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spk07: Good day, and thank you for standing by. Welcome to Revolution Medicine's third quarter 2022 earnings webcast. At this time, all participants are on 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'll need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Peg Horn, Revolution Medicines Chief Operating Officer for opening remarks. Peggy, you may begin.
spk06: Thank you and welcome everyone to our third quarter earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer. Dr. Steve Kelsey, the company's president, research and development, and Jack Anders, our chief financial officer. 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 statements. I encourage you to review the legal disclaimer slide 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?
spk11: Good afternoon, and thank you for joining us. Today, I'll provide an update on our corporate progress, and our Chief Financial Officer, Jack Andrews, will provide highlights of our financial results. In the third quarter, Revolution Medicine's continued advancing our pipeline of groundbreaking Rason inhibitors on behalf of patients with a wide range of RAS-addicted cancers, which represent 30% of all human cancers. We are building momentum with our RAS-on inhibitor pipeline, having now advanced two RAS-on inhibitor development candidates into Phase 1, 1B dose escalation trials. With the transition of these RAS-on inhibitors into early clinical development, we now have four compounds from our cohesive portfolio of RAS cancer-targeted therapeutics in human studies. This progress across our pipeline sets up an exciting and potentially data-rich 2023. I'll now review a number of key achievements that reflect this recent progress regarding our pipeline of RAS-on inhibitors and RAS-companion inhibitors. First, we have entered the arena by advancing clinical development the first two drug candidates from our highly innovative Ras-on inhibitor portfolio. In a Phase I 1B trial evaluating RMC6236, our oral Ras multi-on inhibitor, investigators are dosing patients who have tumors harboring various common KRAS G12 cancer mutations, which may include KRAS G12D, KRAS G12V, and KRAS G12R. We believe RMC-6236 is the first oral direct RAS inhibitor to be deployed against tumors harboring any of these prevalent RAS cancer drivers and marks a significant step in our effort to serve the unmet needs of patients with RAS-addicted cancers. In a Phase 1-1B trial of our oral KRAS G12C-ON inhibitor, RMC-6291, investigators are dosing patients who have tumors harboring the KRAS G12C cancer variant. We have previously reported extensive pre-clinical data demonstrating the differentiated and promising antitumor profile of this highly selective covalent inhibitor of the activated or RAS-on state of the KRAS G12C variant found in lung and gastrointestinal cancers. RMC6291 is the first of a series of mutant-selective RAS-on inhibitors that we intend to bring into the clinic. Next up is our oral covalent inhibitor KRAS G12D, the most common RAS cancer variant causing human cancer, RMC9805. IND enabling work remains on track toward our goal of beginning clinical evaluation in mid-23. This first wave of RAS on inhibitor drug candidates, RMC6236, 6291, and 9805, has the potential to help serve the vast majority of patients with RAS-addicted cancers. And our portfolio contains additional RAS inhibitors lining up behind this first wave. In parallel, we continue a clinical evaluation of two class-leading RAS companion inhibitors, our shift inhibitor RMC4630 and our mTORC1 selective inhibitor RMC5552. both of which have shown clinical evidence of antigen activity. These RAS-companied inhibitors are designed to be deployed primarily as a combination of agents with direct RAS inhibitors. In the third quarter, our clinical collaborator, Amgen, reported encouraging preliminary evidence from its Phase 1b code break 101 clinical study, suggesting promising and durable benefit from combining RMC4630 with Amgen's KRAS G12C inhibitor, Sotiracib, particularly in second-line treatment of patients with non-small-cell lung cancer who were KRAS G12C inhibitor naive. We continue enrolling patients into our Phase II study of this combination, RMC463003, in patients with KRAS G12C non-small-cell lung cancer. Ultimately, we expect to evaluate our RAS companion inhibitors in combination with our own RAS-on inhibitors in the future. Now I'll shift to our corporate progress and comment on our priorities for the remainder of 2022 and 23. In the quarter, we completed a follow-on equity financing, raising gross proceeds of $265 million to strengthen the company's balance sheet and overall financial position to support the continued development and expansion of our product pipeline. With this strong financing behind us, we are focused on timely execution of the multiple development stage activities currently underway, and our highest priority is to deliver on important clinical milestones in the coming year. We continue deploying our development resources primarily in support of our three most advanced RAS-on inhibitors, RMC-6236, 6291, and 9805, and two clinical stage RAS companion inhibitors, RMC-4630 and 5552. Despite this growing clinical pipeline, we continue our strong commitment to research activities that provide critical scientific insights to support ongoing development activities and that also leverage our proven RAS innovation engine to generate exciting new mutant selective RAS-on inhibitors with distinct profiles. We expect to nominate our next RAS-on inhibitor development candidate by the end of the year, which will join a planned second wave of additional RAS-on inhibitor drug candidates, including our KRAS G13C inhibitor RMC8839. We anticipate advancing assets from this collection into development after 2023. With this R&D strategy supported by current cash, cash equivalents, and marketable securities extending operating runway through 2024, we are positioned to deliver on important milestones. In our RAS-on inhibitor portfolio, upcoming milestones are as follows, to provide evidence of first-in-class single-agent activity for RMC6236 in 2023, to provide preliminary evidence of superior activity for RMC6291 in 2023 with this clinical profile potentially indicated by tolerability safety and or anti-tumor effects, and to announce dosing of the first patient in a monotherapy dose escalation study of RMC9805 in mid-23. In our RAS companion inhibitor portfolio, upcoming milestones are as follows. To provide top line data from the 463003 study of RMC4630 plus sotiracib in the second half of 23, and to disclose additional evidence of single agent activity for RMC5552 in 2023. In summary, we remain deeply committed to our science-driven approach to treating patients with RAS-addicted cancers, and our development stage pipeline and research efforts have entered an exciting and important phase. Our first wave of RAS-on inhibitors, which includes three distinct and highly differentiated drug candidates, has advanced significantly, with patients now being dosed with RMC-6236 or 6291 and RMC-9805 continuing its progress toward the clinic. Our differentiated RAS companion inhibitors, RMC4630 and 5552, have each shown evidence of single-agent clinical activity along the path towards strategic combinations with direct RAS inhibitors, and initial clinical evidence has now emerged in support of RMC4630 as a RAS companion inhibitor used in combination with a direct RAS inhibitor. As we intensify efforts to progress these assets to significant milestones in the coming period, we also continue to make a significant investment in pipeline expansion activities based on our productive RAS innovation engine. Building on this strong company momentum, I'll now turn to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack?
spk09: Thank you, Mark. We strengthened our balance sheet in the quarter with the upsized public offering of common stock, raising gross proceeds of $265 million. Net proceeds were approximately $248 million, deducting accounts, commissions, and estimated offering expenses. Our ending cash and investment balance as of September 30, 2022, was $655 million, which is expected to fund planned operations through 2024. Revenue from our collaboration agreement with Sanofi was $3.4 million in the third quarter of 2022 compared to $1.1 million in the prior year period. During the third quarter of 2022, the company recorded a non-cash GAAP accounting adjustment that reduced collaboration revenue by $4.6 million. This non-cash revenue adjustment was due to changes to the company's estimates of the accounting transaction price and estimated percentage of completion of work performed to date under the agreement, which resulted in a cumulative catch-up adjustment that reduced collaboration revenue. We also had a similar catch-up adjustment related to revised estimates during the prior year quarter. which reduced collaboration revenue by $8.5 million for that prior year period. Total operating expenses for the third quarter of 2022 were $79.9 million and increased by 47% over the prior year period. The increase in operating expenses was primarily driven by an increase in RMC 6236 and RMC 6291 costs as a result of commencing clinical trials during the year as well as an increase in personnel related expenses related to additional headcount. Net loss for the third quarter of 2022 was 73.3 million or 87 cents per share. We are reiterating our financial guidance and continue to expect full year 2022 gap net loss to be between 260 and 280 million with non-cash stock-based compensation expense expected to be between 30 and 35 million. That concludes the financial update, and I'll now turn the call back over to Mark.
spk11: Thanks, Jack. Our goal at Revolution Medicines is to outsmart RAS-addicted cancers, and we continue to show our tireless commitment to patients in pursuit of this goal. With recent scientific and business progress, we believe that the company is in an excellent position to fulfill our mission on behalf of cancer 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?
spk07: Thank you. If it's time to ask a question, you'll need to press Star 1-1 on your telephone. Please stand by while we compile the Q&A roster. One moment for our first question. And our first question comes from Alex Shanahan with Bank of America. Your line is now open.
spk03: Hey, guys. Thanks for the questions. Just a couple from us. First, on 6236, given there could be some overlap between the pan-RAF and the individual RAS inhibitors that you're developing in terms of patients who could benefit, I'm curious just how you're thinking about parallel development of these assets, and is the strategy just increasing goal, or do you see discrete market opportunities, either mono or combo, for each of these assets? And then secondly, when you look at 5552, obviously some interesting early activity here is monotherapy, but as you think about combination studies moving forward, are there particular drug partners or tumor types you think are more interesting to start with, or is this really going to depend on the data update that we'll see next year? Thanks.
spk12: Thanks, Alex. Appreciate your question. Maybe I'll comment on the first question and then perhaps Steve can comment on the second. So the first question is about RMC6236 versus mutant selective inhibitors. You know, at this stage, I think we don't know enough to be able to say multiple RAS variants, including wild-type, versus the mutant selective inhibitor. We have some ideas about that, but we're really going to need to see what we learn in the clinic in order to guide that. Our guess is that it will depend on tissue type, other co-mutations, and Ultimately, we might see these put together in combinations anyway. It may be that RMC6236 combined with 6291 is the most effective way to preempt emergence of resistance mutations, and the same could apply for 9805 and other selective inhibitors. It's just too early to tell at this point, and we'll play it. then another paradigm. We shall see. Second question is RMC5552.
spk10: Sure. The primary focus of the single agent dose escalation program that we've been running with RMC5552 so far was really to assess whether or not we have a drug there that is worthy of further development in combination with our RAS-on inhibitors as a companion inhibitor. I think we've so far demonstrated clearly that it is. We have shown on-target toxicity. We have PK exposures that are within the range that are consistent with activity in the pre-tunnel models, and we have efficacy. So we're fairly confident that this is worth taking forward as a combined RAS-on inhibitors. You know, there are really two classes of commutation that occur in combination with RAS mutations that are probably going to be the initial focus of the development for RNC5552. There are the commutations where the enteral signaling pathway is directly affected. The ones that are most common there are to be P10 loss, PO3 kinase mutation, a couple of rarer mutations perhaps in mTOR itself and then there are the other class mutations which are probably more familiar to you that tangentially seem to impact mTOR pathway signaling and those particularly STK11 and KEEP1 and we have plenty of preclinical data now that RNC5452 can act very favorably in combination with our RAS on inhibitors to some really turn-round tumor regressions in tumors that co-express KEEP1 mutations and STK11 mutations. As you know, the KEEP1 commutant tumors, at least the lung tumors, do not do so well with single-agent RAS inhibition, at least the first-generation RAS-off inhibitors. It's a fairly linear development path for RMC5452. Ultimately, down the road, there may be other things we could do in that compound, but the initial focus is the commutants. There are a lot of them. I mean, for instance, if you look at grass-breeding colon cancer, about a third of them co-express a mutation in mTocillin problem.
spk03: Got it. Thank you. Very helpful.
spk07: Thank you. One moment for our next question. Our next question comes from Jonathan Chan with SVB Securities. Your line is now open.
spk01: Hi, guys. This is for Jonathan. I wanted to ask if you could comment at all on pace of enrollment for the multi-RAS versus the mutant-specific programs like the G12C. Do you expect one to go faster than another? And then do you also plan to provide any color as this study goes along on which dose levels have been cleared?
spk12: Thanks for your question. In terms of page of enrollment, they're both doing fine. I think they're both on track with expectations. What were our expectations? Nonetheless, we are seeing both of these studies. I'm sorry. And things are progressing per plan. Your second question was?
spk01: As the studies progress, do you plan to provide any color on which dose levels have been cleared?
spk12: Not as an isolated bit of information. It probably won't really mean much to anybody because these are entirely new compounds. You know, obviously, when we report some additional information about tolerability, safety, and or activity, we'll provide dose information associated with that.
spk01: Got it. Okay. In fact, I'll ask one more. Have you looked at how the chaperone protein levels change over time as you dose? Is this a dynamic thing, or are these kind of consistently expressed in the tumors?
spk10: Steve, do you want to comment on that? Yeah, the chaperone protein of interest is obviously cyclophilid A. It's hugely abundant in most mammalian tissues and certain human tissues and also in cancer. And so far we have struggled very hard to detect any meaningful change in the expression of cyclophilid A over time. in the clinic, even if we had an assay that could deal with the heat masses and the abundance of that protein.
spk01: Got it. Thanks for taking our question.
spk07: Thank you. One moment for our next question, please. And our next question comes from Eric Joseph with JPMorgan. Your line is now open.
spk08: Hi. Good evening. Thanks for taking the question. Actually, a couple from us. So looking to initial data with 6291 next year, Mark, what would qualify as superior activity in your view relative to the RAS-OF inhibitors? Is that a statement in the PR sort of that's a function of PD or activity in RAS inhibitor, prior RAS inhibitor treated patients or perhaps better response rates in certain histologies and to the extent it's the latter, Are there certain tumor types that you're aiming to bias enrollment toward?
spk12: Yeah, thanks, Eric. I appreciate the question. You know, I think as we start to collect data, the things we're going to see initially will be safety and tolerability. And then from there, we'll start to see we expect anti-tumor activity. And obviously, objective responses are the things we'll see earliest, and durability It's something we have to wait to collect that information. That's not something you see early. Any combination of those I think will be helpful to us. You know, keeping in mind that this is a new platform and so we often hear from investors that they simply want to see evidence that you can dose a patient, achieve exposure levels that should be active and then see activity from it. So that's probably where things will start. And then from there over time we'll build the cumulative evidence about its superiority. I think to emphasize the big picture here, in the G12C space, it's very likely that combination therapy is really where the puck is going to be. We're already moving there, as you know. And so focusing too much on trying to prove differentiation around monotherapy isn't probably the wisest thing for us to do, although we certainly believe mechanistically that's the case, and we think we will accumulate some data pointing in that direction. But the real impact for patients is going to come from those combinations, and so demonstrating that Pharmacy 6291 can be combined effectively, tolerably, safely with the other agents.
spk08: move forward from there with with those combinations okay got it and then a follow-up if i could on the g12d rmc 9805 um i guess looking to starting uh patient dosing in mid next year how should we be thinking about the therapeutic window for this compound and i guess relatedly are you able to characterize the PK of the compound relative to the multi-RAS and the G12C candidates. Thanks.
spk12: I'm trying to process the second part of your question, but for the first part of it, is it mutant-selective? Well, it's highly mutant-selective. from the system, there's still covalently bound inhibitor that's blocking G12D in the on state. So it's highly mute selective compared to mediated side effects. And there shouldn't be the same sort of dose ceiling for RMC9805. But, you know, those are just different to some degree technical characteristics. What really matters is can you dose either of them sufficiently to achieve the desired anti-tumor effect safely and tolerably? And we project the answer to that is yes based on preclinical results, but I have to demonstrate that in the clinic. The second part of your question Maybe you could unpack that a little bit for me, which is PK. I wasn't quite sure what you were trying to get at from the PK question.
spk08: I'd like to answer that. Yeah, absolutely. Some competitors in this space have noted challenges in coming up with an oral formulation similar to your approach with 9805. So I guess I'm just looking for a little more color around the PK properties of your compound, how you feel about it. How investors should get comfortable with kind of a favorable oral bioavailability with that compound? I guess, is there a contrast with 6291 that might be informative here?
spk12: Well, look, it's orally bioavailable across multiple species. And you know, F percent that are considered, you know, very much appropriate for oral drugs. So, you know, we have to demonstrate that in humans, but based on the preclinical species, it's an orally available drug. We'll have no difficulty getting above the IC50 or even IC90. And it also has a relatively long half-life. And then it's also retained in tissues because of the covalencies. So you put all of those pieces together, It behaves very much like RMC-6291 in terms of dose, PK, PD, efficacy, and selectivity relationships. Those are all fine, so I don't think that the investigators are going to have concerns about that. They should have concerns about all the other drugs that are not orally bioavailable and not covalent, but I'm not sure there should they've been characterized, I guess we'd be surprised if those properties don't carry over into people.
spk08: Great. I appreciate the color. Thanks for taking the questions.
spk07: Thank you. One moment for our next question. And our next question comes from Mark Fromm with Cowan. Your line is now open. Mark, your line is now open.
spk04: Thanks for taking my questions. Maybe just to start with 6236, just that trial's been open for a few months now and actively enrolling for a few months, you know, and has a pretty broad criteria in terms of mutations and tissue types that are eligible. Are you seeing kind of any bias there of, you know, enthusiasm across different for specific mutations or specific tumor types that we, you know, that should be thinking about the population tending to be enriched in?
spk12: Nice to hear from you. There is a tremendous amount of interest in it, and there are far more patients who are interested in participating in the study than we've been able to release lots for. So I don't think that there's any bias other than that epidemiologically, there are some mutations that are more common than others. G12P and G12P are significantly more common than other mutations, and they have no available targeted therapy. and so they are tending to show up, but they're not the only ones showing up. They just are tending to show up, and they're tending to show up in gastrointestinal tumors because that's where they're most prevalent, but they're not only showing up in gastrointestinal tumors either. So I don't think there's anything from an investigator perspective that's biasing these. Now, keep in mind, we've restricted enrollment based on genotype initially to the KRAS G12 mutations to a small number of those, essentially excluding G12C initially, because those patients have available for them a G12C inhibitor, including now RMC6291 in the clinical trial. particular figure on the scale.
spk04: Okay, thanks. That's helpful. And then can you kind of refer to these initial ones in the clinic as well as the G12D as kind of the first wave, and you have some of these other mutation-specific inhibitors that are being kind of held back as wave two. So just what's your thoughts on kind of what do you need to see from the first wave of agents in order to kind of pull the trigger on wave two and start moving those into the clinic?
spk12: and more about our making sure we have the resources and focus to move those first three inhibitors forward as efficiently and effectively as possible. So I think that's the main thing that's gaining it, is more about resources and less about getting to a particular result. With that said, obviously, amongst these first three inhibitors, we expect to see activity, tolerability, and safety that guide us to confidence That will also likely increase the availability of resources as well. As you know, there's a relationship there. That, at least indirectly, would open up the availability of resources for the second wave. That's how we think about it. I don't think there's a particular result. There are a number of things we could see next year that would give us, and I think investors, confidence that the platform is valid. and that there should be things reading through to other inhibitors in the platform.
spk04: Okay, thanks. Very helpful.
spk07: Thank you. One moment for our next question. And our next question comes from Michael Schmidt with Guggenheim Partners. Your line is now open.
spk05: Hey, guys. Thanks for taking my questions. I had... two development strategy questions, perhaps first on 6291, the G12C inhibitors. So, you know, what are your thoughts on the, you know, possible registration pathway down the road in context of these, you know, moving competitive environment in the KRAS G12C space where you probably have multiple you know, off inhibitors fully approved in second line, perhaps registration studies ongoing in first line. How do you think that could affect, or what are your thoughts on the ultimate development strategy for 6291 in that context?
spk10: Yes, Steve, do you want to come back? Sure, yeah. I think Mark has just laid out the first premise, which is that the The most likely development path for RNC6291 is going to be in combination with something rather than as a single agent. I mean, we are not going to exclude development as a single agent. It is demonstrably superior to the approved KRAS-OV inhibitors. But the most likely thing is it will be developed in combination. You know, really in that context, it's going to be a combination of efficacy and tolerability in combination with whatever the best companion is. We have the opportunity to combine with something, possibly even with RMC-6236 and go chasing after patients that have progressed or failed the leg. that second line space, or we can go head-to-head with them in any of the first line spaces that are currently all available to us. And I think it really largely depends on what we see in the initial phases of the phase one trial, which, of course, will include combinations And we're very optimistic about the potential for RC6291 and we're not shying away from pretty much all of the potential opportunities.
spk12: to demonstrate that the mechanism behind the inhibitor translates into the best possible RAS pathway suppression and therefore anti-tumor effects, regressions, and durability. We believe that. Steve is often fond of saying that in a combination treatment regimen for RAS tumor, you want to combine the very best RAS inhibitor you can with the very best companion or companions you can. And if 6291 is the very best KRS-G12C inhibitor out there, then we will want to combine it with RAS-companied inhibitors. So that's our default path, I think. We assume that's sort of the main path. But if it does stand out in monotherapy in ways that reflect what we've seen preclinically significantly, that could open up a monotherapy path to approval. But it's just not our primary assumption around this.
spk05: Yeah, okay, that makes sense. And then on 6236, perhaps more near term, you know, once you have reached a recommended phase 2 dose in the phase 1 portion of the study, you know, how do you think about pursuing specific tumor histologies or specific mutations, you know, in phase 1B studies or in dose expansion cohorts down the road?
spk12: Yes. Well, I'm going to turn it over to Steve. He said we're open-minded, so maybe you can put some boundaries around how open-minded we are.
spk10: I think it's pretty straightforward in RMC 1636. As you've already said, the preclinical data shows that the activity definitely favors the G12 mutant tumors, and so there are essentially three histotypes there. You've got non-small cell lung cancer, pancreatic And we're planning to develop RMC6236 really in three different ways. The first is as a single agent. We will test it as a single agent, and we will see whether the single agent activity in any of those histotypes is sufficient for a path to registration. The second thing we'll do is we'll do combinations, but only with things that don't have overlapping toxicity. So the most obvious candidate there will be checkpoint inhibitors. The third plank of that is to use RMC6236 as a companion inhibitor for our mutant-selective RAS inhibitors, and the first up there will be RMC6291. So I think you can expect a fairly broad program for RMC6236 once a recommended phase 2 dose in the schedule has been established, and the actual breadth and the focus will really depend on the degree to which it is active as a single agent.
spk12: Michael, were you also asking, though, if we see a signal in both, let's say, G12D and G12D, how would we prioritize one versus the other? Is that what you were asking about also?
spk05: Yeah, just generally. I mean, you know, there will be overlap with the selective inhibitors. There will be overlap in tumor astrology as well. I'm just wondering how you, you know, how you, you know. Yeah, right. prefer one with the other?
spk12: Yeah, sure. Well, I mean, those are different axes, and we'll have to look at those, as Dee said. But with regard to the mutations, I think one of the benefits of doing the backfill strategy that we have loaded up for this is that we will collect additional information than just the information we need to dose escalate. We will also be able to enroll additional patients at the previous dose level and keep doing that as long as we wish to up the dose escalation scale. And that allows us to sample more patients, which means more genotypes and more histotypes. But it's not going to give us a grade of 10 by 100. It's still going to be relatively small numbers. And we'll be very excited if we see signals across multiple histotypes and genotypes that maybe we'll have to decide what to prioritize or maybe not. We'll just have to see what information emerges there.
spk05: Yeah. Okay, great. Thank you so much.
spk07: Thank you. As a reminder, to ask a question, you'll need to press star 1 on your telephone. One moment for our next question. Our next question comes from Chris Shibutani with Goldman Sachs. The line is open.
spk13: Thank you. Good afternoon. My question is that there was recent harassment presented some initial preclinical data for their compound. They screened against . Can you provide us with any thoughts on whether you think this was an appropriate comparator for them to screen against and potentially what differences this might have with respect to 6291? Just put some perspective on benchmarking.
spk12: Yeah, you know, I guess first in terms of the data that we've seen publicly, it seems as if their comparator was really KRS-G12C-off inhibitors, and we would expect to see a difference versus KRS-G12C-off inhibitors. We've published, as you know, extensively on in vivo models, a large number of in vivo lung cancer models, versus a G12C off inhibitor. I think they showed one or two models. So it's really hard to comment on how active that compound is. We're sort of comparing a very large data set with a very small data set, don't know what to do with that. I think in terms of conceptually, it's not clear to us why having G12C off inhibitory activity is advantageous if you have a G12C on inhibitor In other words, the on form is the active pool, it's the oncogenic protein, and the off protein is not active. So it's not clear to us, and frankly, in experiments in which we've combined RMC6291 with a KRS-CoV-2 inhibitor, we didn't see any advantage over RMC6291 alone. So conceptually, we're not sure why there would be any advantage.
spk13: And then using 018, which is a reference, anything to compare there with 6291?
spk12: Oh, RM018. Oh, that was a tool compound that Brian Corcoran reported, and it's not an in vivo tool compound. So I'm not really sure. I'm not sure why we would development candidate that's now being dosed in humans. I don't think that they use, I think they used R018 because it was available. Yeah, I don't think it's a relevant comparator.
spk13: Got it. And then finally, you're going to be announcing a fifth Rathon candidate. I think we'll get that disclosure before the end of the year. Any hints as to the potential venue for that?
spk12: Yeah, I don't know if it will be disclosed just before the end of the year or just after the end of the year. But we will select it by the end of the year. And there may not really be much of a venue to do that, but once we get into the early part of 2023, there are some investor venues that might be available to us.
spk13: Indeed. Okay, great. Thanks, Mark.
spk07: Thank you. One moment for our next question. Our next question comes from Jay Olson with Oppenheimer. Your line is now open.
spk02: Oh, hey. Thank you for taking the questions. We're curious to know your views on the collaboration that was announced today between Insight and Mirati to combine Insight's oral small molecule PD-L1 inhibitor with Mirati's adagracid. Any comments you could share with us with regard to your thoughts about the deal and any plans you may have for partnering your Rasson inhibitors with molecules in development at other companies in terms of types of combinations that would be synergistic and whether or not you think it's important to have an all-oral combination regimen versus combining your oral drugs with an antibody would be great. Thank you.
spk12: Yeah, thanks, Jay. Maybe just take the last part of your question first. You know, chytruda is a you know, big gorilla drug in the field today. It's used by everybody in first-line therapy for lung cancer in particular. And I don't think the fact that it's dosed perennially, you know, really causes any challenge for anybody. So I'm not sure that we're aware of the need for an oral agent. So that's sort of my first comment. I don't know if Steve is agreeing with that. And then with regard to Maradi's study, it's interesting. We always are interested to see what other people go do. It doesn't really change much. I don't think being successful with an oral agent will give them any particular advantage over being successful with Keytruda. Maybe a last question. in the immunology field or elsewhere. Again, I think chytruta is the big gorilla, and doctors are used to using it. It's, you know, well established. There's a lot of data to support it. So I think it is important, particularly in immune-responsive tumors like lung cancer, to find a way to combine with an anti-PD-1, and the most well-validated anti-PD-1 antibody is chytruta. although there are others that are active as well. We're very interested in going sort of beyond that, but everything else beyond that is pretty exploratory at this point, and I think can't be considered a primary path. I'd say stay tuned, but for the moment, I think it's pretty well defined what one needs to do to get your drug in front of the right patients.
spk02: Great. That's super helpful. Thank you for taking the question.
spk07: Thank you. As there are no more questions in the queue, I'd like to turn the call back to Dr. Goldsmith for closing remarks.
spk12: Thank you, operator, and thank you to everyone for participating today. We appreciate the support of Revolution Medicines.
spk07: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone have a wonderful day.
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