Revolution Medicines, Inc.

Good day, and thank you for standing by. Welcome to the Revolution Medicine's Q3 2024 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Acy, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you, and welcome everyone to the third quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer, Dr. Steve Kelsey, our President of R&D, and Jack Anders, our Chief Financial Officer. Dr. Wei Lin, our Chief Medical Officer, will join us for the Q&A portion of today's call. I'd like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended September 30th, 2024 and recent corporate updates. The press release is available on the investor section of our website at RevMed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer.

Mark. Thanks, Ryan. It's good to be with you this afternoon. At Revolution Medicines, we are committed to revolutionizing treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. We believe that we have increasingly been able to demonstrate that our portfolio of RAS-on inhibitors has the potential to provide meaningful impact for patients living with some of the most difficult-to-treat cancers. At the start of the year, we provided a roadmap of strategic development priorities for 2024 focused on our three pioneering Rason inhibitors in clinical development, RMC6236, RMC6291, and RMC9805. The highest priority has been to advance RMC6236, our first-in-class Rason multiselective inhibitor, into its first pivotal trials, one in pancreatic ductal adenocarcinoma, which we refer to as PDAC, and one in non-small cell lung cancer. Our second priority aimed to begin defining the path to expanding the reach of RMC6236 into earlier lines of therapy, particularly in PDAC. Our third priority aimed to qualify our mutant selective inhibitors, RMC6291, a RAS on G12C selective inhibitor, and RMC9805, a RAS on G12D selective inhibitor, for late-stage development. We have made substantial progress against these priorities. We demonstrated compelling durability data, specifically progression-free survival and overall survival, in a cohort of patients with previously treated metastatic PDAC treated with RMC6236. Based on these results, we initiated our first global randomized phase III study in second-line treatment of patients with metastatic PDAC and are now actively dosing patients in this study. Last month, we shared encouraging safety, tolerability, and anti-tumor activity with RMC9805 in patients with KRAS G12b PDAC. We continue to advance and extend our pipeline, including RMC9805 and RMC6291, by exploring new combinations to inform the design of future pivotal studies in earlier lines of therapy and across multiple tumor types, including PDAC and non-small cell lung cancer. And there's more to come. We have a number of disclosure milestones ahead this quarter when we look forward to sharing updates across our RAS on inhibitor portfolio, including several approaches we're taking in non-small cell lung cancer, including both monotherapy and combinations. I'd now like to hand the call over to Dr. Steve Kelsey, our president of R&D. who will summarize the PDAC results we recently shared from the RMC-6236 and RMC-9805 monotherapy studies at the EORTC-NCI-AACR symposium, commonly referred to as the triple meeting. He'll also provide a brief overview of our plans in non-small cell lung cancer. Jack Anders, our CFO, will then provide a summary of the third quarter financial results before I share a few closing remarks and open the call to Q&A. Steve?

Thanks, Mark. At the recent triple meeting in October, we had the opportunity to present data on two of our Rason inhibitors in PDAC, including updated progression-free survival and overall survival from our RMC6236 monotherapy study and initial safety and antitumor activity from our RMC9825 monotherapy study. Before I review these results, I would like to provide some perspective into RevMed's R&D approach relating to this devastating disease. More than 60,000 pancreatic cancer patients are diagnosed every year in the United States alone, with more than half of all cases being diagnosed at the metastatic stage. Over 90% of cases are driven by RAS mutations, with the majority being G12X. G12D is the single most common RAS mutation, found in approximately 40% of PDAC. Chemotherapy is the current standard of care for pancreatic cancer. Based on published clinical trials, median progression-free survival, or PFS, is 2 to 3.5 months for second-line patients who have progressed on first-line therapies. And median overall survival in these patients is six to seven months. We believe these treatment results indicate a need for improved outcomes for patients. While patients treated with first-line combination chemotherapy at initial diagnosis of metastatic PDAC do better, the reported median PFS of approximately seven months and median OS of approximately 11 months still leave room for improvement. I will now provide a brief summary of the results recently presented for our oral Rason multiselective inhibitor RMC6236 and our oral Rason G12D selective inhibitor RMC9805. The details can be found on the events and presentations page of our corporate website at revmed.com. Beginning with RNC6236, as the data have matured and as the data cut off of the 23rd of July, 2024, we can now report that patients who had received one prior chemotherapy regimen for metastatic PDAC with G12X mutations and who received RNC6236 monotherapy across the dose levels of 160 to 300 milligrams daily, achieved a median PFS of 8.5 months with a median OS of 14.5 months. For all second-line patients with RAS mutant PDAC at these dose levels, the median PFS was 7.6 months and median OS was 14.5 months. At these doses, including the highest dose of 300 milligrams daily, The safety and tolerability profile was manageable, and the average dose intensity of RMC6236 was 92%. The overall response rate for patients with G12X tumors in the second-line setting at these doses was 29%, also reflecting increasing maturation of the data. This clinical profile is clearly encouraging, and the robustness of these data continue to justify our optimism about RASILU-302, our phase three registrational study in patients who have received one prior line of therapy for metastatic pancreatic cancer. This study is actively recruiting patients, as highlighted in last month's press release announcing the first patient dosed in the study. Moving to RMC9805, our Rason G12D selective inhibitor. At the triple meeting last month, we presented the initial clinical data from the phase one monotherapy study of RMC9805 with a main focus on patients with PDAC. As of the September the 2nd, 2024 data cutoff date, RMC 9805 demonstrated encouraging preliminary clinical antitumor activity. We reported a 30% objective response rate and an 80% disease control rate for patients treated with 1200 milligrams daily, which is the candidate recommended phase two dose. RMC 9805 was well tolerated at this dose level with manageable and predominantly low grade treatment related adverse events. one grade three adverse event was reported amongst 179 patients. While the data are early, the safety and tolerability profile, as well as the initial read on anti-tumor activity, are clearly encouraging. Based on our experience with RMC6236, it will take more time for the RMC9805 data to mature sufficiently to characterize the true overall response rate and the durability of the RMC9805 anti-tumor activity as represented by the more relevant outcome measures of progression-free survival and overall survival. The initial profile of 9805 is also consistent with potential use in combinations, which continues to be an important strategic priority for us. The encouraging data from both RMC6236 and RMC9805 provide us with several options for development in RAS G12d PDAC, including the RAS on doublet combination of RMC6236 with RMC9805, which is currently undergoing clinical evaluation. Ultimately, we hope that these agents will provide important optionality for pancreatic cancer patients with tumors harboring KRAS G12D, the largest genetically defined subset of PDAC patients. Switching gears, I'd like to share a brief overview of our work in non-small cell lung cancer. We anticipate a number of upcoming disclosures for both RMC6236 and RMC6291, our Rason G12C selective inhibitor. We remain fully committed and look forward to sharing the remaining 2024 data disclosures in the remaining part of the fourth quarter, when we plan to share updated RMC6236 monotherapy activity data in non-small cell lung cancer, as well as initial data from our exploratory combination studies, including RMC6236 plus pembrolizumab and the Rasson inhibitor doublet, of RMC6236 plus RMC6291. We expect to reach regulatory alignment and initiate a phase three registrational study evaluating RMC6236 as monotherapy in patients with previously treated advanced RAS mutant non-small cell lung cancer in the first quarter of 2025. Now I'd like to turn the call over to our CFO, Jack Anders, to provide a financial update.

Jack. Thanks, Steve. We ended the third quarter of 2024 with $1.55 billion in cash investments, which we project can fund planned operations into 2027 based on our current operating plan. Turning to expenses, R&D expenses for the third quarter of 2024 were $151.8 million compared to $107.7 million for the third quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial-related expenses for our first wave of RAS on inhibitors, personnel-related expenses associated with additional headcount, and stock-based compensation expense. G&A expenses for the third quarter of 2024 were $24.0 million compared to 15.5 million for the third quarter of 2023. The increase in G&A expenses was primarily due to increases in personnel-related expenses associated with additional headcount, commercial preparation activities, and stock-based compensation expense. Net loss for the third quarter of 2024 was 156.3 million, compared to $108.4 million for the third quarter of 2023. The increase in net loss was due to higher operating expenses. We are reiterating our 2024 financial guidance and continue to expect projected full-year 2024 gap net loss to be between $560 million and $600 million, which includes estimated non-cash stock-based compensation expense of between 70 million, and 80 million. That concludes the financial update. I'll now turn the call back over to Mark. Thank you, Jack.

Revolution Medicines continues to make substantial progress across our portfolio. The recent triple meeting presentations for RMC 6236 and RMC 9805 underscore the compelling opportunities we have to meaningfully impact outcomes among patients with PDAC. Based on the profiles demonstrated so far, we are advancing both programs with intensity and speed. As Steve shared, the PFS and OS results for RMC6236 in previously treated PDAC patients support our optimism that if reproduced in the ongoing global randomized controlled phase three study, RMC6236 could become a potential new standard of care in this setting. These data also position us well to move into evaluation in the frontline PDAC setting. The initial RMC9805 monotherapy data in PDAC are also very encouraging. We recognize it will take time for the data to mature sufficiently to provide clarity about the optimal development approach and portfolio strategy, including understanding the potential for combinations. Nonetheless, based on their differentiated clinical profiles, we believe there should be a place for both compounds in the potential emerging targeted therapy paradigm for patients with PDAC. We're very pleased that RMC9805 is the third Rason inhibitor from our portfolio to achieve proof of concept with an acceptable safety profile, representing important validation of our innovation engine and a significant milestone for Revolution Medicine as an organization. Our TriComplex platform has delivered three distinct oral inhibitors with compelling clinical profiles. This work has charted new territory in oncology by targeting the oncogenic Rason protein state, an extraordinary achievement. These three investigational drugs include two covalent Rason inhibitors and one non-covalent Rason inhibitor, one Rason inhibitor designed for breadth and two designed for mutation selectivity, and one Rason inhibitor that covalently, irreversibly, and selectively engages aberrant aspartic acid at amino acid position 12 in RAS. To our knowledge, a chemistry first in a clinical stage investigational drug. Importantly, the strength of the clinical data we've obtained with the first wave of RAS on inhibitor programs highlights the clinical translatability of our discovery and preclinical efforts and encourages us to continue driving progress in this space. In conclusion, we are successfully executing and making significant progress on our key 2024 priorities and laying the foundation for long-term sustainable progress, supporting our goal of revolutionizing treatment for patients with RAS-addicted cancers. Initiating our first Phase III clinical study in second-line pancreatic cancer is a significant milestone in this company's evolution and an important step in our mission to improve outcomes for patients with RAS-addicted cancers. We anticipate it will be the first of many registrational studies in patients with RAS-addicted cancers. Our non-small-cell lung cancer monotherapy and combination studies are ongoing, and we look forward to sharing an update with you this quarter. And we remain well-capitalized, enabling us to continue to advance our pipeline in these high unmet need cancers. I'd like to take a moment to recognize and thank the patients and caregivers, clinical investigators, scientific and business collaborators, advisors, and shareholders, and the tireless efforts of RevMed employees on behalf of patients. Without their commitment and support, the progress we've made wouldn't be possible. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.

Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from Peter Lawson with Barclays. Your line is now open.

Great. Thanks so much. Thanks for taking the questions. I guess the first one would just be around what we should be looking for in the combination data sets that we get over the next few months to six months in terms of the combination with PEMBRO and then the combinations between the multi and the G12C and how we should be thinking about those in terms of side effect profiles versus any efficacy signals.

Thank you, Peter. I appreciate the question. Well, I think there is a difference between the PEMBRO studies and the RASP-on inhibitor double-up study. The PEMBRO study is primarily a safety study, and there the most important signal that we are, you know, zeroed in on is the hepatotoxicity signal that was seen with the first-generation RASP-off GMO-C inhibitors. We want to clear that issue. As we've mentioned a number of times in the past, we did have data reported actually about 12 months ago that referred to patients who had recently come off of pembrolizumab and started RMC6236. And those patients who were considered to be at high risk for hepatotoxicity if there was a combination problem did not really show any evidence of significant hepatotoxicity. So that gives us some level of preview but what we have underway now is concurrent administration of the two compounds, and that's primarily what we're looking for. With the RMC6236 plus 6200001 combination, we're less focused on tolerability because we don't really have a particular issue that we anticipate needing to clear, but there we're looking for some sort of qualitative evidence that the activity that we saw, the characteristics, the profile that we saw in preclinical models in which the combination outstripped and really distinguished itself even qualitatively from the monotherapy agents, that we see something that translates that into people. And that's about the best that I can tell you today about those two studies. Obviously, we're getting closer to disclosing those And from here to that point, I think we'll just have to leave it open.

Great. Thanks so much.

Thank you. Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is now open.

Hey, guys. Thanks for taking my questions. Just to follow up on the RAS on inhibitor doublet combination, could you just remind us of the patient background, the patient population in that study? Is that exclusively lung cancer patients, or are there other histologies included as well? And what about prior treatment with a covalent G12C inhibitor? And then a question on the planned phase three study in lung cancer. I know you sort of slightly pushed that timing out. Can you just comment on what some of the items are that you have to align with the FDA before?

Sort of faded out a little bit at the end there, but I think you were asking about the timing, what drove the timing of the phase three lung cancer trial. Is that the second part of your question?

Yeah, what are some of the things that you need to align with the FDA on that front?

Yeah. So on the first question, we can't provide a lot of detail about that, about the eligibility. Obviously, it's patients with KRS-G12C-bearing tumors. It's a mixture of solid tumor types. It's a mixture of prior treatment backgrounds. And it'll be best understood when you see the data. And with regard to the lung cancer trial, I want to make it really clear that we remain committed to launching a phase three registrational trial in lung cancer in the near future. And we fully expect, as Steve pointed out, to complete our analysis and our internal deliberations on an updated phase one data set and to share these this quarter. But practically speaking, with the December holiday just around the corner, it's just become too much of a stretch to assume that on top of these activities, all of which are critical paths to the program, that we could also obtain regulatory alignment on the study details and initiate the trial before the end of the year. And simply having recognized this reality, we wanted to be transparent about it. I do want to point out that we were able to accelerate the launch of the Phase III pancreatic But apparently, we were a bit too optimistic on the timing for the lung cancer study initiation. We will certainly continue pushing hard to achieve a liftoff on this second pivotal trial as soon as practical. Again, let me just emphasize, we do expect to be able to move forward, but can't provide any more detail today. Just ask everybody to stay tuned for the promised data disclosure this quarter.

Great. Thanks for clarifying, Mark.

Thank you. Our next question comes from Jay Olson with Oppenheimer. Your line is now open.

Oh, hey. Congrats on all the progress and thanks for taking the questions. Since you have a clinical collaboration with Tango Therapeutics evaluating the combination of 6236 and 9805 with their PRMT5 inhibitor, Can you provide some color on the clinical development strategy there and indications that you're focusing on? Thank you.

Thanks, Jay. Unfortunately, no. We can't really provide any more information than what Tango reported. We're obviously happy to be participating, but we're providing clinical drug supply to Tango, who will sponsor the studies. Can't really give you more information. Other than that, we have done some preclinical work with that combination. Each of these two agents addresses a different signaling component that may be contributing to oncogenesis in those patients who have both the RAS mutation and MTAP deletion. And so, it certainly makes sense to try to suppress both of those signaling contributors, and the preclinical results were encouraging in that regard. So, we're excited to be able to help support the combination study.

Great. Thank you.

Thank you. Our next question comes from Mark Fromm with TD Cohen. Your line is now open.

Hi, thanks for taking my questions. Just following up on Michael's earlier question, just, you know, about a year ago, you put out the kind of initial statement that you intended to start phase threes for pancreatic and lung. You know, so that kind of decision seems like it was made kind of in parallel. Can you just kind of explain why, you know, how the questions you still needed to answer to actually, you know, move forward from that decision you made a year ago to starting the trial differed and kind of how the timelines seem to have diverged for the two?

I don't really think there's much color we can give to that. I mean, the steps that we have to go through for those are essentially the same. And, you know, enrollment paces can differ. It's just a practical reality. It's very hard to predict a year ago exactly what they will be able to start a study. I don't think there's really much more to be able to provide than that.

Okay. And then maybe not so much about the Tango collaboration itself, but just talk through kind of your strategy moving forward with kind of novel, novel combinations, just how are you approaching that with 6236? Should we see a lot more of these deals or these types of collaborations, or is this more of a one-off?

I doubt it's going to be a one-off. We have a long list of requests for collaboration for combination with RMC 6236. It almost overwhelms us just in terms of reviewing the list. So I do expect there will be other agents, other targets, other things for which we'll do collaborative studies. Of course, we've prioritized the studies that we feel we need to do as priority studies, and you know what those are. We're combining RMC 6236 with We're combining RMC6236 with temporalizumab. We're combining RMC6236 with chemotherapy and various combinations, you know, multiplex combinations of those. So those are our near-term priorities, but I do expect there will be other combination studies that will emerge over time.

Okay. Thank you.

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

Hey, guys. Thanks for taking our questions. Just looking ahead to the preclinical AML data, we should expect that at ASH. Curious to hear your thoughts around the application of the RAS on platform to liquid tumors and maybe what you'd want to see to proceed to clinical studies here and Any color around combinations in the settings seems like glitter and venetoclax are maybe some options being considered based on the abstract. Thank you.

To be true, Alex, the hematology component of our program has almost been completely outsourced to academic collaborators up to now. And they're going to be the ones that will be presenting data at ASH and other meetings going forwards. We have been so focused on pancreatic cancer, non-small cell lung cancer, and colorectal cancer that we have not really had an opportunity to plan any clinical development in some of the more infrequent tumors that carry grass mutations like AML. We do appreciate the We do appreciate the mechanistic basis there and the unmet medical need. And that is increasing, of course, as it becomes clear that one of the major mechanisms by which AML escapes from targeted therapies like FIT3 inhibitors is through acquisition of RAS mutation. But right now, for a relatively medium-sized biotech company on the west coast of the United States, it's not a top priority for us. We do very much appreciate the work that's being done by the academic collaborators that might set us up for clinical development at some point in the not-too-distant future.

Makes sense. Thank you.

Thank you. Our next question comes from Jonathan Chang with Lerink Partners. Your line is now open.

Hi, guys. Thanks for taking the question. Just one from me. On cash runway guidance, can you provide some color on what's baked into the runway guidance, specifically what's baked in in terms of the different ways you could proceed in pancreatic cancer and lung cancer across your pipeline? Thank you.

Thanks, Jonathan. I think Jack can comment on that.

Yeah, with regards to the cash guidance, what's baked in there is the two phase three second-line studies that we've disclosed that we are moving ahead with.

Beyond that, we use a probability-adjusted model with regards to costs. And each, you know, there is a multitude of potential opportunities and programs that we can push forward in additional pivotal trials, but we use... and we use the probability-adjusted model. So we can't really describe specifically what additional programs are in the cash primary forecast, but what's fully baked in there are those two Phase III second-month trials.

Understood. Thank you.

Thank you. As a reminder, to ask a question, please put a star 11 on your phone. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.

Thank you. Thanks for taking the questions. Just on the combination work of 6236 with Pembro-Lizumab, I'm curious to know if you're also looking at combinations of a triplet 6236 Pembro and chemotherapy. Because how do you think about the strategic utility of that triplet regimen potentially as you look to expand in frontline opportunities in non-fossil lung cancer?

Well, you want to comment on that? Yeah. Within the study, the way you referred to a triplet really is a quadruplet of R6236 plus PEMBRO plus platinum double chemotherapy. That's actually going into the protocol cell. We're actually doing it sequentially after clearing and identifying the appropriate dose for the doublet of 6-3-6-12-10-BRO, then we'll initiate the combination with the chemotherapy and have it off.

So, both will be ultimately .

Okay, got it. And just with the, just on, The OpEx side, you know, pretty significant jump this past quarter, but you're keeping full year spend guidance intact. I'm just wondering whether there's any one-time items or non-recurring items you should keep in mind and, you know, I guess how should we be thinking about sort of the sequential ramp from here into the early part of 2025 in spend?

So with regards to one-time items or potential one-time items, Within the historical results and what we've reported to date in 2025, nothing that stands out as one-time items. If you kind of take a look at the midpoint of our guidance for 2024 and look at where we are here to date, so we probably are about $405 million in net loss here to date. The midpoint of our guidance is $580 million, so that assumes a little bit of a ramp going into

a net loss perspective.

And with regards to 2025, we haven't guided to any specific guidance, and we will likely do that in the future. However, I think that it's fair to assume that our expenses are going to go up. Obviously, we kind of started two phases. We started one phase three term. We finally started another. We are also kind of we're going to be launching. So, no specific guidance for 2025. Outside, we do expect expenses to increase.

Okay, got it. Thanks for taking the questions.

Thanks, Eric.

Thank you. Our next question comes from Laura Prendergast with Raymond James. Your line is now open.

Hey, guys. Quick question regarding the Nature paper that was published last week out of MSK. So just proof of concept that 6236 actually increases RasG12X GTPase activity. Is this a mechanism that you guys have also been looking at internally and just generally any comments on how you're thinking about this, especially in regards to potential combinations or just in general? Thank you.

Yeah, thanks, Laura. Yeah, of course, we're very aware of this additional mechanism. And, in fact, we discovered it some time ago, and we first disclosed it ourselves at an NCI RAS scientific conference a few years ago. So, yes, we're quite familiar with it. We think it's quite interesting. It may, in fact, contribute to the therapeutic index of RMC6236 by affecting RAS signaling more in cancer cells with upregulated RAS-on signaling than in normal cells that have a lower level of RASOM signaling. So we were happy to see it. We were familiar with the work, for sure, and helped lay the foundation for it. And we think it is likely to be a contributor to RMC666.

Great. Thank you.

Thank you. Our next question comes from Ellie Merle with UBS. Your line is now open.

Hey guys, it's Sam on for Ellie. I guess just as you're thinking about a potential phase three study in first-line PDAC, I guess what are the different potential strategies that you could be kind of looking for here? And then like in terms of timing, would this be something where you would potentially wait for second-line data, or could we potentially see the second-line and first-line studies being run in parallel? And related to this, moving into the first line, just like mechanistically, is RAS like more or less of a driver? And like, I guess, how might we expect efficacy to translate into this earlier setting? Thanks.

Okay. Thank you for the questions. I think there were three questions in there. And I think I remember two of them. So the one I remember most is, are we waiting for results from the base three second line study before launching a first line study? That one's the easiest one. No. We'll move into that first line study as soon as we have the regimen sorted out, the optimized regimen and overall trials design. That, I think, sets up. What's going to be in that study and how are we going to get there? Maybe Wade can talk to us a little bit about the various things that we have going on, helping us determine what we might include in that. Okay, yeah, happy to answer that. So right now, I think we believe the set line data with our PFS OS exceeding the first line benchmark already established the proof of concept in our mind of this agent as a monotherapy being active in the first time setting. So I think, so we are eagerly moving forward with planning for a recreational phase three with a single agent monotherapy as one of the potential therapy arms. We're also actively developing a combination and those potentially can be enabled as additional treatment arms in that Phase III trial. So that's kind of the way we're thinking about the first-line study. I think, expanding on, I think, your question, I'm going to rephrase it. Please let me know if I addressed it correctly. I think what you're trying to ask is, do you believe that RAS is a driver across different lines of therapy, whether that changes or not, and whether the efficacy could potentially change or not. I think, number one, I think we do believe that RAS is a fundamental driver regardless of line of therapy. And without providing selective pressure with a RAS inhibitor in any line of therapy, then the sensitivity should remain the same across lines. because there has not been a certain pressure for resistance to develop. Therefore, we do believe the second line proof of concept should be translated to the first line. We have also shown data for third line, which really demonstrate that it's also after the third line plus patients, and so validating that scientific concept. And in that comparison between second line and third line data, we've shown that with more than double the PFS, in either line. And I think among target therapy, there's this concept of treatment effect building in terms of measure by house ratio, right? So proportionally, we actually have a greater than 50% risk reduction in progression in second and third line. So we hope that if that basic concept holds, then we can expect similar treatment effect applying to first line as well, meaning a reduction of risk progression in first line of 50% or greater. So those are kind of our current thinking.

Thank you so much. Thank you. Our final question comes from Kelly Shee with Jefferies. Your line is now open.

Hi, this is Clara. I'm for Kelly. Thanks for taking our question. So, just a quick follow-up question on TANGO's clinical collaboration. Wondering if you can add any color on the reason for the choice of collaboration partner among other clinical PRMT5 programs. Thank you.

Oh, yes. So, you're asking about our choice, not TANGO's choice of us, but our choice of TANGO's countdown. Sure. It looks like an interesting compound. There certainly are other compounds in the field. We've done some preclinical work with the Tango compound, as I mentioned earlier. And they've done some preclinical work with our compounds. So, you know, we have some visibility into what that combination looks like in preclinical model systems. But that doesn't mean that we wouldn't do a collaboration study with another PRMT5 inhibitor. You know, we are actively trying to find the best combination partners for RMC6236, and it's far too early for us to make any declarations about that. But we're happy to be in the collaboration, and it's one of, as I mentioned earlier, probably many different combination studies we'll do with agents across many different disease targets.

Appreciate the call.

I'm showing no further questions at this time. I would now like to turn it back to Mark Goldsmith, Chairman and Chief Executive Officer, for closing remarks.

Thank you, Operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.