Good day, and thank you for standing by. Welcome to the Revolution Medicines's Third Quarter 2022 Earnings webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you'll need to press star one one 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 Margaret Horn, Revolution Medicines's Chief Operating Officer, for opening remarks. Peg, you may begin.
Thank you, and welcome everyone to our Third Quarter Earnings Call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines's 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 Medicines's Chairman and Chief Executive Officer. Mark.
Good afternoon, and thank you for joining us. Today I'll provide an update on our corporate progress, and our Chief Financial Officer, Jack Anders, will provide highlights of our financial results. In the third quarter, Revolution Medicines continued advancing our pipeline of groundbreaking RAS(ON) 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 2 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 4 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 to clinical development the first two drug candidates from our highly innovative RAS(ON) inhibitor portfolio. In a phase 1, 1b trial evaluating RMC-6236, our oral RAS(ON) 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 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 preclinical 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. RMC-6291 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 of KRAS G12D, the most common RAS cancer variant causing human cancer, RMC-9805. IND-enabling work remains on track toward our goal of beginning clinical evaluation in mid-2023.
This first wave of RAS(ON) inhibitor drug candidates, RMC-6236, RMC-6291, and RMC-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 SHP-2 inhibitor RMC-4630 and our mTORC1 selective inhibitor, RMC-5552, both of which have shown clinical evidence of antitumor activity. These RAS companion inhibitors are designed to be deployed primarily as combination agents with direct RAS inhibitors.
In the third quarter, our clinical collaborator, Amgen, reported encouraging preliminary evidence from its phase 1b CodeBreaK 101 clinical study, suggesting promising and durable benefit from combining RMC-4630 with Amgen's KRAS G12C inhibitor, sotorasib. 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 2 study of this combination, RMC-4630-03, 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 2023.
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, RMC-6291 and RMC-9805, and two clinical stage RAS companion inhibitors, RMC-4630 and RMC-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, RMC-8839. We anticipate advancing assets from this collection into development after 2023. With this R&D strategy, supported by current 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 RMC-6236 in 2023, to provide preliminary evidence of superior activity for RMC-6291 in 2023, with this clinical profile potentially indicated by tolerability, safety, and/or antitumor effects. To announce dosing of the first patient in a monotherapy dose escalation study of RMC-9805 in mid-2023. In our RAS Companion Inhibitor portfolio, upcoming milestones are as follows: to provide top-line data from the RMC-4630-03 study of RMC-4630 plus sotorasib in the second half of 2023, and to disclose additional evidence of single-agent activity for RMC-5552 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, RMC-4630 and 5552, have each shown evidence of single-agent clinical activity along the path toward strategic combinations with direct RAS inhibitors and initial clinical evidence has now emerged in support of RMC-4630 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?
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 $0.87 per share. We are reiterating our financial guidance and continue to expect full year 2022 GAAP net loss to be between $260 million and $280 million, with non-cash stock-based compensation expense expected to be between $30 million and $35 million. That concludes the financial update, and I'll now turn the call back over to Mark.
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?
Thank you. At this time, to ask the question, you'll need to press star one one on your telephone. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from Alec Stranahan with Bank of America. Your line is now open.
Hey, guys. Thanks for the questions. Just a couple from us. First on 6236, given there could be some overlap between the pan-RAS 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 shots on goal, or do you see discrete market opportunities either with mono or combo for each of these assets? Then secondly, when you look at 5552, obviously some interesting early activity here as 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?
Is this really gonna depend on the data update, that we'll see next year? Thanks.
Thanks, Alec. Appreciate your question. Maybe I'll comment on the first question, and then perhaps Steve can comment on the second. The first question is about RMC-6236 versus mutant selective inhibitors. You know, at this stage, I think we don't know enough to be able to say exactly which indications will best or most benefit from the multi RAS inhibitor that hits multiple RAS variants, including wild type versus the mutant selective inhibitor. We have some ideas about that, but we're really gonna 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 perhaps even stage of disease. That's something we'll just have to learn. At this point, we're in dose escalation.
We'll figure out the optimal way to dose each of these compounds, and then we'll begin to see where the activity is and what the limitations are of each. Ultimately, we might see these put together in combinations anyway. It may be that RMC-6236 combined with RMC-6291 is the most effective way to preempt emergence of resistance mutations. The same could apply for RMC-9805 and other mutant selective inhibitors. It's just too early to tell at this point, and we'll play out all of these. As I said, our guess is that there will be certain circumstances in which one particular paradigm might apply more completely than another paradigm. We shall see. Second question is RMC-5552.
Sure. The primary focus of the single agent dose escalation program that we've been running with RMC-5552 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 or 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 preclinical models, and we have efficacy. We're fairly confident that this is worth taking forward as combined RAS on inhibitors. You know, there are really two classes of co-mutation that occur in combination with RAS mutations that are probably gonna be the initial focus of the development for RMC-5552.
They are the co-mutations where the mTOR signaling pathway is directly affected. The most common there ought to be PTEN loss, PI3 kinase mutation, a couple of rarer mutations perhaps in mTOR itself. There are the other class of mutations which are probably more familiar to you, that tangentially seem to impact mTOR pathway signaling and those particularly STK11 and KEAP1. We have plenty of preclinical data now that RMC-5552 can act in, you know, very favorably in combination with our RAS(ON) inhibitors to really turn around, you know, tumor regressions in tumors that co-express KEAP1 mutations and STK11 mutations. As you know, the KEAP1 co-mutant 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 RMC-5552. Ultimately, down the road, there may be other things we could do with that compound, but the initial focus is the co-mutants. There are a lot of them. I mean, for instance, if you look at perhaps colon cancer, about a third of them co-express a mutation in mTOR signaling pathway.
Got it. Thank you. Very helpful.
Thank you. One moment for our next question. Our next question comes from Jonathan Chang with SVB Securities. Your line is now open.
Hi, guys. This is Pascal Mesquida for Jonathan. 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? Do you also plan to provide any color as this study goes along on which dose levels have been cleared?
Thanks for your question. You know, in terms of pace of enrollment, they're both doing fine. I think they're both on track with expectations. What were our expectations? Well, we expected that RMC-6236 would have an abundance of patients and investigators highly interested because of the absence of approved targeted therapies in most of those indications, and that's what we're seeing. We have very, very high demand for the, you know, the fixed number of spots that are available. Nonetheless, we are seeing enrollment in both of these studies. I'm sorry. Things are progressing per plan. Your second question was?
As the studies progress, do you plan to provide any color on which dose levels have been cleared?
Not as an isolated bit of information. It probably won't really mean much to anybody since 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 it.
Got it. Okay. If I could 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?
Steve, do you want to comment on that?
Yeah. The chaperone protein of interest is obviously cyclophilin A. It's hugely abundant in most mammalian tissues and certain human tissues and also in cancer. So far, we have struggled very hard to detect any meaningful change in the expression of cyclophilin A over time with really any given exposure to our RAS(ON) inhibitors. We don't expect that to be something that is going to be possible to detect in the clinic, even if we had an assay that could deal with the massive overabundance of that protein.
Got it. Thanks for taking our questions.
Thank you. One moment for our next question, please. Our next question comes from Eric Joseph with JPMorgan. Your line is now open.
Hi. Good evening. Thanks for taking the question. Actually a couple from us. Looking to initial data with RMC-6291 next year, Mark, what would qualify as superior activity in your view, relative to the RAS off 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? To the extent it's the latter, are there certain tumor types that you're aiming to bias enrollment toward?
Yeah. Thanks. Thanks, Eric. Appreciate the question. You know, I think as we start to collect data, the things we're gonna see initially will be safety and tolerability. Then from there, we'll start to see, we expect anti-tumor activity. Obviously, objective responses are the things we'll see earliest. Durability is 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, 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. That's probably where things will start.
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. 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. The real impact for patients is going to come from those combinations. Demonstrating that RMC-6291 can be combined effectively, tolerably, safely, with the other agents will be extremely important.
That can only come after we get to reach a recommended Phase 2 dosing schedule, and then can move forward from there with those combinations.
Okay, got it. A follow-up, if I could, on the G12D RMC-9805. I guess looking to starting patient dosing in mid next year, how should we be thinking about the therapeutic window for this compound? I guess relatedly, are you able to characterize the PK of the compound relative to the multi-RAS and the G12C candidates? Thanks.
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. You know, it is a covalent compound. It's the only known KRAS G12D covalent compound, and it carries all of the benefits of covalency, which is that even after you take away drug from the system, there's still covalently bound inhibitor that's blocking G12D in the on state. So it's highly mutant selective compared to, let's say, RMC-6236, which is sort of by definition equipotent against all variants of RAS, including wild type.
There certainly is going to be a ceiling for dosing RMC-6236, at which point you would start to see on pathway normal tissue RAS mediated side effects. There shouldn't be the same sort of dose ceiling for RMC-9805. 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 antitumor effect safely tolerably? We project the answer to that is yes, based on preclinical results, but 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. I'd like to answer it.
I need to understand.
Yeah. No, yeah, absolutely. Some competitors in this space have noted challenges in coming up with an oral formulation similar to your approach with RMC-9805. I guess just looking for a little more color around the PK properties of your compound, how you feel about how investors should get comfortable with kind of a favorable oral bioavailability with that compound. I guess, is there a contrast with RMC-6291 that might be informative here?
Well, look, it's orally bioavailable across multiple species and, you know, at percents that are considered, you know, very much appropriate for oral drugs. 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. It also has a relatively long half-life, and it's also retained in tissues because of the covalency. You put all those pieces together, it behaves very much like RMC-6291 in terms of dose, PK/PD, efficacy, and selectivity relationships. Those are all fine. I don't think that the investigators are gonna 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 be any particular issue about RMC-9805. Of course, we have to validate that in humans, you know, what I've just described to you is the preclinical, but given how extensively they've been characterized, I guess we'd be surprised if those properties don't carry over into people.
Great. Appreciate the color. Thanks for taking the questions.
Yeah. Your-
Thank you. One moment for our next question. Our next question comes from Marc Frahm with TD Cowen. Your line is now open. Marc, your line is now open.
Thanks for taking my questions. Maybe just to start with 6236, you know, 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 any bias there of 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?
Thanks, Mark. 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 slots for. I don't think that there's any bias other than that epidemiologically, there are some mutations that are more common than others. G12D and G12V are significantly more common than other mutations, and they have no available targeted therapy. They are tending to show up. They're not the only ones showing up, they just are tending to show up. 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.
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 you know a small number of those, essentially excluding G12C initially because those patients have available to them a G12C inhibitor, including now RMC-6291 in the clinical trial. Eventually we'll come back to those G12C patients after we get to a dose that we think is gonna be most appropriate for those who have, for example, failed the G12C inhibitor. Other than that, I don't really think we've seen any particular finger on the scale.
Okay. Thanks. That's helpful. 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, you know, being kind of held back as wave two. 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?
Yeah, that's a very good question, Mark. I think our concept here is less about that they're being gated by a particular result in the first wave 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. I think that's the main thing that's gating it. It's more about resources and less about you know, 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 the platform itself delivers as expected and so on. 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. I mean, 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.
Okay, thanks. Very helpful.
Thank you. One moment for our next question. Our next question comes from Michael Schmidt with Guggenheim Partners. Your line is now open.
Hey, guys. Thanks for taking my questions. I had two development strategy questions, perhaps first on 6291, the G12C inhibitor. You know, what are your thoughts on the possible registration pathway down the road in context of the sort of moving competitive environment in the KRAS G12C space where you probably have multiple 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?
Yes. Steve, do you wanna-
Sure.
I mean, I can.
Yeah. I think Mark has just laid out the first premise, which is that the most likely development path for our RMC-6291 is gonna be in combination with something rather than as a single agent. I mean, we are not going to exclude development as a single agent if it's demonstrably superior to the approved KRAS off inhibitors. The most likely thing is it'll be developed in combination. You know, really in that context, it's gonna 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 on a KRAS G12C off inhibitor.
We can go head-to-head with them in 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. I think it really largely depends on what we see in the initial phases of the phase 1 trial, which of course will include, you know, combination dose escalation components as we get further up the single-agent dose escalation. I think let's keep an open mind. We're very optimistic about the potential for RMC-6291, and we're not shying away from pretty much all of the potential opportunities for developing it, Ryan.
If I could add to Steve's comment there. I think he said a couple of important things I wanna tie back together. Preclinically, we of course showed a pretty extensive data set comparing it head-to-head with one of the leading KRAS G12V ON inhibitors. That didn't necessarily foreshadow that that's going to be the primary path forward in the clinic. That was simply to demonstrate that the mechanism behind the inhibitor translates into the best possible RAS pathway expression, and therefore, antitumor effects, regressions and durability. We believe that. Steve is often fond of saying that in a combination treatment regimen for a RAS tumor, you wanna combine the very best RAS inhibitor you can with the very best companion or companions you can.
If 6291 is the very best KRAS G12C inhibitor out there, then we will wanna combine it with RAS companion inhibitors. That's our default path, I think. You know, we assume that's sort of the main path. 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. It's just not our primary assumption around this.
Yeah. Okay, that makes sense. On RMC-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?
Yes. Well, I'm gonna turn it over to Steve. He said we're open-minded, so maybe he can put some boundaries around how open-minded we are.
I think it's pretty straightforward with RMC-6236. I mean, as you've already said, the preclinical data shows that the activity definitely favors the G12 mutant tumors. There are essentially three histotypes there. You've got non-small cell lung cancer, pancreatic cancer, and colorectal cancer. We're planning to develop RMC-6236 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. The most obvious candidate there will be checkpoint inhibitors.
The third plank of that is to use RMC-6236 as a companion inhibitor for our mutant selective RAS inhibitors. The first one up there will be RMC-6291. I think you can expect a fairly broad program for RMC-6236 once a recommended Phase 2 dosing schedule has been established. You know, the actual breadth and the focus will really depend on the degree to which it is active as a single agent.
Michael, were you also asking, though, if we see a signal in both, let's say G12V and G12D, how would we prioritize one versus the other? Is that what you were asking about also?
Yeah, just generally. I mean, you know, there will be overlap.
Yes.
With the selective inhibitors. There will be overlap in tumor histology as well. I'm just wondering how you know, put?
Yeah.
-how you know-
Right.
prefer one versus the other.
Yeah, sure. Well, I mean, those are different axes, and we'll have to look at those, as Steve said. With regard to the mutations, I think one of the benefits of doing the backfill strategy that we have kind of 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. That allows us to sample more patients, which means more genotypes and more histotypes. It's not gonna give us a grid of, you know, 10 by 100. You know, it's still gonna be relatively small numbers.
We'll be very excited if we see signals across multiple histotypes and genotypes, you know. Maybe we'll have to decide what to prioritize or maybe not. We'll just have to see what information emerges there.
Yeah. Okay, great. Thank you so much.
Yeah.
Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. One moment for our next question. Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.
Thank you. A few questions. There was a recent RAS inhibitor. BridgeBio presented some initial preclinical data for their compound. They screened against a full complement of RMC-6291. Can you provide us with any thoughts on whether you think this was an appropriate comparator for them to screen against? Potentially, what differences this might have with respect to RMC-6291? Just to put some perspective on benchmarking.
Yeah. You know, I guess, first in terms of the data that we've seen publicly, it seems as if their comparator was really KRAS G12C off inhibitors, and we would expect to see a difference versus KRAS 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, is the oncogenic protein, and the off protein is not active. It's not clear to us then. Frankly, in experiments in which we've combined RMC-6291 with a KRAS G12C off inhibitor, we didn't see any advantage over RMC-6291 alone. Conceptually, we're not sure why there would be any advantage. From a data point of view, it's just comparing apples and oranges at this point. We just keep moving RMC-6291 forward.
using RM-018, which is what your tool reference anything to compare there with RMC-6291?
Oh, RM-018. That was a tool compound that Ryan Corcoran reported. It's not an in vivo tool compound. I'm not really sure. I'm not sure why we would compare to a tool compound. I mean, RMC-6291 is the development candidate that's now being dosed in humans. I think they used RM-018 because it was available. Yeah, I don't think it's a relevant comparator.
Got it. Finally, you're going to be announcing a fifth RAS(ON) candidate. I think we'll get that disclosure before the end of the year. Any hints as to the potential venue for that?
Yeah. I don't know if it'll be disclosed just before the end of the year or just after the end of the year. We will select it by the end of the year. There may not really be much of a venue to do that. Once we get into the early part of 2023, there are some investor venues that might be available to us.
Indeed. Okay, great. Thanks, Mark.
Thank you. One moment for our next question. Our next question comes from Jay Olson with Oppenheimer. Your line is now open.
Hey. Thank you for taking the questions. We're curious to know your views on the collaboration that was announced today between Incyte and Mirati to combine Incyte's oral small molecule PDL1 inhibitor with Mirati's adagrasib. Any comments you could share with us with regards to your thoughts about the deal and any plans you may have for partnering your RAS(ON) 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.
Yeah. Thanks, Jay. Maybe just to take the last part of your question first. You know, KEYTRUDA 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. I don't think the fact that it's dosed parenterally, you know, really causes any challenge for anybody. I'm not sure that we're aware of the need for an oral agent. That's sort of my first comment. I don't know if Steve is agreeing with that. With regard to Mirati'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 your last question was a much, much bigger question, which is what are all the possible things we might combine with in the immunology field or elsewhere? Again, I think KEYTRUDA is the big gorilla, and doctors are used to using it. It's well-established. There's a lot of data to support it. I think it is important, particularly in immune responsive tumors like lung cancer, to find a way to combine with an anti-PD-1. The most well-validated anti-PD-1 antibody is KEYTRUDA. 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
As I 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.
Great. That's super helpful. Thank you for taking the question.
Thank you. As there are no more questions in the queue, I would like to turn the call back to Dr. Goldsmith for closing remarks.
Thank you, operator, and thank you to everyone for participating today. We appreciate support of Revolution Medicines.
This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.