RVMD - NASDAQ

Good day and welcome to Revolution Medicine's First Quarter 2023 Earnings Conference Call. [Operator Instructions] As a reminder, today's conference is being recorded. I would now like to turn the conference over to your host, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Erin, please go ahead.

Thank you and welcome, everyone, to the first quarter 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer; Dr. Steve Kelsey, our President of R&D; and Jack Anders, our Chief Financial Officer. Peg Horn, our Chief Operating Officer, 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 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. During this call, we will be referring to a few slides from our corporate presentation which was posted to our website prior to this call. 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 2023 earnings. On today's call, I'll provide a brief update on our company progress, Dr. Kelsey will cover a few highlights of our R&D progress and Jack Anders will provide highlights of our financial results before we open the line for questions. We're off to a strong start this year with 2 important steps that we shared in the first quarter. First, we communicated early findings from the Phase I/Ib study of RMC-6236, our first-in-class RASMULTI(ON) inhibitor which showed encouraging antitumor activity, safety and tolerability for patients with advanced solid tumors harboring a range of distinct KRAS-G12X mutations, particularly KRAS G12D and KRAS G12V. While covering a relatively small sample size, this was an important update as it provided initial validation of the novel mechanism of action and potential clinical utility of RMC-6236 and also carried positive implications across our pioneering and deep portfolio of RAS(ON) inhibitors. A second important step was a successful public equity offering in March which raised $345 million of gross proceeds and further reinforced our strong financial position. The additional capital is allowing us to consider additional near-term and long-term investments to strengthen clinical development of our first wave of RAS(ON) inhibitors and to prepare our organization for the advancement of RMC-6236 through the hiring of additional senior leaders and staff. We'll now turn to Dr. Steve Kelsey to review several clinical and preclinical highlights from the quarter. Steve?

Thank you, Mark. Let me provide a few additional comments on our first wave of development stage RAS(ON) drug candidates, beginning with updates on dose escalation of RMC-6236, our RASMULTI(ON) inhibitor in the RMC-6236001 trial. First, I am pleased to report an update on the case we highlighted in February of a patient with previously treated metastatic pancreatic cancer harboring a KRAS G12D mutation. We reported that this patient had an unconfirmed partial response at cycle 5 day 1 on RMC-6236 at 80 milligrams daily. The partial response was subsequently confirmed by RECIST with an 82% reduction in tumor measurements on cycle 7 day 1. The CT scans are shown on Slide 14 of the corporate deck and this patient continues on treatment. Second, we have escalated the dose level through 160 milligrams daily and are now evaluating 220 milligrams daily while also continuing to backfill the 120- and 160-milligram dose levels. We are encouraged that we continue to accumulate clinical evidence of antitumor activity for RMC-6236 at doses that appear to be well tolerated. We currently plan to provide additional updates on the program via multiple clinical updates this year. These will be a combination of corporate disclosures and presentations at scientific meetings beginning in Q3. We expect to be able to provide a more detailed schedule of these updates in connection with our Q2 earnings release. We'll next discuss RMC-6291 our mutant selected KRAS G12C(ON) inhibitor. At the recent AACR Annual Meeting, we presented new preclinical data and provided the first disclosure of the chemical structure of this drug candidate. This is the first structure disclosure of a drug candidate from our pioneering RAS(ON) inhibitor collection. RMC-6291 exemplifies how we are able to bring favorable drug-like properties, including potency, selectivity and oral bioavailability, to these Beyond Rule of 5 macrocyclic compounds. We are continuing to dose escalate in the RMC-6291001 study and are now focused on a twice daily dosing schedule to maximize continuous drug exposures. RMC-6291 continues to be well tolerated and we have not yet reached the maximum tolerated dose or selected a recommended Phase II dose. We remain on track to provide an update in the second half of this year. RMC-9805, our mutant selective oral and covalent KRAS G12D(ON) inhibitor, remains on track in support of the goal of beginning clinical evaluation of this groundbreaking compound in mid-2023. Hence, we'll shortly have our entire first wave of 3 RAS(ON) inhibitors under clinical evaluation. As many RAS mutant epithelial tumors have a propensity to metastasize to the brain, it is important to define the potential activity of these RAS(ON) inhibitors against tumors that have metastasized into the central nervous system. This may become particularly important if improvements in treatment of systemical visceral disease allow more cases involving the central nervous system to emerge. Today, we highlight preclinical studies demonstrating antitumor activity in intracranial tumors by each of the 3 first wave RAS(ON) inhibitors. As shown on Slide 21 of the corporate deck, we used a well-validated intracranial xenograft model of human non-small cell lung cancer carrying the KRAS G12C mutation, the LU99 model in which an embedded luciferase gene enables noninvasive quantitation of tumor size. The graph on the far left of the slide shows the bioluminescent signal intensity of tumors in untreated animals and for validation adjacent to it as a group of animals treated with adagrasib at 100 milligrams per kilogram day twice daily that showed a roughly 10x lower signal representing significant tumor reduction. This model and results match those published by Mirati an important point since adagrasib was reported last year to display antitumor activity against brain metastases in patients with KRAS G12C lung cancer consistent with the preclinical results. The next group in orange shows the signal for implanted brain tumors treated with RMC-6236 at 25 milligrams per kilogram daily showing encouraging antitumor impact which is essentially in indistinguishable from that of adagrasib. And the next group in blue, is mice treated with RMC-6291 at 100 milligrams per kilogram twice daily, a dose selected to be identical to the adagrasib treatment regimen, where a greater antitumor effect was observed. And finally, on the right is an analogous study of RMC-9805 versus control in an intracranial model of pancreatic cancer carrying KRAS G12D showing a profoundly reduced signal indicating a significant antitumor effect by this compound as well. Despite the limitations of these orthotopic models, collectively, these favorable preclinical results define a shared property of all 3 RAS(ON) inhibitors to potentially penetrate into central nervous system metastasis, a property not shared by all anti-cancer agents. This will be evaluated in subsequent clinical trials. Finally, I'd like to provide a brief status update on our 2 clinical stage RAS companion inhibitors. First, our SHP2 inhibitor, RMC-4630. The global Phase II RMC-4630 03 trial, evaluating RMC-4630 in combination with sotorasib for patients with KRASG12C non-small cell lung cancer is fully enrolled and we remain on track to read out top line results in the second half of this year. Second, our mTORC1-selective inhibitor, RMC-5552, continues its evaluation as monotherapy in patients with tumors carrying mutations associated with hyperactivation of mTORC1 signaling with the goal of advancing into combination studies with RAS(ON) inhibitors in select patients. Previously, we were focused on dose optimization in the 6 to 8 milligrams a week range after observing dose-limiting mucositis in patients treated at higher doses, a side effect that is common with mTOR inhibitors. Since then, we have successfully piloted a revised prophylaxis strategy that appears to diminish both the frequency and severity of mucositis and has allowed dose escalation above 8 milligrams per week. We plan to provide a clinical update on RMC-5552 at a scientific meeting in the second half of this year. Back to you, Mark.

Thank you, Steve. In conjunction with the clinical momentum described above, we've also continued building our organization with a particular emphasis on enhancing our late-stage capabilities to support further progression of assets such as RMC-6236. I'm especially pleased to announce today several new executives who have joined the leadership group at RevMed and bring substantial experience and track records to our efforts. Dr. Wei Lin, an oncologist with academic and industry experience, has joined us as Chief Medical Officer, a significant leadership addition to Dr. Kelsey's R&D organization. After completing medical training at Harvard Medical School and the MD Anderson Cancer Center, Wei led early-stage and late-stage cancer drug development programs during a career at Genentech, Nektar and Erasca and he now oversees clinical strategy and medical affairs at Revolution Medicines. Alicia Gardner has joined as Senior Vice President for Commercial. In her career at Genentech, Alicia held a variety of leadership roles across its oncology and hematology franchises including life cycle management, commercial strategy and launch planning. And we have also welcomed Nisha Brown as Vice President of Commercial Development;

Thank you, Mark. During the first quarter, we strengthened our balance sheet with the upsized public offering of common stock, raising gross proceeds of $345 million. Net proceeds were approximately $324 million after deducting underwriting discounts, commissions and estimated offering expenses. Including the financing, our ending cash and investments balance as of March 31, 2023, was $909.8 million which is now expected to fund planned operations into 2025. Revenue from our collaboration agreement with Sanofi was $7.0 million in the first quarter of 2023. Total operating expenses for the first quarter of 2023 were $82.2 million, an increase by 25% over the prior year period. The increase in operating expenses was largely due to R&D expenses related to the advancement of RMC-6236 and RMC-6291 into clinical trials as well as an increase in personnel-related expenses related to additional headcount. Net loss for the first quarter of 2023 was $68.1 million or $0.72 per share. We are updating our financial guidance for 2023 and now expect full year 2023 GAAP net loss to be between $360 million and $400 million which include estimated noncash stock-based compensation expense of $40 million to $50 million. The increase in expected GAAP net loss is a result of increased investments to support and strengthen clinical advancement of our first wave of RAS(ON) inhibitors including expanded clinical supply and additional senior leaders across late-stage development, manufacturing and commercial planning for RMC-6236. And with that, I'll now turn the call back over to Mark.

Thank you, Jack. We are highly energized by the exciting pipeline and organizational progress so far this year with ambitious plans to continue amplifying this momentum. We look forward to sharing further clinical updates on our first wave of RAS(ON) inhibitors and RAS companion inhibitors in the second half of the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisers and shareholders and the tireless efforts of our RevMed employees in pursuit of our mission to outsmart RAS-addicted cancers. 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.

Congrats on the progress and the little bit of data update, Steve, that you dropped in there. Just looking forward to the additional 6236 updates. Maybe to start off, just can you give some context for the kind of patient numbers? Right now, most of the data has been in G12D patients in part from the epidemiology. Should we expect in these next updates to see the POC kind of get broadened out to other mutations and histologies? Or is this really staying given the epidemiology just very focused on G12D? And then I'll probably have a follow-up there.

Thanks, Mark, for your question. I don't think we can really give you a lot more color around that right now. Obviously, we're still accumulating data. We're still following patients who have been on study. We are enrolling into escalation cohorts and then we're backfilling at doses below the escalation dose. So we'll certainly have a larger hand. As you know, to a large degree, we think that the patient population represented the epidemiology broadly which is that KRAS G12D is the most common mutation and that's what we're seeing in the study. But we are seeing additional genotypes. In terms of histology, clearly, we continue to see most patients in the pancreatic cancer and non-small cell lung cancer tumor types but there are some others as well. So it's hard to say from where we are today, we'll know better as we get closer to that disclosure point.

Okay. That's helpful. And then, obviously, the net loss guidance implies a significant growth in expenses kind of here over the remainder of the year. Can you just kind of walk through what some of those priority trials are that you're looking to start? Is that the monotherapy expansion for the multi-RAS and maybe the G12C but -- or is that is really the combo work getting underway? And kind of what's the priorities there.

Yes, I don't think today we're necessarily announcing new studies. I think it's more along the lines of plans that we've already had but the probability for those plans, of course, has gone up because of the progress. And we do feel that there -- it is justified to increase our commitment to supply which will supply both this year and continue providing support into studies that extend into next year as well, as well as expanding the personnel, the senior leadership that we talked about and so on. So, I don't think it's really today a point for us to start disclosing the broader development plan around RMC-6236 specifically but you can certainly expect that we're continuing monotherapy and expanding there and that a priority as well to run in parallel is to get into the combination studies but no specific update today on that. I think as we get later into the year and after we've unveiled more clinical data, then I think it will be more appropriate to sort of combine that with projections about what's coming next.

And our next question comes from the line of Eric Joseph with JPMorgan.

Just on the dose escalation update now at 220 mg. Can you talk a little bit about what you saw in terms of tolerability at 160 mg that you're comfortable with widening the dose interval and I guess do you think currently -- where you are right now if there's perhaps headroom to further dose escalate?

I think Steve will comment on that.

Sure. The tolerability profile of RMC-6236 continues to be what we consider favorable. There have been no qualitative changes in the tolerability profile of RMC-6236 since our last update. And so we feel comfortable in continuing to dose escalate. And as we somewhat laboriously went through back in February, even though rash is the most frequent toxicity -- remains the most frequent toxicity, it really is difficult to predict ultimately, what is going to become dose limiting. We had previously articulated, I believe that we would expect on the basis mechanistic studies and nonclinical toxicity studies that maybe GI toxicity would ultimately become dose limiting. But as of now, that's not happening. And so we're continuing to dose escalate. It's very difficult to, Eric, to predict where we're going to stop with this. I honestly cannot give you color on that I may do even if I could. Other than that, the program continues extremely well.

Okay. I don't know if you have visibility on this but just having highlighted the expectation of being at a medical conference in the third quarter. I guess, should investors expect sort of a meaningful difference from the -- meaningful difference in the scope of data reading out sort of midyear from what you might present at a medical meeting with this program.

Well, I think what we're communicating, Eric, is that our midyear update will be a set of multiple updates, including corporate and scientific meeting presentations that begin in Q3. But I don't think we're going to be having an update next week, followed by an update series that starts in Q3. I think those are all part of the same series that will begin in Q3.

And we have Michael Schmidt from Guggenheim.

Question on 6291 now that we've seen a few more clinical data sets from other G12C inhibitors at AACR. I guess what are you looking for in the clinic for your program? I guess, what degree of differentiation, be it either on efficacy or safety, are you looking for at a minimum, relative to the others which look rather comparable. And then, a follow-up question on the switch to the BID dosing. Just help us understand a little bit more what drove that decision to move into twice daily from the only planned once-daily dosing schedule.

Yes, Michael. I might just take both of those and Steve can add to it if there's anything to add. So the question of BID dosing, really nothing specific drove it other than the fact that the PK and the daily dosing is -- turns out to be consistent with what we saw preclinically. And preclinically, we saw and have reported that, that the half-life of RMC-6291 in animals and now we've seen in people, is shorter than a full 24-hour type of coverage from daily dosing. We didn't really see much impact of that -- adverse impact of that preclinically. In fact, almost all of the preclinical data we reported were from daily dosing. And so the preclinical differentiation that we reported was supported by that daily dosing. But nonetheless, in humans, we want to have every opportunity to be successful here. And there's really not a good argument for going to -- staying at daily dosing. Twice daily dosing will give us more continuous coverage and if there's a benefit that comes from that, we'd like to have that on behalf of patients. So that's really all there is there's nothing else from the clinic that drove that decision. And your -- the first question was?

I was just asking about the degree of differentiation you're sort of looking for in the clinic relative to the other G12C inhibitors out there which look fairly comparable so far?

Yes. Well, I think that's the sort of the key point is that the entire RAS(OFF) inhibitor pool of drug candidates, they look relatively similar. And we -- that's what we've expected based on the biology of inhibiting the reserve pool of RAS that's in the off-state and that you're always going to be chasing trying to get a leg up but without much biological ability to do so. So ultimately, we like regimens that incorporate RMC-6291 to give us greater clinical benefit. And as we've talked about in the past, we're not exactly sure whether that's going to be in higher response rates or greater durability response and/or greater tolerability. Those are all features that we've seen preclinically and any or all of those could be manifested in humans. I think you're asking, though, how much of that do we need to see in monotherapy before we start our combination studies since we've indicated pretty explicitly multiple times that our strategy around RMC-6291 is to move it into combination studies as quickly as we can and to focus the long-term plan on combinations because I think the puck has already moved past monotherapy. And so we're trying to play where the puck is going to be in the future on behalf of patients. And the answer to that is we're not really prepared to define for you an answer to that. We're going to move into combination studies as quickly as we can and we need to get sort of the basic profile in monotherapy and we need to compare that to the benchmarks and how much superiority or differentiation we see relative to those benchmarks. We just -- we don't know. And we're not too concerned about it because we know mechanistically it is going to be differentiated, qualitatively differentiated. So we're not too hyped up about exactly what we see in a relatively small number of patients. So I think if we're in the ballpark of the benchmarks, we'll be going into those combination studies. If we are vastly superior in a way that one could draw such conclusions from a relatively small study, that might allow us to continue down a monotherapy pathway but we don't really anticipate that from a Phase I dose escalation study.

Chris Shibutani joins us from Goldman Sachs.

This is Charlie [ph] on for Chris. It's nice to see the CNS activity that we're seeing across the RAS(ON) platform at this point. So I just wanted to get your take in terms of the potential for that intracranial activity to translate into the human subjects as we proceed and advance further into the clinic. Is there anything in particular that you would call out about the tri-complex mechanism of action that might influence the translatability of that intracranial activity that you're seeing in mouse models so far?

I don't think so. I think the impact of penetrating into CNS mets is going to be determined to a very large extent by the patient population in which these drugs are being tested. So ultimately, as we get into earlier lines of therapy as we have the opportunity to control the visceral disease more effectively, then I think that brain metastases are going to be an increasingly large part of the unmet medical need and that's when you will see the impact or the translatability, so to speak, of compounds getting into CNS metastases. With regards to the tri-complex technology per se, particularly the mutant selective compounds which caused these regressions in these implanted tumors. They're highly selective for mutant RAS. So there's unlikely to be any translation into CNS-based toxicity from any impact in penetrating the normal CNS. We honestly really don't have a very good handle on how much of the -- how much of these compounds gets into normal CNS. All of the evaluations to date have been done in tumors that are specifically growing within the central nervous system. And I think that's the message that we would like to convey at the moment.

Great. That's helpful. And then maybe just a quick one on 6236 with the profile that's still emerging. Is there anything in particular in terms of combination partners that -- are you seeing a particular combination partner that's maybe more or less likely to be combinable with 6236 at this point? Or are you really seeing a relatively tolerable profile thus far that's leaving all potential combination partners on the table at this time?

Yes. I mean I think at this point, everything is open. Obviously, with the RASMULTI inhibitor that is suppressing to some degree, suppressing normal or wild-type RAS in normal tissues, there would in principle be overlap with other inhibitors that also suppress RAS signaling in normal tissues. So for example, a SHP2 inhibitor and RMC-6236 they may be combinable or they may not be but you would worry more about that combination than you would about combining with something that's highly selective and has a nonoverlapping mechanistic effect. An example of that might be PD-1. So 6236, mechanistically targeting RAS and PD-1 not mechanistically targeting, you can imagine those might in principle, be more combinable. And preclinically, we've combined a lot of things and can see impact in the preclinical models. So I just think it's hard to predict today exactly what will work out best. But we do have some priorities and I've just given you some sort of guidance about how you might think about those priorities.

Alec Stranahan joins us from Bank of America.

This is John [ph] on for Alex. Just a quick one on 9805. Obviously, we saw some preclinical data at AACR. In terms of getting into the clinic as you dosed the first patient in your monotherapy dose escalation study, what's the kind of like patient baseline characteristics we can expect? And what tumor types are you going to go for in the study. If you could shed some light on that?

Well, right now, the plan for RNC-9805 is to identify a recommended Phase II dose as expediently as possible and obviously convince ourselves that that's the right dose and persuade other constituents out there that we have the right dose. So apart from an obvious restriction of patients with tumors harboring a KRAS G12D mutation, I don't think you're going to see a lot of difference from the RMC-6236 dose escalation, frankly. We know the histo types in which KRASG12D mutations predominate. And we have enough experience now with 6236 to get a handle on the types of patients that we're going to get in the Phase I study. They're going to be predominantly patients with lung cancer, pancreatic cancer and colorectal cancer. And I think that's pretty much all we can say right now. There is nothing unusual about the Phase 1 plan for this compound.

It might be worth adding -- I don't know, slightly underlying it was a question about access to patients which we sometimes get asked about. There are 55,000 -- we estimate 55,000 new U.S. cases of KRAS G12D cancers each year. And given that even across multiple companies studies that might be underway at the same time, you're talking about dozens or at most hundreds of patients. I don't think there's going to be any impact of either competition from others to the extent that there is any versus competition from RMC-6236. We'll have plenty of access to patients with KRAS G12D tumors.

Okay. And a quick follow-up to that. You mentioned that CRC is likely going to be one of the type of patients recruited. So given the complexity of colorectal cancer in general, other than screening for KRAS suppressant of KRAS G12D, are you also going to be screening for the absence of other mutations?

Well, I think just to build on Steve's comments, the first thing to do with the compound is a Phase I dose escalation and that's not typically a time at which one wants to apply a whole bunch of restrictions. That comes later after you've seen how it behaves and have a good sense of where you might prioritize. So I think Steve mentioned that there will be relatively few restrictions other than sort of conventional exclusion criteria and then the inclusion is a KRAS G12D mutation but I don't think we'll be putting up any other genetic -- significantly other genetic restrictions.

Our next question comes from Ben Burnett with Stifel.

I just want to build off an earlier question. Just about the regulatory path for the RASMULTI RMC-6236. I realize its early days but do you have a sense for how many different sort of genetic variants of KRAS you need to show data on to get a broad sort of mutation agnostic label?

Ben, no, we don't know. It will just depend on how much activity there is when we have a more mature data set and then that will ultimately depend on conversation with the people who make that decision.

And Jay Olson joins us from Oppenheimer.

Congrats on all the progress. Can you talk about any feedback you received from physicians following AACR? And also, is the brain penetrant property of your 3 molecules by design? Or is there a particular reason for the high CNS activity?

So the first -- I was sort of thinking about your second question but remind me what the first question was -- could you say it again?

Any feedback from physicians following AACR?

And are you asking about -- Jay, are you asking about the feedback on our programs? Or are you asking about feedback on other things at AACR. Could you just clarify?

Feedback on the data you presented.

I think generally, the feedback continues to be very positive. Our investigators are quite enthusiastic. We've said that previously. We are not able to make available as many investigational study slots as we'd like to be able to make available. They're constrained just by the escalation sort of paradigm and there's high demand and patients waiting and investigators waiting. And we continue to receive feedback that, so far, the compound appears to be well tolerated and active. And so there's quite a lot of excitement about RMC-6236. And then now I forgot the second question.

Was it by design?

Oh, was it by design. It depends on who you ask. Yes. I think in a certain sense, there are physicochemical properties that the chemists at RevMed have determined and also, most importantly, have figured out how to incorporate those properties into these compounds and those create more drug-like molecules. So it is notable, I think, that all 3 of these have this property and all 3 are orally bioavailable which as somebody who's lived through the history of this, that was not universally accepted as a set of assumptions going into the discovery and development of these RAS(ON) inhibitors based on macrocyclic large chemical backbones. But they now have been endowed with these properties through pretty directed efforts. So, I think we should acknowledge that the medicinal chemistry team with support by many others was able to do that. Whether or not they design them specifically aiming to get them into the CNS probably, maybe more of a philosophical question than anything else. So I don't have to answer philosophical questions, yes.

Okay, great. And if I could, maybe one follow-up on 6236. Can you just talk about the next data update and what sort of data you'll have and what investors should expect to learn from that?

Well, sure. As we've noted, we're following any patient who stays on drug. We continue following them. So we'll get a much better sense of durability and the course of the treatment for those patients who have already been on drug and who remain on. We're going to get a sense from backfill patients, a deeper sense of tolerability and a deeper sense of antitumor activity from those backfill patients, might not have as much durability data from those if they're enrolled later in the game. And then, of course, we have escalation data that shows us where we are on the tolerability scale and get a better sense of how, when and at what level we'll reach a recommended Phase II dose or candidates for a recommended Phase II dose. The tumor types are going to be, as we talked about earlier, they are what they are and the mutations are with the epidemiology dictate them to be. And so depending on how large the total set is, that will determine what's the absolute number of each of those histotypes in each of those genotypes, just too hard to say today. So, I think investors should be looking for a larger data set than what we've shown before with more information that's kind of deeper and broader. And we'll see whether the trends that we described earlier, to what degree they continue, to what degree, if there are differences, to what degree there are differences. And we'll couple that with we hope clarity about what comes next. We've already given you in our body language that we are definitely looking beyond the Phase Ib dose escalation. We're definitely thinking about where this compound needs to go and are sort of scaling up our activities to support all of that. But more detail when we have the data to support it.

Ami Fadia joins us from Needham.

With regards to RMC-6236, can you discuss where the 220-milligram dose is relative to the dose that you tested in the preclinical models? And how important is it to achieve a comparable dose in order to really reach the ORRs that you were able to see in the preclinical studies. And maybe let me pause there now. I'll ask the next question after that.

Okay. Ami, I appreciate the questions. Just to remind you how the selection is made. There's a dose selection committee which is made up of all the investigators. They review all the activity data and tolerability and safety data in a big package that they received before a meeting is called. They look at that. They look at the PK. And if we've cleared the DLT window, then they proceed to a dose escalation and they determine, of course, with input from RevMed, how much to increase and they determine the 220-milligram increase versus the 160. So just to make sure everybody understands how we arrive at those numbers. With regard to what dose -- what exposure level will be at 220 milligrams, we'll know after we dose the patients and obtained their blood samples and determined PK. So we don't know. We can't know our priority. We have projections around that but we -- but projections are projections. So I can't answer that question today. And then, your second or third?

How important is [indiscernible] keep going up?

Yes. I mean I think we've said in various ways, more is always better. That seems to be the case for most of these compounds, not just ours but for most antitumor drugs. So we'd like to get up as high as we can within the bounds of safety and tolerability. And you're sort of asking your question that project optimist is also asking and it's an equally difficult question to answer for project optimist which is how much is enough. We're not in that realm right now because as Steve pointed out, we're continuing to see good tolerability. So we're not in the zone where we even have to be worrying about it. But at some point, there will be side effects. It's just hard to conceive that there won't be side effects and even more significant side effects than we've seen so far. But we're pretty pleased with the exposures we've had at the other dose levels up through 160 mg. And it's -- we're above what we believe is the equivalent in mouse exposure of 10 milligrams per kilogram which was very much an active dose level in the mice -- or exposure level in the mice. And so we're well above that. We've been above it for a bit. And -- but exactly where we are at 220 mg is hard to say.

I guess my follow-up question is maybe just what do you. At what point do you think the clinical data will support the sort of superiority to other KRAS(OFF) drug, that RAS(OFF) drug that you saw in the preclinical data set? And then perhaps if you could in terms of time to respond relative to the data set that you shared at the last earnings call, do you expect responses to improve beyond that time frame in at least that patient's uplift?

Okay. I think your second follow-up question there was, do we expect response rates to improve over time as patients stay on drug. I think that's how I heard that question.

Sure. Yes.

Yes. Well, we made that statement back at the end of February. We did assert that and we stand by that assertion. We're continuing to accumulate evidence of antitumor clinical activity but we stand by the assertion we made previously. And we'll see over time whether that holds as we dose escalate. And when we report it out, with the data set, we'll have a firmer answer as opposed to a preliminary answer at that point. So ON versus OFF, yes, RMC-6236 is probably not the best place to test the ON versus OFF because it is unique in its profile as far as we know for any compound that's in the clinic or about to be in the clinic in that it's active against so many different genotypes. And so it sort of stands -- it's sort of defines a class with its own and it has to stand on its own. And so it will be compared more to standard of care in each of the histologies. I think RMC-6291 is one where, ultimately, the treatment regimen must show differentiation from standard of care and standard of care, at least in second line now includes a targeted KRAS G12C(OFF) inhibitor. So -- but that is likely to come from us in the form ultimately of combination strategies. That's what we've conveyed is our vision for the RMC-6291 program. And in the combinations, we'd like to have the very best RAS inhibitor that there is and we think RMC-6291 is a candidate to be the best KRAS G12C inhibitor in large part because of its ON mechanism. But that will be additive to whatever combination play is put together when it's tested in a Phase II kind of context.

Stand by for our last question. And it comes from the line of Jonathan Chang with SVB Securities.

Just one for me. What do you see as the competition for RMC-6236?

Jonathan, that's a good question. For most of the indications, the competition is standard of care. That's what we're going up against. For example, for G12B or any of the other G12X mutations aside from C, there aren't other compounds in the clinic today. For G12D, obviously, there are some other compounds that have entered the clinic. And so in principle, those are competitive for that population, the KRAS-G12B genotype. That's not a statement of my judgment about which compound is superior. You just want to know what's on the list. And those compounds that are in the clinic or about to be in the clinic, those would have to be considered competition.

And that concludes our Q&A. I would like to turn it now back to Dr. Mark Goldsmith, Chairman and Chief Executive Officer, for closing remarks.

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