operates through licensed U.S. physicians and that's who we're authorized. And outside of the U.S., we understand the urgency for patients elsewhere as well. there are local specific requirements in each country. We have people on the ground exploring that and exploring that with the right officials as well and to understand that. The main thing we're doing outside the U.S. is expanding our clinical trial footprint. -- and we've increased the size of that footprint by an order of magnitude, and that will allow more opportunities for clinical trials as the nearest term thing that we can do. CRC, I'm just going to put it off to Dave, do you want to comment on the third line, who's eligible in the EAP with our third lineation cel.

The answer is yes for third line. So it mirrors the second line and beyond with the appropriate parameters that are seen in the 302 study, which is performance status at homes.

This concludes our Q&A session. At this time, I'd like to turn the call back over to Dr. Mark Goldsmith, Chairman and CEO for closing remarks.

Thank you, operator, and thank you to everyone who joined us today. We are indebted to patients and their families who participated in RESOLUTE 302 in other studies to investigators and scientific collaborators to investors who have financed the work and, of course, to our remarkably dedicated employees. We are highly motivated by these significant results from the RESOLUTE 302 trial from the potential therapeutic impact for patients with pancreatic cancer or other RAS-addicted cancers and the profound opportunity ahead for Revolution Medicines. We very much appreciate your continued interest and support. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.