RVMD - NASDAQ

Good day, and thank you for standing by. Welcome to the Revolution Medicines First Quarter 2024 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Thank you, and welcome, everyone, to the first quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; and Jack Anders, our Chief Financial Officer; Dr. Steve Kelsey, our President of R&D, will also join us for the Q&A portion of today's call. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statement. I encourage you to review the legal disclaimer side of our corporate presentation or the earnings press release as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Thanks, Erin. It's good to be with you this afternoon and to provide an update on our first quarter 2024 earnings. On today's call, I'll provide a brief update on our company progress and Jack Anders will provide highlights of our financial results before we open the line for questions. We began 2024 with ambitious goals for our pioneering RAS(ON) inhibitor pipeline. We provided a road map outlining our 3 strategic priorities for the year and anticipate a catalyst-rich second half of the year that has the potential to be transformative for Revolution Medicines. Our highest priority in 2024 is to advance RMC-6236 into its first pivotal monotherapy trials in major cancers driven by oncogenic RAS variants. In the second half of the year, we expect to share updated clinical data from the ongoing RMC-6236 first-in-human study from each of the pancreatic ductal adenocarcinoma and non-small cell lung cancer cohorts, including durability data. Elements of these data are part of the regulatory packages, supporting engagement with the FDA to determine a go-forward dose and to obtain feedback on pivotal trial designs prior to initiating each of these studies. We are currently setting the operational foundation to enable initiating these global, randomized, controlled registrational trials, comparing RMC-6236 monotherapy to standard of care treatments in the second half of this year. We anticipate that the first of these trials to launch will evaluate RMC-6236 as second-line treatment for patients with advanced pancreatic cancer and that we will disclose the updated clinical data supporting this trial near the study launch. Similarly, we expect that the second trial to launch, we'll evaluate RMC-6236 as second-line treatment for patients with advanced non-small cell lung cancer and that we will disclose the updated clinical data supporting this trial near its launch. We believe that initiating these trials will represent an exciting step forward for RMC-6236 on behalf of patients with these common RAS-mutated cancers. And these major steps will transition Revolution Medicines to an important new stage of company maturity. Our second development priority is focused on expanding the reach of RMC-6236 beyond G12X mutations into different RAS genotypes and tumor types. This work was amplified recently with an oral presentation at the AACR Annual Meeting and 3 original scientific publications in Nature and Cancer Discovery that described the mechanistic foundations of this groundbreaking RAS(ON) multi-selective inhibitor and illustrate its compelling clinical potential. At the meeting, we also presented 4 clinical cases, which, while anecdotal, showed the potential for RMC-6236 to drive deep antitumor responses at tolerated doses across a wide range of oncogenic RAS genotypes beyond KRAS-G12X variants, we have described previously, including the NRAS isoform and Oncogenic G13X and Q61X variants -- RAS variants that drive cancers or RAS-mediated drug resistance. A further note, 2 of the patients described at the AACR on with advanced pancreatic cancer and 1 with advanced melanoma, experienced complete responses on treatment with RMC-6236, both having progressed through prior treatment. Although clearly, complete responses to RMC-6236 are much less common than partial responses or absence of an objective response by RECIST criteria. Observation of complete responses in lung, pancreatic and melanoma patients signifies the potential power of targeting RAS addiction with this compound and further motivates us to seek to expand the reach of RMC-6236 into earlier lines of treatment. In some instances, we anticipate that first-line treatment with RMC-6236 will be based on a combination approach. This year, we are studying several key combination regimens to determine feasibility and to define options for first-line registration trials with drug combinations. A high priority combination is the RAS(ON) inhibitor doublet of RMC-6236 plus RMC-6291, our RAS(ON) G12C mutant-selective inhibitor in patients with RAS G12C solid tumors. A study of this doublet is ongoing, and we anticipate reporting initial clinical data for the combination of RMC-6236 and 6291 in the second half of the year. A second combination study is evaluating RMC-6236 plus pembrolizumab with or without chemotherapy in patients with advanced RAS-mutated non-small cell lung cancer, since pembro is part of most first-line standard of care regimens in this indication. We anticipate providing initial clinical data for this combination in the second half of the year. We're also happy to share today that we've initiated 2 new combination studies evaluating RMC-6236 with current standard of care regimens in GI cancers. The first is evaluating RMC-6236 in combination with standard of care chemotherapy in first-line treatment of patients with pancreatic cancer, and the second is evaluating RMC-6236 with chemotherapy in first-line treatment for colorectal cancer. These 2 additional studies will provide us with important insights into potential first-line registrational paths as a crucial component of our development vision for RMC-6236. Our third priority for the year is to qualify our first 2 RAS(ON) mutant-selective inhibitors in the clinic, RMC-6291, our G12C-selective inhibitor and RMC-9805, our G12D-selective inhibitor for late-stage development. While we continue first-in-human monotherapy studies for both of these compounds, we are initiating combination studies to explore opportunities in early-line treatment settings. The first-in-human study evaluating RMC-6291 has yielded encouraging initial clinical data in second-line monotherapy treatment of patients with KRAS G12C non-small cell lung cancer, including those previously treated with an approved KRAS G12C (OFF) inhibitor, and in patients with KRAS G12C colorectal cancer who had not been previously treated with a RAS(OFF) inhibitor. At AACR, we presented data from preclinical models in which the RAS(ON) inhibitor doublet RMC-6236 plus RMC-6291 demonstrated significant improvement in response rates and durability relative to either monotherapy. These encouraging data reinforce our hypothesis that RAS(ON) doublet combining a RAS(ON) multi-selective inhibitor with RAS(ON) mutant-selective inhibitor may deliver meaningful benefit to patients with RAS-mutant cancers. As mentioned, an initial clinical study this combination is ongoing. A clinical study of the combination of RMC-6291 with pembrolizumab is also ongoing, and we anticipate disclosing initial data for RMC-6291 with pembrolizumab in the first half of 2025. We also anticipate evaluating the triplet regimen comprising the RAS(ON) inhibitor doublet RMC-6326 plus RMC-6291 with pembrolizumab for patients with RAS-mutated non-small cell lung cancer in the first-line setting. If exploration of the triplet proved supportive, it could open the path to pursuing late-stage development of a chemotherapy-free first-line treatment regimen for patients with RAS-mutant non-small cell lung cancer. Regarding RMC-9805, the first RAS(ON) G12D-selective inhibitor, we presented preclinical data in the New Drugs on the Horizon session at AACR, showing that RMC-9805 induced deep and durable regressions in preclinical models of several KRAS G12D tumor types. As disclosed earlier this year, oral bioavailability in patients has been confirmed, and we have cleared several dose levels with good tolerability and no dose-limiting toxicities reported thus far. We expect to share initial safety, tolerability and antitumor activity data in the second half of 2024. We are also planning for our second RAS(ON) doublet combination study, evaluating RMC-6236 plus RMC-9805 in patients with advanced RAS G12D-mutated cancers. We also anticipate studying RMC-9805 in combination with other standard of care treatments for RAS G12D tumors. Overall, we continue pursuing our ambitious plans covering a rich set of potential opportunities toward the goal of maximizing the clinical impact of our RAS(ON) inhibitors in monotherapy and combination treatments for patients living with RAS-addicted cancers. In the second half of the year, we anticipate launching our first registrational studies of RMC-6236 for second-line treatment in 2 major RAS-driven cancers, qualifying potential paths forward for evaluating RMC-6236 in first-line treatments for these tumors and establishing potential opportunities for advancing our first 2 clinical RAS(ON) mutant-selective inhibitors. I'll now turn to Jack Anders, our CFO, to provide a financial update. Jack?

Thank you, Mark. We ended the first quarter of 2024 with $1.7 billion in cash investments, this compares to $1.85 billion at the end of 2023. The decrease in cash and investments for the quarter was primarily driven by net loss plus a $50.9 million decrease in accounts payable and accrued liabilities. Please note that we saw some lumpiness in the timing of expenses and the related cash payments which caused a onetime increase in accounts payable and accrued liabilities of $56.7 million during the fourth quarter of 2023. This normalized by the end of the first quarter of 2024 and resulting in anticipated cash payments and a corresponding decrease in accounts payable and accrued liabilities. Turning to expenses. R&D expenses for the first quarter of 2024 were $118.0 million compared to $68.9 million for the first quarter of 2023. The increase in R&D expenses was primarily due to clinical trial expenses and related manufacturing expenses for our first wave of RAS(ON) inhibitors as well as an increase in personnel-related expenses related to additional headcount and an increase in stock-based compensation. G&A expenses for the first quarter of 2024 were $22.8 million compared to $13.2 million for the first quarter of 2023. The increase in G&A expenses was primarily due to an increase in personnel-related expenses related to additional headcount and an increase in stock-based compensation. Net loss for the first quarter of 2024 was $116.0 million or $0.70 per share. We are reiterating our 2024 financial guidance and expect projected full year 2024 GAAP net loss to be between $480 million and $520 million, which includes estimated noncash stock-based compensation expense of between $70 million and $80 million. And with that, I'll turn the call back over to Mark.

Thank you, Jack. Revolution Medicines is off to a strong start for the year. We are well capitalized and remain focused on delivering key data and actions to advance RMC-6236 into its first registrational trials while qualifying the range of potential opportunities extending the reach of our RAS(ON) inhibitors into earlier lines of treatment for patients living with RAS-addicted cancers. Our work in progress would not be possible without the support of our patients, clinical investors, scientific and business collaborators, advisers and shareholders and the tireless efforts of Rev Med employees on behalf of patients. This concludes our prepared remarks for today. And I'll now turn the call over to the operator for the Q&A session.

[Operator Instructions] Our first question comes from Marc Frahm with TD Cowen.

Maybe on pancreatic cancer for 6236, I guess what questions are you still looking to find answers to finalize that design for the second line, just regulatory feedback that you need? Or is there still clinical data that you're looking to gather to know kind of exactly what you want to ask regulators? And then thinking forward to first line, just -- is it really dependent upon combinations because it seem how you talking about it? Or might monotherapy also ultimately get developed in the first line?

Thanks, Marc. Appreciate your questions. To the first question of time, what's driving the timing for the pancreatic cancer study. It basically is the same as the issues we've identified before. We need to come to agreement with the FDA on a dose and as well as on the trial design. So I think those are first half of the year events were in May. So we're still in the first half of the year, and we'll get those done. And then in the second half of the year, we'll likely move forward and provide the data that we've said, we would provide. On the question about first-line study. I think you asked whether we would result of the second-line monotherapy pivotal trial before initiated first line...

It seems like you're very focused on kind of combinations in that opening up the first-line opportunity. Is that -- is that really the main path forward in first line in your mind? Or is monotherapy also on the table for first line?

Yes, I don't think we know yet. I think as we've said before, we want to qualify what the options are. We know what the option would be for monotherapy, it would be monotherapy, but we don't know what the options are for chemotherapy. We need to evaluate that from a safety point of view. So that's why doing that exploratory work is very important. And once we know that, we'll be able to decide what kind of trial is most appropriate? Is it a 2-arm trial? Is it a 3-arm trial, are we evaluating both of those paths or just 1 of them compared to standard of care. We don't know yet.

Our next question comes from Michael Schmidt with Guggenheim Securities.

On RMC-6236, I think we've recently seen the announcement from Bristol at the KRYSTAL-12 trial met its primary endpoint in second-line lung cancer setting, and we'll probably get a few additional Phase III readouts from other KRAS G12C inhibitors in the coming year or so. And yes, I was just wondering how that potentially increased use down the road of those G12C inhibitors might impact your study or perhaps enrollment, do you think it might be biased in any way away from KRAS G12C patients in your study -- in your planned study and -- or may affect your trial design at all?

Michael, thanks for your question. I think it depends on what indication you're talking about in pancreatic cancer, it won't have any impact at all because G12C represents such a small subpopulation and I don't know that they're even seeking approval in that indication, but it wouldn't make much difference. And then in lung cancer, obviously, roughly 12% of non-small cell lung cancer is KRAS G12C and another 13% are other KRAS G12 mutations, and then there's another 5% or so beyond that, that are other mutations. So that is a significant population. It's already a crowded space from a patients' perspective. They have access to 2 approved drugs today. They might have access to 2 approved drugs tomorrow and then maybe a few more that will come after that potentially, we don't know for sure. So patients do have options today, and it's very credible for them to consider one of the approved drugs instead of entering a registration trial. I think we'll try to deal with that in some form in the design of the trial. But ultimately, if -- to the extent that G12C patients are eligible for that population, we'll get what we'll get and I don't think it will necessarily affect the overall outcome because we do expect that RMC-6236 would be active on G12C just as is active on the others, although we've not reported any clinical data on that, but preclinically, that's the case. So we'll get what we get. Obviously, the most important thing here is offering potential treatment for patients without G12C, the patients that have non-G12C mutations, that's really the main driver for proceeding. But we're interested in G12C, and we'll get them if we can get.

That makes sense. And then a specific question on your press release. I think you're guiding to presenting initial data from the 6236 pembrolizumab combination in the second half. And I think I was just wondering, is that specifically in first-line lung cancer patients? Or is that in late-stage patients?

Yes. Thanks for the question. I was just handing the microphone over to Steve.

I'll deal with the question. The study evolves, the initial safety, even though first-line patients are not precluded from the study, most of the initial safety data will probably not be in the first-line space to be completely honest with you. But as the safety emerges, then the study will increasingly start to focus on the first-line patients. How that reads into what we will actually report or disclose at any given time and at any given forum. I think, is subject to some further discussion when we get closer to the event. But if your question is largely about how enabling will the data be for moving the program forward. I think that from our perspective, it's likely to be extremely -- it's like to be extremely compelling and conclusive in that respect.

Largely because the most important question we're asking there is a safety question.

Correct. It's not really an efficacy-driven proof of concept at this stage, it's more of a can you combine with pembrolizumab full stop. And I don't think that the number of prior therapies or even really the disease of interest is going to determine that. Having said that, obviously, for obvious reasons, the actual combinations are largely restricted to patients with lung cancer.

Our next question comes from Eric Joseph with JPMorgan.

Great. Actually, I just really wanted to pick up on the last point you made there, Steve. -- appreciating sort of what you're looking for -- what you're looking for really focusing on establishing safety with pembro plus RMC-6236. I wonder whether in your regulatory interactions over your planned second line trials in non-small cell lung cancer, you've had the opportunity to discuss first line development. We've seen that Merck has gone straight into frontline with their G12C inhibitor plus pembro on like 25 patients' worth of data. I wonder whether you might have similar optionality to pursue a frontline trial and perhaps pivot from the second line strategy earlier than expected.

Okay. Let's distill 3 questions. So firstly, -- what -- we are not -- firstly, we're not in a position to report out on our regulatory interactions with regards to 6236 either in pancreatic cancer or non-small cell lung cancer. And I think we've deliberately guided to second half of the year with regards to that because we really need to be able to report something that is definitive rather than speculative. Secondly, does the emerging data or will the emerging data on the combination of RMC-6236 with pembro enable a first-line strategy? Absolutely. That's what the study is designed to enable. And we've deliberately focused. We've said several times that accelerating what is clearly an active drug into earlier lines of therapy where we expect the clinical benefit to be even more impactful as a very high priority for the company. The third question, I think was implicit in your question is whether or not if we were accelerating into first-line lung cancer, whether we would do a second-line lung cancer study. Right now, we have no reason to deviate from the plan that we have communicated. And if -- if at any point in the future, we do deviate from that plan. No doubt, we'll communicate that and the reasons for doing so. But right now, we are committed to a second-line single-agent non-small cell lung cancer study for RMC-6236 and at the same time, in parallel, we're trying to enable -- not just first-line -- metastatic first-line advanced disease, but even treatment in non-small cell lung cancer, even earlier lines of therapy as well.

Yes, go ahead, Mark.

Yes. I was just going to add 1 little line of color to that. I mean, bear in mind that for another G12C inhibitor coming in play, they do face quite a bit of competition for G12C patients in second line. So that it's quite crowded there. For RMC-6236, more than half of the patients that we'd be targeting don't have a G12C inhibitor option available to them. So I think the dynamics aren't exactly the same for a G12C inhibitor coming into play versus 6236, but with that said, as Steve pointed out, we have a current plan. If the plan changes, we'll disclose as the plans change, but that is our current belief.

Should we expect any of the combination data with 6236 whether it's with pembro or other regimens to be paired with either of the data updates with the monotherapy in pancreatic and then lung cancer in the second half.

I don't know the answer to that, to be honest. I mean, as we pointed out, there's -- there are scientific meetings that we'd like to present that if we have an opportunity, their corporate presentations that we can present sort of at our leisure when the opportunity -- when we have the data and we are ready to say something and how those all line up and how we sort of [indiscernible] and allocate the data to different things. I don't know the answer to that yet. I would just say I think our goal here is to be really crystal clear about what we're trying to enable in the second half of the year. And that is #1 priority, those second-line studies that we've just talked about, and those don't really require any other information than the monotherapy data. And then everything else is there to help guide our future studies, which are primarily first-line studies or studies in other indications, et cetera. So I think of them conceptually as being really different baskets, but that doesn't mean we might not bundle them together in some context, I don't really know.

Our next question comes from Jonathan Chang with Leerink Partners.

Two questions. First, for the initial RMC-6236 combination data with your mutant-selective inhibitors. Can you discuss what you're hoping to see that would give you confidence for further development of these combinations? And second question, how are you thinking about potential business development opportunities given the breadth of the company's efforts?

Jonathan, thanks for joining us. Thanks for your question. 6236 plus 6291. Well, the first question, of course, is also a safety question, just like always, not that we have any particular concern, but we do need to establish that. And then the second one is an activity question. And in a perfect world, we'd identify situations where response rates or some other indicator of antitumor activity is low for monotherapy and where we'd look to see something from the combination that differentiates that. Obviously, much harder to do if you're talking about, let's say, G12C second-line lung cancer, you have to run a pretty large Phase II trial if you were trying to establish superiority of an ORR, for example. And so I don't think that's likely that we would be doing something like that. So that's the conceptual framework, if we can find opportunities to sort of qualitatively differentiate them as opposed to looking for a difference of X percent in response rate, I think that would be more meaningful to us. With regard to business development, I think our posture on this is really very much the same as it's been for quite a while now, which is that we have an integrated portfolio and rich portfolio of RAS(ON) inhibitors, 3 of which are already in the clinic. That in and of itself is highly differentiated in the field today. And there may be interactions among these 3 -- and we have a whole stack of compounds behind those that can be brought into the clinic targeting different mutant-selective profiles. Therefore, it is hard to tease apart different parts of the portfolio for partnering purposes. It's not impossible, but it's just harder to do it. That's 1 comment. Second is that we're pretty committed -- deeply committed to U.S. operations extending into the commercialization of these compounds and at this point, don't really see a need to have a partner help us do that in the U.S. If anything that complicates things and potentially if the partnership is around any slice of the portfolio. It might create strategic misalignment between the partner's interest and ours. So I think in the U.S., our intention is to commercialize on our own. The exact inverse of that is true outside the U.S., where we have no intention in the foreseeable future of commercializing ourselves, and therefore, would expect a partner or multiple partners to be a part of that. And again, the question of dividing the portfolio and potentially creating strategic misalignment versus unifying the portfolio and having everybody on roughly the same page is going to be a factor in sorting all of this out. So I think when you take all of that put together, I think it's reasonable to expect that we would have 1 -- potentially more than 1, but 1 partner for marketing outside the U.S. and potentially development that involves a footprint outside the U.S. as well. But inside the U.S., I think we can manage the commercialization on our own once we built that capability, acknowledging that we don't have that capability today, but we are very much already investing in it and expect to be able to feel the competitive sales force at the right time.

Our next question comes from Ellie Merle with UBS.

Just a high-level strategy one. How are you thinking about which indication you would next start a pivotal study in? And how are you thinking about prioritization around moving into another tumor type relative to moving into a combination, say in [ first-line ] lung?

Thanks for joining us, and thanks for the question. Yes, very straightforward. Our top priority is going to be to move into first-line indications in the disease areas that we've identified, pancreatic cancer and lung cancer, because we have the most traction there, we have the most data there, we are moving forward in the second line and so it is our immediate priority behind those pivotal trials, second line is to get this compound into first-line settings. And there's a lot of opportunity across first-line settings for pancreatic and lung that's not necessarily just 1 trial for each. There are a lot of subsets of early-stage disease, so there's quite a lot to do there. Behind that would be other indications going beyond -- other tumor types going beyond lung and pancreatic cancer. And as you saw from the ACR, we certainly have evidence of activity in multiple tumor types and multiple genotypes beyond the core that we have studied previously. So we feel like there's a great opportunity, but we definitely prioritize these in the way that you alluded to and that I described.

Our next question comes from Ami Fadia with Needham & Company.

This is Poorna on for Ami. My first question is, at AACR, you presented patient cases where 2 patients had dose reductions. So just wondering, based on the mechanism of action and preclinical profile, do you anticipate the safety profile for 6236 to be different based on the mutation profile? And the second question is that given the competitive space in non-small cell lung cancer, what would you need to see in terms of clinical profile from the triple therapy to move forward with development?

Okay. Well, on the first question, maybe I could just sort of put that in context and then if Dr. Lin wants to add anything he can. We did show a couple of cases with dose reductions I don't think one should take those as representative of the percentage of patients across hundreds of patients receiving compound. Those were -- those cases were picked to illustrate certain mechanistic points about the activity of the compound against different genotypes and tumor types, which they did very successfully, including showing examples of complete responses. They weren't particularly picked to show a safety or tolerability profile that really comes from a much larger kind of aggregate data set. And if anything, we might have leaned towards showing more examples of tolerability or side effects, just to illustrate that the compound does carry some side effects. I mean that's for sure, true, not sure of any drug that doesn't. And even though the profile for the compound has been quite attractive and people have seen that and commented on it. That doesn't mean that there are no side effects associated with it. And so we want to be just very clear, especially when we're picking out a few examples of particularly interesting responses to make sure that people are saying that there can be side effects across dose reductions. And the last point I'd make maybe this might transition over into Wei Lin space. But even in those cases where there were dose reductions, the doses were still quite substantial. And their responses were persistent that they were sustained. And so those dose reductions really didn't seem to have much impact. So Wei, is there anything you'd like to add to that?

I think you answered completely. Yes, we agree.

You trained me well.

Okay. I guess for the second question, just wanted to understand what would you need to see from the clinical profile of the triple therapy 6291, 6236 plus pembro to move forward with clinical development?

Yes. Well, I think there are 2 different parts. What is 6291, 6236 look like? And I think an earlier question asked, what would give us confidence about the activity. And that's really comes from those 2 targeted agents. So that's a separate question. And then for safety, we have to be confident that we could combine those 3 agents together to be able to move forward into a registrational study. I don't think it's likely that the triplet, we would have a great deal of efficacy data that would drive it specifically. But again, maybe Wei wants to comment on that.

Yes, I agree. I think we initially want to establish the combinability of each of these component of doublet and then establish safety of all three. I think if each of the double component within the triplet is combinable then we feel pretty confident that triplet will be combinable. I think on the efficacy side, without putting any numbers. I think you can appreciate with the benchmark is really -- the chemo alone typically give a 30% to 40% response rate. In combination with Pembro, we have about a 50% response rate. So far, in the clinical data, we presented each of our monotherapy, whether it be 6291 or 6326, it's about 40% in non-small cell lung cancer, right? So if we're able to combine the 2, -- we're optimistic that we'll have an agent that we superior to chemo alone, then combining pembro should actually produce a fully promising triplet that could improve on the standard care.

And I should just clarify the person who was just speaking, Dr. Wei Lin, our Chief Medical Officer, who we didn't introduce earlier, but he's joined us, so you get the benefit of his input.

Our next question comes from Alec Stranahan with Bank of America.

Just 2 for me. Maybe first on your RAS(ON) inhibitor doublets. I thought it's interesting that you're combining G12C or G12D specific inhibition with your multi-RAS as they will likely have some target overlap. I guess maybe could you talk about your thought process here? Is this primarily driven by thoughts around mechanisms of resistance or maybe something else like optimizing the therapeutic window?

Dr. Kelsey is jumping up to answer that question.

There are -- there's 1 empiric reason, I think, predominantly, and 1 mechanistic reason why we wanted to put those 2 combinations together. The original concept biologically goes back to the observations that were made by multiple researchers looking at mechanisms by which tumors escape from mutant-selective RAS inhibitors, particularly the G12C (OFF) inhibitors and demonstrating that there are really to major mechanisms, both of which involve up regulation or certain navigation of the mutant RAS so that signaling through the RAS pathway can continue. And we felt very strongly that if that is the main mechanism by which tumors are escaping from our mutant-selective RAS(ON) inhibitors than a really good solution to that potentially would be our RAS Multi-inhibitor because it does a number of things. Firstly, it stops signaling through the emergence of other mutations other than the 1 -- the original oncogenic mutation -- and we've seen G12C mutant tumors escape by acquiring clones with G12D, G12R and other mutations, all of which are amenable to inhibition of 6236. And secondly, we've seen tumors escape by regulation of wild-type RAS again, which is amenable to inhibition with RMC-6236. So the original concept was that we could prevent tumor escape and therefore, significantly prolonged progression for survival and potentially overall survival if we were to combine the mutant-selective inhibitor with the RAS multi-inhibitor. Now there are some empiric observations which were exemplified by our recent presentation at AACR that, in fact, you may also be able to increase the depth of response and potentially the frequency of response as well by having the combination versus the single agent. And it may be that certain tumors that just don't respond very well to either agent when given as a single agent, respond extremely well to the combination. So it turns out that there may be there may be even more reasons for giving those combinations than we had originally invoked from the preclinical data and early emergent data on sotorasib and adagrasib. But it all points in the same direction.

Okay. Great. Steve, that's very clear. And then -- maybe 1 more, if I may. Just on the second half updates for 6236. Sorry if I missed this, but just to be clear, do you think data will be mature enough to provide an early look at PFS since I think you mentioned previously, this is one of the gating factors for moving into late-stage studies, particularly for PDAC or is duration of disease control, maybe still the best surrogate to look at here.

Yes. I mean, I think we do expect our ability to be part of those presentations for launching those trials. In the past, we've shown DCR data that actually were quite strong. And so I think we already know the answer to it from DCR point of view. But the PFS is really going to be an important component of those updates.

Our next question comes from Laura Prendergast with Raymond James.

Congrats on the exciting progress you guys have made this year. As you're thinking about the Phase III design in non-small cell lung cancer, thinking as I think about how the CodeBreaK 200 study unfolded where the FDA had suggested they use overall survival as an endpoint and then we saw it happened there. Do you do you expect -- do you think there's any chance that the FDA might require you to use an overall survival endpoint versus a PFS endpoint? And how you think maybe the KRYSTAL-12 readout will relate into that?

I believe to call on Dr. Lin to answer that question.

I think the -- with regard to -- I think with regard to bladder cancer, I think, in an over survival is probably expected to be required -- with regard to non-mall lung cancer, I think the -- I think the FDA's position is less clear at this point. I think at multiple meetings, I think the message they've since giving out is if the PFS improvement is something meaningful. Obviously, they never give a precise benchmark. But if it's falling in their criteria being constantly meaningful, they would consider granting full approval based on PFS alone, knowing that the number of available therapy in lung cancer is very different than pancreatic cancer. And so obviously, if you do deliver overall survival, that's -- that will definitely clear the bar. I think the [ adagrasib's ] re-review will probably be very informative on that regard on FDA's position about the requirement of overall survival in non-small cell lung cancer.

Great. And then just regarding the expansion cohorts of RAS genotype and tumor type, is that data set still expected for the second quarter or third quarter of this year?

No. We think we've really already ticked the box for that milestone. The intention was to provide an initial or preliminary look at that, which we did at the AACR with the cases that we presented. And again, it was really primarily to make a mechanistic point that really across now multiple isoforms of RAS mutations -- different mutations even within G12 and different mutations outside of G12, including Q61 with some level of confidence. And then also, there was a case that contained a G13 mutation in the colorectal cancer case. So from a mechanistic point of view, I think we can sort of check the box that RMC-6236 behaves as it does preclinically active against all of those mutations. What we won't be reporting on later this year is any sort of quantitative response rates across different mutations. I'm just not even sure we'll collect enough data to really come to stable estimates of what that might be. So I think we're done with that question now, and now we're moving into trial designs and so on.

Our last question is from Ben Burnett with Stifel.

One, RMC-6236 program. you've talked in the past that you're seeing ORR trends that have sort of tracked more favorably since ESMO as you expanded the higher dose cohort. Just curious if you can comment further today. Are you still seeing similar trends as you accrue more, for follow-up here?

Ben, that will be the first question that I won't comment on since we're not reporting any new data today. [Technical Difficulty]

Apologies. I think we lost you. Are you still there?

We're still here. Could you hear us?

Yes. Sorry about that. I think my question may not have gone through. I wanted to ask also about the G12D dose escalation study. If you just speak to the types of patients that you're enrolling, do you expect to enroll, I guess, -- should we expect this to be largely in line with the epigenetics of G12D, so like mostly CRC or PDAC. Are you focusing more specifically in 1 tumor type versus another?

Oh, I see. I'm sorry. So you're asking about for the RMC-9805 trial for our G12D-selective inhibitor, do we expect the demographics of the patient population to match the demographics of the real-world patient population? Is that what you're asking?

Exactly.

Yes. I think, to a large degree, that's true. I don't think it's specifically designed that way. It's an old tumors eligibility but that basically ends up meaning that you'll get something that represents the real world and G12D mutations are predominantly found in gastrointestinal tumors. G12D is the, I think, the third most common lung cancer mutation. But it's the first most common mutation across all solid tumors and across all gastrointestinal tumors. So yes, I think gastrointestinal tumors will be the most common.

This concludes the question-and-answer session. I'd now like to turn it back to Mark for closing remarks.

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