Revolution Medicines, Inc. (RVMD) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to Revolution Medicines Conference Call. Today's program is being recorded. [Operator Instructions] I'd now like to introduce your host for today's program, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome, everyone, to this afternoon's webcast. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer; Dr. Steve Kelsey, our President of Research and Development; and Dr. Wei Lin, our Chief Medical Officer. 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?

Thanks, Ryan, and thank you to everyone who has joined us today. Slide 3. At Revolution Medicines, we remain committed to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative, targeted medicines. We are making important strides in pursuit of this mission as we advance broad development programs for our first 3 highly innovative RAS(ON) inhibitors in the clinic, daraxonrasib, which targets a broad array of oncogenic RAS variants and 2 RAS mutant selective inhibitors, elironrasib and zoldonrasib for RAS G12C and G12D, respectively. Our ambition is to address unmet medical needs in common RAS-addicted cancers, including pancreatic cancer, lung cancer and colorectal cancer. To date, we've disclosed encouraging clinical progress. Today's presentation will focus on our first-line treatment strategy for patients with metastatic pancreatic cancer, a highly RAS-addicted disease centered on daraxonrasib, a promising and our most advanced investigational RAS(ON) inhibitor. Momentarily, Dr. Steve Kelsey, our President of R&D, will provide an overview of current clinical practice and outcomes in first-line treatment and the new approach we are developing. Dr. Wei Lin will then present 3 new clinical data sets supporting this approach and concluding with our RASolute 303 trial design. I'll then close with a few remarks and open the call to Q&A. Steve?

Thanks, Mark. Moving on to Slide 4. Pancreatic adenocarcinoma, or PDAC, is a devastating disease. It remains the third leading cause of cancer death in the United States with an urgent need for better treatment options. PDAC is the most RAS-addicted of all major cancers. More than 90% of PDAC tumors harbor a RAS-driver mutation. And in PDAC, as in other RAS-driven tumors, excessive signaling by RAS in the active or on state or RAS(ON) is a primary driver of tumor growth and a major contributor to drug resistance. Approximately 56,000 patients are diagnosed with PDAC each year in the U.S. alone, and the unmet medical need remains huge. Most patients are diagnosed with metastatic disease, and those who are not will eventually progress to metastatic disease. Five-year survival is only 3% despite the best available current therapies. Cytotoxic chemotherapy is currently the standard of care in all lines of therapy for metastatic PDAC, although patients with resectable disease may typically receive chemotherapy with surgery. Not all patients with metastatic disease ought to receive or are fit enough to receive first-line chemotherapy, which typically consists of either a 5-FU-based or gemcitabine-based regimen. Of those who do receive chemotherapy in the first-line setting, nearly half will progress and die during treatment, less than half of patients may receive a second-line therapy. Significant improvements in the treatment of advanced and metastatic PDAC are required. A deeper look at conventional outcome measures for patients receiving first-line chemotherapy for metastatic PDAC further highlights the need for treatments with improved efficacy and tolerability. Slide 6 outlines reported results from Phase III trials evaluating both 5-FU-based and gemcitabine-based regimens. These 2 types of cytotoxic chemotherapy are used globally, albeit with some geographic differences due to physician preferences. In the United States, most people are considered eligible for gemcitabine with nab-paclitaxel or GnP, while the modified FOLFIRINOX or NALIRIFOX regimens are generally reserved for patients with superior performance status. Efficacy and safety outcomes across the 2 regimens are generally similar. Commonly, GnP and 5-FU-based regimens have had reported objective response rates in the 30% range with selected examples reaching the low 40s percent. Note that sometimes unconfirmed responses are included in the ORR reporting. The disease control rates are generally in the 60% range for both types of regimens with selected examples reaching as high as the mid-70s. The high end of the reported range for median progression-free survival for both regimens reaches approximately 7 to 8 months, and the upper end of the reported range for median overall survival for both regimens is short of a year at 11.7 months. Chemotherapy is generally challenging for patients and usually requires dose modification. The Grade 3 or higher treatment-related adverse event rate was reported to be approximately 70% for both GnP and 5-FU-based regimens. Dose reductions and dose discontinuations due to treatment-related adverse events were reported to be approximately 50% and 25%, respectively, for each regimen. Overall, patients who receive first-line combination chemotherapy for PDAC typically spend most of their final year of life receiving chemotherapy and managing the difficult side effects thereof. Since pancreatic cancer is commonly caused by excessive RAS(ON) signaling due to oncogenic RAS-driver mutations, targeted treatment with a RAS(ON) inhibitor seems like a compelling opportunity. Daraxonrasib is a groundbreaking RAS(ON) multi-selective tri-complex inhibitor that is designed to inhibit all or nearly all oncogenic variants of RAS, including wild-type RAS. It also suppresses many of the common drug resistance mechanisms that are mediated through RAS signaling. Preclinically, daraxonrasib has shown deep and durable monotherapy and combination activity across numerous cancer models, including pancreatic cancer xenografts and PDX models. And importantly, we have reported promising clinical activity for daraxonrasib with an acceptable safety profile in patients with previously treated PDAC, non-small cell lung cancer and other solid tumors. Furthermore, the FDA recently granted breakthrough therapy designation for daraxonrasib in previously treated metastatic pancreatic cancer with KRAS G12 mutations. We are currently conducting the RASolute 302 global randomized Phase III trial of daraxonrasib in second-line PDAC. Today, we'd like to explain our rationale and plans for developing daraxonrasib in first-line metastatic PDAC. As previewed in this high-level schema, we are preparing to conduct a randomized 3-arm Phase III study that will compare each of 2 new treatment regimens to GnP, an accepted and widely used standard of care. The first regimen is daraxonrasib monotherapy. The second treatment arm will be daraxonrasib with concurrent GnP followed by daraxonrasib. Our previously reported data in second-line PDAC provides some confidence that the efficacy profile of single-agent daraxonrasib could exceed combination chemotherapy in first-line metastatic PDAC. In addition, the tolerability profile of the first-line therapy could be improved by a targeted agent like daraxonrasib and intensive chemotherapy could be held in reserve for salvage second-line therapy. The rationale for the chemotherapy combination arm will be covered later in this presentation. In a few minutes, Dr. Lin will provide additional details of the RASolute 303 study. But before doing so, he will present 3 new clinical data sets that support our plan. First, updated data from long-term follow-up of the patients in the daraxonrasib monotherapy cohort of the first of the Phase I trial in patients with second-line metastatic PDAC that reinforces the strong underlying proof of concept. Second, a first disclosure of data on daraxonrasib monotherapy in first-line metastatic PDAC. And third, a first disclosure of data on daraxonrasib combined with GnP in the first-line metastatic PDAC setting. Wei?

Thank you, Steve. I'll begin with an update on the long-term follow-up for daraxonrasib monotherapy in second-line metastatic pancreatic cancer. As a reminder, reported efficacy in second-line PDAC for current standard of care regardless of the chemotherapy regimen evaluated is characterized by median progression-free survival in the range of 2 to 3.5 months and median overall survival of approximately 6 to 7 months. Slide 10 shows an updated waterfall plot, demonstrating robust antitumor activity in PDAC patients previously treated with 1 line of systemic therapy and median follow-up of approximately 17 months. Daraxonrasib at 300 milligrams daily achieved an objective response rate of 35% in RAS G12X mutant PDAC and 29% in the broader RAS mutant PDAC population, with a longer follow-up since the last data we shared for this patient population. All the responses have been confirmed. The disease control rates were 92% for RAS G12X patients and 95% for all RAS mutant patients. Of note, 6 patients remain on study treatment as indicated by the small arrows beneath the waterfall. I also want to note here that the tolerability and safety profile in this cohort has remained stable with a longer follow-up and is generally consistent with our earlier report. Slide 11 shows the updated progression-free survival analysis from this longer follow-up. The median PFS in the second-line population exceeds 8 months for both RAS G12X and all RAS mutant groups. The lower bounds of 95% confidence intervals are around 6 months. More than 80% of patients were progression-free at 3 months and over 60% at 6 months. These compelling data suggest a sustained suppression of RAS as a key driver in pancreatic cancer may translate to prolonged response and disease control. Slide 12 shows the updated overall survival analysis. With a longer follow-up, the median OS is now estimable at 13.1 months for the RAS G12X group and 15.6 months for all RAS mutant group. Of note, the estimated median overall survival is over 1 year in both groups, something that hasn't been achieved previously in any reported line of treatment for patients with metastatic pancreatic cancer. The lower bounds of 95% confidence intervals are nearly 11 months. The proportion of patients who were alive at 6 months is over 90% and at 12 months is over 50%. We're encouraged by the potential for long-term clinical benefit suggested by these data, which show consistency with earlier readouts and strengthen our belief that daraxonrasib is highly differentiated from chemotherapy in terms of antitumor activity, durability of effect and tolerability. The ongoing RASolute 302 pivotal study in second-line metastatic PDAC will evaluate these potential long-term benefits in a randomized Phase III trial. Now I'll share our newest daraxonrasib data in first-line metastatic pancreatic cancer. Slide 14 shows that the safety profile of daraxonrasib monotherapy in the treatment-naive setting is generally consistent with what was observed and reported in the second-line setting. As of the July 28 data abstract, 40 treatment-naive patients carrying RAS mutant pancreatic cancers had been treated with daraxonrasib at 300 milligrams daily. Approximately 1/3 of patients experienced a Grade 3 treatment-related adverse event or TRAE. And there were no Grade 4 or 5 TRAEs. Similar to the second-line setting, the 3 most common TRAEs were rash, diarrhea and stomatitis/mucositis. For individual TRAEs, the rates of Grade 3 events were all 10% or less. These adverse events were manageable with routine clinical interventions based on our learnings from the previously treated setting and implemented here as well as in our ongoing RASolute 302 pivotal trial. The rates of selected adverse events such as liver enzyme elevation and cytopenias, both of which are relevant to the combination development of daraxonrasib with standard of care chemotherapy remain low. This observation has implications for combination regimens we're developing in the first-line setting, which I'll present later in this presentation. Slide 15 shows that the safety and tolerability profile of daraxonrasib has translated to an acceptable rate of dose modification, achieving a favorable dose intensity. Approximately half of patients were able to stay on daraxonrasib without any dose interruption, 2/3 of patients remained on 300 milligrams daily while on treatment with only 1/3 requiring a dose reduction. The rate of discontinuation due to treatment-related adverse events was a modest 10%. This resulted in a mean dose intensity of 85%. Similar to the experience in second-line patients, these data suggest that daraxonrasib at 300 milligrams daily can be given consistently to PDAC patients in the first-line setting, a property that is designed to translate into sustained inhibition of RAS signaling in tumors. Slide 16 shows the impact of this approach on tumors. This slide focuses on 38 patients with first-line metastatic PDAC. Note that 2 patients in the safety cohort did not meet the definition of first-line metastatic disease and were excluded from efficacy assessment. One patient had locally advanced PDAC and the other had a synchronous neuroendocrine tumor. Daraxonrasib monotherapy induced deep tumor regressions in many of the patients with first-line metastatic PDAC. The objective response rate was 47%, and the disease control rate was 89%. The majority of patients remained on study treatment as of the data extract date of July 28. These initial findings demonstrate that daraxonrasib is highly active in the first-line setting and are highly encouraging with regard to daraxonrasib's potential as a first-line treatment for patients with PDAC. We continue to follow these patients for deepening of response and to evaluate durability of the clinical benefit. Next, I plan to share our data for the combination of daraxonrasib with gemcitabine, nab-paclitaxel or GnP, in first-line metastatic PDAC. Before doing so, I want to provide the rationale for advancing this combination. First, why a combination with chemotherapy? As shown in the patient flow Steve presented earlier, attrition from first line to second line is high, and the majority of first-line patients do not receive second-line chemotherapy. Therefore, some physicians will have a preference for a combination regimen in first line, aiming to ensure that patients may gain survival benefits from both daraxonrasib and chemotherapy. Furthermore, resistance to therapy is often due to tumor heterogeneity, meaning that the tumor may be a mix of 2 or more cancer cells with different phenotypes. In principle, potential heterogeneity in cellular sensitivity to different treatments may be overcome by combining the different mechanisms of action of daraxonrasib, a targeted RAS(ON) inhibitor and chemotherapy. Second, why a combination with GnP? It is a globally used standard of care in first-line PDAC. Its safety and tolerability profile means that more patients are eligible for GnP than for FOLFIRINOX, while the clinical outcomes from the 2 types of regimens are objectively quite similar. So if one were to select only one first-line chemotherapy for combination development, it will be GnP. I'll comment a little further on FOLFIRINOX later. Slide 18 shows the preclinical data that support development of the combination of daraxonrasib with GnP. In the left panel, our daraxonrasib monotherapy itself proved superior to GnP in a KRAS G12V PDAC model at clinically translatable doses. The combination of daraxonrasib plus GnP further deepened and sustained tumor regressions. In the right panel, our treatment with daraxonrasib monotherapy delivered greater progression-free survival than the GnP in this experiment, studying 10 different PDAC xenograft models. The combination of daraxonrasib with GnP significantly prolonged the PFS compared to either regimen alone. These preclinical experiments provide a strong basis for our clinical evaluation of the daraxonrasib plus GnP combination. Slide 19 summarizes the rationale for the selection of the doses and schedules for the daraxonrasib plus GnP regimen. In constructing this regimen, the objectives are to sustain continuous suppression of RAS signaling via high dose intensity for daraxonrasib to leverage the antitumor contribution of chemotherapy and to achieve an overall safety profile that is competitive against standard chemotherapy. For daraxonrasib, we considered our prior experience with monotherapy in second-line pancreatic cancer in which daraxonrasib showed robust antitumor activity at 160 to 300 milligram daily with small dose-dependent increases in exposure, activity and side effects observed within this range. For monotherapy treatment with daraxonrasib in PDAC, we regularly use 300 milligrams daily in order to maximize the potential antitumor activity for each patient while maintaining an acceptable safety profile. In combination with GnP, we evaluated a few exploratory cohorts of patients at different daraxonrasib doses and selected 200 milligrams daily as the go-forward dose in order to optimize the risk benefit in the context of concurrent GnP with its characteristic side effects. We know from our experience in second-line PDAC that 200 milligrams is a highly active and generally well-tolerated dose of daraxonrasib. Regarding GnP dosing. In clinical practice, both gemcitabine and nab-paclitaxel are routinely given at the approved full doses regardless of frequency, and we did not make any adjustment to full dose in combination with daraxonrasib. Regarding dosing frequency. GnP is typically given under 1 of 2 standard schedules over a 28-day cycle, dosing on days 1 and 15 or dosing on days 1, 8 and 15. It is understood among many practitioners that the days 1, 8 and 15 schedule is associated with higher rates of dose interruptions and reductions due to bone marrow toxicity and neuropathy. Often patients started on a days 1, 8 and 15 schedule are unable to consistently receive all doses and practically end up converging on a days 1 and 15 dosing regimen. Further, studies from the Mayo Clinic and MD Anderson suggested that the days 1 and 15 schedule significantly reduced cytopenias and neuropathy while maintaining efficacy similar to that of the days 1, 8 and 15 schedule. In this context, based on a small number of exploratory daraxonrasib plus GnP cohorts, we selected the days 1 and 15 regimen for GnP as the go-forward schedule for the improved safety, tolerability and patient convenience, while aiming to preserve its potential contribution to efficacy in the combination. I'll next present the clinical data from patients with first-line PDAC treated with daraxonrasib 200 milligrams daily and full dose GnP with biweekly dosing. Slide 20 shows an acceptable safety profile for this daraxonrasib plus GnP combination. The TRAEs are additive of the profiles of individual agents and the rates are as expected based on the monotherapy safety profiles. No new safety signals emerged. The combined Grade 3 or higher TRAE rate was close to 60%, largely due to the inclusion of chemotherapy. The key overlapping toxicity of diarrhea was 13% for Grade 3 with no Grade 4 or 5 TRAEs related to diarrhea. Grade 3 were higher anemia and neutropenia are around 20% and Grade 3 liver enzyme elevations were in the single digits. There were no Grade 5 TRAEs. The safety profile of the combination regimen translated to an acceptable degree of dose modification as well as favorable dose intensity for daraxonrasib, as shown on Slide 21. Approximately half of patients were able to receive daraxonrasib without interruptions caused by TRAEs and 3/4 did not require a dose reduction. The rate of daraxonrasib discontinuation was only 5%. This rate of dose modification resulted in a mean dose intensity exceeding 80% for daraxonrasib. For GnP, a dose intensity of over 60% is consistent with expectations for GnP alone. The daraxonrasib dose modification rate and dose intensity are consistent with those observed with daraxonrasib monotherapy at 300 milligrams. By selecting daraxonrasib at 200 milligrams to combine with GnP, we aim to achieve sustained RAS inhibition similar to that of daraxonrasib monotherapy while gaining an additional contribution to antitumor activity from cytotoxic chemotherapy. Slide 22 shows the encouraging preliminary efficacy of this daraxonrasib plus GnP combination. Here, we're showing data for 31 patients who received a first dose of daraxonrasib plus GnP, at least 18 weeks prior to data cutoff date. The waterfall plot shows that deep and sustained tumor regressions were achieved in the majority of patients, most of whom remained on study treatment as of the July 28 data abstract date. The objective response rate was 55% with an associated disease control rate of 90%. These initial findings are highly encouraging with regard to daraxonrasib's potential as a first-line treatment for patients with PDAC. With a median follow-up of a little over half a year, median PFS and OS are not mature enough to be estimated at this time. We presented 3 main sets of data in support of late-stage development of daraxonrasib in first-line PDAC, the mature overall survival provided by daraxonrasib monotherapy in second line, the highly encouraging antitumor activity and acceptable safety profile of daraxonrasib monotherapy in first line and the highly encouraging antitumor activity and acceptable safety profile of daraxonrasib plus GnP in first line. In aggregate, these findings support initiation of a pivotal trial in patients with treatment-naive metastatic pancreatic adenocarcinoma to evaluate the efficacy of daraxonrasib monotherapy and daraxonrasib in combination with GnP. The schematic of the expected design is shown here on Slide 23. We plan to randomize approximately 900 all-comer patients with first-line PDAC regardless of RAS status to evaluate these 2 experiment regimens as well as full dose GnP as the comparator. Study participants will be stratified by RAS mutation status to balance potential differences in outcome due to prognostic or predictive value of RAS mutation. Daraxonrasib monotherapy will be given at 300 milligrams daily. Daraxonrasib will be given at 200 milligrams daily in combination with GnP, which will be given at full dose on the days 1 and 15 schedule and patients will transition to daraxonrasib 300 milligrams daily after completion of chemotherapy. In all 3 arms, treatment will continue until disease progression or intolerance. The primary endpoints will be PFS and OS. Each investigational arm will be compared independently with the control. The protocol has not been fully finalized yet, so some details of the study design may change by the time the study is initiated. In addition to the daraxonrasib plus GnP combination, we also evaluated the combination of daraxonrasib with FOLFIRINOX. We observed robust antitumor activity, further validating the concept of combining RAS inhibition with cytotoxic chemotherapy. However, FOLFIRINOX itself has a wide range of toxicities than GnP, especially GI toxicities. And patients receiving a combination regimen required a high level of management by the physician, making it less practical to implement on a wide basis across diverse institutional settings. Furthermore, as noted, treatment with FOLFIRINOX demands a higher baseline performance status, limiting its use to less than half of metastatic pancreatic cancer patients. Finally, GnP is the most widely used first-line therapy in Japan and certain countries in Europe. Therefore, based on these considerations, we have elected to develop daraxonrasib in combination with GnP in our effort to change the standard of care globally for patients with treatment-naive PDAC. We are optimistic that daraxonrasib as both monotherapy and in combination with GnP could be options that help achieve our goal. We plan to reserve potential combination with FOLFIRINOX for our mutant selective inhibitors such as zoldonrasib. With that, I'll hand the mic back to Mark.

Thank you, Wei. I'll conclude our prepared remarks with Slide 25, which highlights our bold vision for daraxonrasib to become a new global standard of care for patients with PDAC in metastatic and non-metastatic disease settings. As noted throughout this presentation, current treatment options for PDAC leaves significant room for improvement. Today, for those who receive standard of care chemotherapy, outcomes are clearly suboptimal, and many patients are simply not able to receive or benefit from such treatment. Daraxonrasib's highly innovative mechanism of action, breadth of RAS mutation coverage and extensive preclinical profile suggests it is well matched to counter the oncogenic drivers of PDAC. And we have generated substantial and growing evidence of daraxonrasib's compelling profile across lines of treatment for PDAC. The long-term follow-up data we reported today for monotherapy in patients with second-line PDAC reaffirms the promising activity, durability and acceptable safety and tolerability we have previously reported. The new findings we presented this afternoon for monotherapy in the first-line PDAC setting are highly encouraging and monotherapy represents a core component of our first-line Phase III trial. Additionally, the new initial findings we presented for a combination with chemotherapy in the first-line setting are also highly encouraging and combination treatment is a second core component of this trial. Both monotherapy and combination with GnP hold great promise in support of our ambition to improve treatment outcomes for patients with first-line PDAC. As noted, we are conducting a broad-based late-stage global development program to evaluate daraxonrasib in multiple lines of treatment for PDAC. We have either initiated or are on track to initiate this year 3 Phase III clinical trials across lines of therapy in PDAC. RASolute 302 in patients with second-line metastatic PDAC has been enrolling well, and we expect to complete global enrollment this year to enable an expected data readout in 2026. As described today, RASolute 303 in patients with first-line metastatic PDAC is progressing toward a Phase III trial initiation in Q4. And RASolute 304, evaluating adjuvant treatment for patients with resectable PDAC, is also progressing toward a Phase III trial initiation in Q4. We have intentionally kept today's focus on the first-line metastatic setting and plan to share the trial design for RASolute 304 next quarter. With each clinical achievement, we advanced one step further toward developing the leading global targeted medicines franchise for patients living with RAS-addicted cancers. Based on the compelling data shared today, we are increasingly confident in the potential to establish daraxonrasib as a new global standard of care for patients living with pancreatic cancer. I'll now turn the call over to the operator for the Q&A session.

[Operator Instructions] Our first question for today comes from the line of Jonathan Chang from Leerink Partners.

This is Albert Agustinus dialing in for Jonathan Chang. Congratulations on the progress. So my first question is regarding the efficacy in first-line PDAC. How should we think about the relatively similar response rates between daraxonrasib monotherapy and daraxonrasib plus gem nab-pac? And I guess as a follow-up on that, how should we think about the potential durability of responses in monotherapy versus daraxonrasib plus gem nab-pac?

Thanks very much for your question. So I guess there were 2 parts to that. One is how similar was monotherapy to combination and what about durability? Wei, would you like to comment on that?

Yes, sure. Thanks for the question. So I think the -- certainly, we're very encouraged by the improvement in the monotherapy activity going from second line to first line, and that's typically seen in any drug, and this certainly holds. And it just highlights to the degree of addiction of these tumors and also the lack of other treatment creates higher degree of sensitivity. Now 47 and 55, they are within 10 points each other, of course, but we do see some contribution of chemotherapy, I think, to the addition of the regimen. And I think one of the hypothesis we're testing in this is really in terms of long-term benefit of the patients, is it more important to give them together or sequentially, right? I think that's one of the outcomes of this 3-arm design. So in terms of long-term durability, I think it's a little too early to assess. I think many of our experiences, it really shows that disease control rate does have some -- is one of the earlier correlates. And certainly, we have a very high 90% disease control rate. And so with longer follow-up, we'll be closely monitoring and then reporting on those long-term durability benefits.

Yes, if I could just add a comment to that. In our view, across these 3 different data sets, results are really unprecedented for pancreatic cancer patients with metastatic disease, the second-line responses, but more importantly, the durability, the OS benefit that Wei alluded to, the first-line monotherapy with a 45% response rate but a high DCR rate to go with it. And then the combination strategy delivering a 55% response rate with a similar DCR rate. All 3 of those are encouraging. And again, to emphasize the point that Wei made, we really are testing 2 independent hypotheses here. And ultimately, the OS will inform each of those hypotheses as to their validity and may create multiple options for physicians caring for patients.

And our next question comes from the line of Michael Schmidt from Oppenheimer -- or Guggenheim.

Congrats on the nice update here in PDAC. Could you expand a bit more about your decision to go with the 200 milligrams daraxonrasib dose with full chemo as opposed to maintaining the 300 milligrams QD daraxon and using a lower chemo dose for the combination arm? So that's question one. And then the other question I just had on durability, do you think you'll need to see more mature durability data, including PFS in order to sort of finalize powering for the RASolute 303 study?

Thank you, Michael. Nice to hear from you. I think Wei can give us probably a more fulsome comment here. I would emphasize that 200 milligrams delivers an exposure level that, as you know, from several years of looking at this is very attractive with regard to its antitumor activity in preclinical species and correlates quite nicely in humans. So we've always felt that 200 to 300 were pretty similar, although there is some subtle difference between them.

Yes. So happy to address this question. So as Mark pointed out, there's a slight dose response in the range from 160 to 300. But across the entire dose range, we have achieved what we have preclinically predicted as a very active. So we believe as long as we're in that dose range, we'll be delivering fully outstanding clinical benefit to patients, and that's being tested. The 200 milligram really allow us to deliver that in combination with chemotherapy. And then we do acknowledge there's some safety AEs overlapping between daraxonrasib and chemotherapy. And then giving at 200 milligrams really allow us to achieve sustained RAS inhibition, which in our experience is what really drives long-term clinical benefit. And so be able to give at 200 milligrams and keep that in a sustained way such that RAS inhibition can be maintained throughout the treatment duration and then transitioning to 300 milligrams without the chemotherapy where that RAS inhibition can be continued is the optimal way that we have discovered. And hence, that's the regimen we have landed on.

The second question has to do with powering the study and whether or not we need PFS to help guide that. Do you want to comment on that?

For the powering of the study, this is, again, a study that's designed for demonstrating overall survival similar to our second-line trial. I think as Mark had pointed out, this is -- the outcome even in the second line has been really unprecedented because no one has broken the 1-year barrier, and that's really the goal we're trying to strive for. And now so OS is still the metric because even in the first-line setting, people do not live for yet a year. So given that, that is the primary endpoint, so the sample size and all the testing is really revolving around the OS and so the readout and so on. And then I also want to point out that there's independent testing between the 2 arms, and hence, it's actually powered such that both the monotherapy and then the chemotherapy will be evaluated independent of each other.

And our next question comes from the line of Charles Zhu from LifeSci Capital.

Congratulations on the pretty strong data out here and formalizing a lot of these plans where we had a lot of questions. Maybe also just if I could squeeze in 2 real quick for me. How do you think [ about ] of a daraxonrasib plus GnP relative to FOLFIRINOX, especially in patients that are hyperfit for FOLFIRINOX, how many of them do you think you could peel over to something like daraxon plus GnP? And also similarly, maybe one on the time lines for this frontline study. Could you provide color around how much time this could take? Could this overlap with, for example, the availability of a commercially available daraxonrasib in the second line? And how have you kind of baked that possibility into some of your trial design assumptions?

Charles, thanks very much for your question. So the first one was, if I understood it correctly, will patients who might otherwise be eligible for modified FOLFIRINOX be interested in the either monotherapy or GnP combination strategy. Probably depends on how it performs in the Phase III trial. Certainly, the evidence is pretty encouraging right now, given that there -- really it's not a consistent difference in the literature between GnP and modified FOLFIRINOX. I think we can be pretty encouraged that these results will be attractive to people. But as to what happens, I think we need to see what the final definitive results are, and then it will be up to patients to discuss with their doctors. Wei, anything you want to add to that?

Yes. I think there's -- just to address the efficacy of FOLFIRINOX versus GnP, I think there's this perception that GnP may have inferior OS compared to FOLFIRINOX. And that was certainly true, I think, for the initial registration trial a decade ago. But I think since then, subsequent trials have really shown that the overall survival with GnP can approach that of FOLFIRINOX. So I think even meta-analysis show that there's not a substantial difference between those 2 regimens. And the other consideration is when a patient is discussing their -- with their physician about the option joining this trial, they're not joining the trial for option to be treated with FOLFIRINOX, they're joining the trial really looking for an opportunity to receiving daraxonrasib. And this trial, given a 3-arm design and 1:1 randomization, the patients have 2 out of 3 chance of getting daraxonrasib. So I think this trial should be highly attractive to any patients who are looking for vascular agents that has the potential really to improve their survival.

I think that's a critical point. I mean what we're trying to do here is stop the debate as to whether people should get a chemotherapy that's toxic and might be marginally better than another chemotherapy that's toxic. We want to change the narrative to should they get an inhibitor of the primary oncogenic driver of their disease versus not an inhibitor of the primary oncogenic driver of disease irrespective of whether they get chemotherapy with it or not. And so this is a complete paradigm shift. And we're trying to get away from that thread the needle in between whether oxaliplatin is better than gemcitabine. It's really hopefully will become a completely obsolete question at the end of this study.

And then your second question was whether the availability of daraxonrasib at some point in the future were that to happen, would that create a crossover challenge? I guess that's what was implied by your question. It could. That could be a variable that will come into play. We certainly have considered that in the design of the trial, the kinetics of everything that we're doing, and we expect to be able to manage that.

And our next question comes from the line of Andrea Newkirk from Goldman Sachs.

This is Morgan on for Andrea Newkirk. Congrats on the data. Can you please speak to the rationale for transitioning patients from the combo to daraxonrasib mono versus keeping them on combination regimens the entire time? And then over what time frame do you expect the switch from combo to daraxonrasib mono would occur? And is it at the physician's discretion or based on tumor response?

Thanks for your question. Wei?

Sure. Yes. So I think -- again, I think to Steve's earlier point, I think we certainly believe that the long-term driver here is RAS, and hitting RAS hard is going to -- what's going to carry out the longest clinical benefit for patients. And therefore -- so that's one strong consideration to -- for this specific design. Now chemotherapy, so there are 2 key considerations. I think one is the amount of benefit patients derived from chemotherapy is really achieved mainly in the first 4 to 6 cycles. And beyond that, number one, the benefit becomes reduced. And number two is majority of patients would have either dose reduced or have dropped one or both agents. And therefore, maintaining the chemotherapy along with daraxonrasib 200 doesn't really gain that much going beyond 6 cycles. And so it's actually more optimal knowing that daraxonrasib is really the largest carrier of clinical benefit in this regimen. After the chemotherapy have really done their job in the first 4 to 6 cycles, the transition will actually happen and go on to daraxonrasib at 300 milligrams to really maximize the RAS inhibition and achieving the longest-term benefit for patients.

And I would just sort of emphasize that it is actually key to continue on daraxonrasib, that's the compound that appears to be showing significant durability and there's no chemotherapy that can provide that, Wei.

Yes. And I think that's -- I think most patients would look forward to the day when they can stop chemotherapy. And this really -- this design offer them an improved quality of life when that chemotherapy can be stopped.

And our next question comes from the line of Ellie Merle from UBS.

Congratulations on the results. Just in the frontline patients, what was the median duration of response and the proportion of these patients that are still in response? And for the adjuvant Phase III PDAC design, I guess, what are you looking for at this point to finalize the design? And can you walk through some of the differences that you could see in the trial design versus in the frontline setting?

Thanks, Ellie. Appreciate the questions. Let me just say, I think for the first-line median duration of response, we don't have that information yet. We didn't report it in this particular set. At some point, we'll have it, but we just don't have it today. With regard to the adjuvant, we'll talk about adjuvant next quarter. There's not additional information that we're seeking associated with that. We just wanted to keep this investor discussion today focused on first line. Was there anything specific in your question you want to ask?

I think the only other thing, Ellie, the patients that are still on study are indicated on the waterfall by an arrow underneath. So we don't usually provide swimmer plots because we don't like them. But we do put the arrows on the chart and they're still on treatment at the time of the data abstract, so that should give you some sense of what's going.

Steve is saying you can do your own calculation, but we won't do it at this stage.

Well, I'm not going to give you [indiscernible]. If the median is NE, then we can't report it.

Right, that's the issue.

And our next question comes from the line of Marc Frahm from TD Cowen.

Congrats on all the data that you're disclosing. Maybe put a finer point on the FOLFIRINOX debate that's out there. I get, as you guys were saying, the data is pretty equivocal as to whether it really is a better regimen or not, but there is that kind of impression out there. Can you maybe speak to just the powering that's in this Phase III design and what that implies about like if any -- if either arm is positive, how it will almost certainly compare to even the most aggressive kind of FOLFIRINOX comparisons?

Yes. I mean the primary endpoint going to be OS. And as we pointed out, I think the highest OS that's been reported is under a year. The OS that we've reported for second line, albeit in the single-arm trial is well over a year. The ORR tells us that we're moving into greater activity in early lines as we -- exactly as we'd expected and predicted, as you know, from many previous conversations. So it seems likely that OS would deliver in that context and deliver a significant advantage. So I'm not sure how FOLFIRINOX could ever catch up with that. I mean it's pretty well characterized. Maybe I'm missing something here, but it seems like that's pretty much the answer to that question. Is there something more? Marc...

I think that's helpful, yes. And then just back on this operational aspect of the combo arm of kind of the switch to higher dose maintenance dosing of daraxonrasib. Is it entirely driven by patients reaching a 6-month time point on the combination? Or is there an ability with some of the earlier patients who may be doing very poorly with tolerating chemotherapy and dropping dose very quickly to kind of rapidly move to 300 milligrams because they've gotten to a dose of gem/Abraxane that really is kind of pointless even if they haven't gotten to 6 months.

Sure. That will be structural, but Wei go ahead.

Yes. No, absolutely. It's -- for the GnP combination, it's up to 6 cycles. And so a standard practice, if a patient -- some patients actually discontinue GnP entirely before 6 cycles, and they have option to go up to 300 milligrams. And that's typically how it is done in the adjuvant setting. So adjuvant setting, the chemotherapy is given for 6 cycles and not everyone actually achieved it if you look at how things are reported. In fact, majority of patients do not achieve all 6 cycles.

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

Congrats on the update. I guess how important do you think physician education on RAS inhibition will be specifically in the community setting for frontline uptake of daraxonrasib longer term?

Thanks for your question, Kelly. The underlying assumption to your question is valid that a lot of people don't know that RAS drives pancreatic cancer. They might have heard it at some point in the past or they might not have even been taught that in medical school or residency because it didn't matter. There was nothing you could do about it. And so given the flood of detailed technical information that doctors are exposed to every day, they sort of have to pick and choose what to bother using ATP to fire on in their nurse and try to remember. So -- and as you move further away from academic centers, that awareness goes down. It's actually quite high, although not 100% in academic centers, and then it does get discounted the further, maybe the greater the distance to your community center. So there will be need for education. That education will be a lot easier with data. And here are data certainly, that will be noted. It will be noted at scientific conferences. It's noted by KOLs. And then there will be more data that we hope would support approvals in which case that data will become widely available and will be much easier for physicians to remember it. So yes, there is going to be a need for education. We're actively engaged in education now. Our medical affairs organization is highly engaged with physicians broadly, but it will tend to stick more when there's an even stronger reason for it to stick when people have a drug they can prescribe.

And our final question for today comes from the line of Asthika Goonewardene from Truist.

I offer my congratulations as well on the data. I want to talk a little bit about resistance mechanisms. So for the frontline daraxonrasib monotherapy, did that data resemble the resistance data that you presented at AACR? And then for the daraxon plus GnP, I know you only had 2 patients who progressed, but what's your hypothesis on the resistance mechanism there? And then second question is that in frontline pancreatic, you still get a significant amount of patients who opt for palliative chemotherapy as these patients generally would be intolerant to the combo chemo regimens. Do you envision that daraxonrasib will be an attractive option -- monotherapy daraxon would be an attractive combination option for these patients instead of palliative chemo? And how are you putting guardrails on recruitment so you don't kind of skew that the daraxon monotherapy arm with maybe patients who would have been intolerant to the combination chemotherapy?

Thanks very much for your questions and for your coverage. First, with regard to the palliative first line, it was your second question, if a patient wants to enroll in the trial, they'll have to be eligible for chemotherapy because they may be randomized to chemotherapy or chemotherapy plus daraxonrasib or daraxonrasib alone. So they'll have to be of a condition and willingness to be able to participate in that. And there may be some people, I suppose, on the edge. It will be up to sort of the criteria -- enrollment criteria to be applied appropriately, and that should be balanced because they'll be randomized after they enroll. So I think that's probably the best that we can do with that. With regard to resistance, we don't have -- certainly aren't reporting today any resistance data from the first-line cohorts. These cohorts were all conducted this year. And we just simply don't have enough data to be able to declare what the resistance mechanisms are. It will be interesting to find out over time, although they're not large data sets, but we might be able to get some glimpses about what's going on there. Anything else you want to add to it?

Only that, as Wei alluded to in the initial remarks that we don't have any evidence that RAS -- that pancreatic cancer is more or less addicted to RAS depending on the line of therapy. And so the fundamental biology of the disease is the same, whether the patient has received chemotherapy previously or hasn't received chemotherapy previously. And so in that respect, you may be able to make some predictions as to what we're going to see. But Mark is right, although we are collecting the same samples from this cohort as we did from the second-line cohort, we don't have any actual data to corroborate that.

Yes. And as Steve pointed out, the little arrows indicate there's hardly any patient who progressed on either monotherapy or the chemo combo. So for the sake of these patients, I hope that it will take a long time for us to learn about...

Yes. Maybe I can just reinforce something Steve just said, which is, I think, a prevailing question over the last year, question we didn't really fully understand, but nonetheless, we heard was whether or not first line would somehow be less sensitive to a RAS inhibitor than second line. And I think it's pretty clear from these data, both for the monotherapy and the combination cohort that just as Steve said, pancreatic cancer is a RAS-driven disease from the beginning. It doesn't become a RAS-driven disease after you had first-line treatment. And so the fact that we're seeing some improvements in the outcomes measured by ORR and DCR, particularly ORR in the first line is consistent with past experience with other targeted agents in other cancers and suggests that this is how these are going to play out here, too. So I think we've now validated biologically, these are no different from second line, and we're very excited to have a compound that can be used and explored now in a Phase III trial.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Mark Goldsmith, Chairman and CEO, for any further remarks.

Thank you, operator, and thank you, everyone, for joining us today and for your ongoing support of Revolution Medicines.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.