Good day and thank you for standing by. Welcome to 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. [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 today, Ryan Asay, 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 would 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 30, 2024 and recent corporate updates. The press release is available in the Investors section of our website at revmed.com. With that, I’ll turn the call over to Dr. Mark Goldsmith, Revolution Medicines’ Chairman and Chief Executive Officer. Mark?

Thanks, Ryan. 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 RAS(ON) inhibitors in clinical development: RMC-6236, RMC-6291 and RMC-9805. The highest priority has been to advance RMC-6236, our first-in-class RAS(ON) multi-selective 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 RMC-6236 into earlier lines of therapy, particularly in PDAC. Our third priority aimed to qualify our mutant-selective inhibitors RMC-6291 a RAS(ON) G12C selective inhibitor and RMC-9805 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 RMC-6236. Based on these results, we initiated our first global randomized Phase 3 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 RMC-9805 in patients with KRAS G12D PDAC. We continue to advance and extend our pipeline including RMC-9805 and RMC-6291 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 is 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 RAS(ON) inhibitors in PDAC, including updated progression-free survival and overall survival from our RMC-6236 monotherapy study and initial safety and antitumor activity from our RMC-9805 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 therapy 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 RAS(ON) sulti-selective inhibitor RMC-6236 and our oral RAS(ON) G12D selective inhibitor RMC-9805. The details can be found on the Events and Presentations page of our corporate website at revmed.com. Beginning with RMC-6236. As the data have matured and as of a data cutoff of the 23rd of July 2024, we can now report that patients who had received one prior chemotherapy regimen for metastatic PDAC with G12X…

Thanks Steve. We ended the third quarter of 2024 with $1.55 billion in cash and 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 GAAP 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 RMC-6236 in previously treated PDAC patients support our optimism that if reproduced in the ongoing global, randomized, controlled Phase 3 study, RMC-6236 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 RMC-9805 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 RMC-9805 is the third RAS(ON) 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 Medicines 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 RAS(ON) protein state, an extraordinary achievement. These three investigational drugs include two covalent RAS(ON) inhibitors and one non-covalent RAS(ON) inhibitor; one RAS(ON) inhibitor designed for BRET; and two designed for mutation selectivity; and one RAS(ON) 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…

Thank you. [Operator Instructions] 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 kind of 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 RAS(ON) inhibitor doublet study. The pembro study is primarily a safety study. And they are the most important signal that we are zeroed in on is the hepatotoxicity signal that was seen with the first generation RAS(OFF) G12C 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, it started RMC-6236 and those patients 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 RMC-6236 plus RMC-6291 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. That’s all.

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 3 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 3 lung cancer trial? Is that the second part of your question?

Yes. What are some of the things that you need to align with still with the FDA on that front?

Yes. So on the first question, we can’t provide a lot of detail about that, about the eligibility. Obviously, it’s patients with KRAS-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 3 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 1 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 path 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 3 pancreatic cancer trial. We call that the RASolute 302. 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 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.

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. We 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 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 Marc Frahm with TD Cowen. Your line is now open.

Hi, thanks for taking my questions. Just following-up on Michael’s earlier question, just about a year ago, you put out the kind of initial statement that you intended to start Phase 3s for pancreatic and lung, so that kind of decision seems like it was made kind of in parallel. Can you just kind of explain why, how the questions you still needed to answer to actually move forward from that decision you made a year ago to starting the trial differed and kind of what – how the timelines seem to have diverged for the two.

I don’t really think there’s much color we can get to that. I mean, the steps that we have to go through for those are essentially the same. And enrollment phases 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 accommodation with RMC-6236. It almost overwhelms us just in terms of reviewing the list, but – so I do expect there will be other agents, other targets, other things for which we’ll do collaborative studies. Of course, we 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 other RAS(ON) inhibitors. We’re combining RMC-6236 with pembrolizumab. We’re combining RMC-6236 with chemotherapy and various combinations, 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 setting seems like fedratinib and venetoclax or 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 RAS mutations like AML. 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 FLT3 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 Leerink Partners. Your line is now open.

Hi guys, thanks for taking the question. Just one for 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.

Yes. With regards to the cash guidance, what’s baked in there is the two Phase 3 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 there is a multitude of potential opportunities and programs that we push forward in additional pivotal trials. But we use the probability adjusted model. So we don’t – we can’t really describe specifically what additional programs are in the cash runway forecast. But what’s fully baked in there are those two Phase 3 second long trials.

Understood. Thank you.

Thank you. [Operator Instructions] Our next question comes from Eric Joseph with J.P. Morgan. Your line is now open.

Yes. Thank you. Thanks for taking the questions. Just on the combination work of 6236 with pembrolizumab, I’m curious to know if you’re also looking at combinations of triplets 6236 pembro and chemotherapy. I guess, how do you think about the strategic utility of that triplet regimen potentially as you look to expand in frontline opportunities in non-small cell lung cancer?

Wei, you want to comment on that?

Yes. Within the study, what you referred to as triplet, really it’s a quadruplet of our 6236 plus pembro plus platinum doublet chemotherapy. That’s actually go into the small cell. So we’re actually doing it sequentially after clearing identifying appropriate dose for the doublet of 6236 plus pembro and we’ll initiate the combination with the chemotherapy rapid on. So both lines will be ultimately valuable.

Okay, got it. And just with the – just on the OpEx side, 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, non-recurring items you should keep in mind. And I guess, how should we 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 within 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 year-to-date. So we probably are about $405 million net loss year-to-date in our – the midpoint of our guidance is [indiscernible] million, so that assumes a little bit of a ramp going into Q4 from 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 plan on starting two Phase 3 – we start one Phase 3 trial and we plan on starting another. We are also kind of building out the organization, at least from a – preparing from a commercial launch perspective. And we have a lot of opportunities outside of those two pivotal trials that we’ve said that we’re going to be launching. So no specific guidance of 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 that showed proof of concept that 6236 actually increases RAS G12X CCPA GTTA [ph] effectivity. 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.

Yes, hi. Thanks, Laura. Yes, 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 RMC-6236 by affecting RAS signaling more in cancer cells with upregulated RAS(ON) signaling than in normal cells that have a lower level of RAS(ON) 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 RMC-6236.

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 3 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 and moving into the first line just like mechanistically is graphic more or less of a driver and 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 Phase 3 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 trial design that I think sets up. What do we have to – what’s going to be in that study and how are we going to get there? Maybe Wei 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.

Yeah, happy to answer that. So right now, I think we believe the second line data with the PFS, OS exceeding the first line benchmark or the established the proof-of-concept in our mind of this agent as a monotherapy being active in the first line setting. So I think – so we are eagerly moving forward with planning for a registrational Phase 3 with a single agent monotherapy as one of the potential therapy arms. We’re also actively developing in combination with standard-of-care that includes a five review based regimen, as well as gemcitabine based regimen. And those potentially can be enabled as additional treatment arms expandable investigation arms in that Phase 3 trial. So that’s kind of the way we’re thinking about the first line phase. I think expanding on, I think your question, I’m going to rephrase it. Please let me know if I address it correctly. I think what you’re trying to ask is, do we 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 to remain the same across lines because there has not been a selective pressure resistance at all. Therefore, we do believe the second line proof-of-concept should be able to translate to the first line. We have also shown data for third line, which really demonstrate that it’s also active in 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 we’re more than double the PFS in either line. And I think among target therapy, there’s this concept of treatment effect built in terms of measure by hazard 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 for progression in first line of 50% or greater. So those are the kind of our current thinking.

Thank you so much.

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

Hi, this is Clara on 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 compound. 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 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. We are actively trying to find the best combination partners for RMC-6236 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 color.

I am 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.