Revolution Medicines, Inc. Q1 FY2023 Earnings Call

Good day and welcome to Revolution Medicine's First Quarter 2023 Earnings Conference Call. 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 current beliefs of the company concerning 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 two 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 exposure. 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 three 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 systemic 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 three 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 is 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 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 three 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 two 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 Revolution Medicines 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; Zane Rogers as Vice President of Regulatory Affairs; and Sriram Naganathan as Vice President of Chemistry, Manufacturing and Controls. With these highlights of our recent R&D and organizational progress, I'll now turn to Jack Anders, our CFO to provide a financial update. Jack?

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 of 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 includes 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 Revolution Medicines 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.

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, Marc, 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, or is it really the combo work getting underway? And what's the priorities there?

I wouldn't say we're announcing new studies today. Instead, we're discussing plans that have been previously established, and the likelihood of those plans moving forward has increased due to our recent progress. We believe it’s appropriate to enhance our commitment to supply, which will benefit both this year and support studies extending into next year. Additionally, we are looking to expand our senior leadership team. While we're not ready to share the broader development plan for RMC-6236 today, we will continue with monotherapy and look to expand in that area. A key focus will also be on initiating combination studies, although there are no specific updates to provide at this moment. As we approach the end of the year and release more clinical data, it will be a better time to align that information with projections about future developments.

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

Can you discuss the tolerability you observed at 160 mg that supports your decision to widen the dose interval at 220 mg? Additionally, do you believe there is potential to further escalate the dose at this stage?

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, it 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 of 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.

I’m not sure if you have insight on this, but since I mentioned the expectation of attending a medical conference in the third quarter, should investors anticipate a significant difference in the scope of data presented midyear compared to what will be shared at the medical meeting for 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 will address both of those points, and Steve can provide additional insights if necessary. Regarding the BID dosing, there wasn't a specific factor that prompted this change besides the fact that the pharmacokinetics and daily dosing are consistent with our preclinical findings. In our preclinical studies, we observed that the half-life of RMC-6291 in animals, and now in humans, is shorter than a full 24-hour coverage from daily dosing. We didn't notice any significant adverse effects from this in our preclinical data, which primarily came from daily dosing. The differentiation we reported based on preclinical results was bolstered by that daily dosing. However, in humans, we want to maximize our chances for success. There isn’t a solid justification for maintaining a daily dosing schedule. Switching to twice daily dosing will provide more continuous coverage, and if that brings any benefits to patients, we want to implement it. That sums up the reasoning; there’s nothing else from the clinical data that influenced this decision. What was your first question?

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. The main point is that the pool of RAS(OFF) inhibitor drug candidates appears quite similar. This aligns with our expectations regarding the biology of inhibiting the reserve pool of RAS in the off-state. We recognize that while it’s challenging to gain a significant advantage biologically, we prefer treatment regimens that include RMC-6291 for enhanced clinical benefits. As we've previously mentioned, we aren’t entirely certain if these benefits will manifest as higher response rates, longer durability of response, or improved tolerability. We have observed these characteristics in preclinical studies, and any combination of these outcomes could potentially be seen in humans. You're inquiring about the extent of results we need to observe from monotherapy before initiating combination studies. We have clearly communicated our strategy to advance RMC-6291 into combination studies as swiftly as possible and focus our long-term plans on these combinations, as we believe the trend has shifted away from monotherapy. We're focused on where the future of treatment is headed for patients. Regarding your question, we aren't ready to provide a concrete answer on the specifics we need before starting combination studies. We intend to move into those studies as fast as we can while establishing a basic profile from monotherapy and comparing that to existing benchmarks. We simply don’t have definitive answers yet, but we’re not overly concerned because we understand that mechanistically our approach will be qualitatively different. If our findings remain in alignment with benchmarks, we will proceed with combination studies. If we find ourselves significantly superior in a manner that conclusions can be drawn from a limited patient population, that might allow us to maintain a monotherapy path, though we don’t anticipate that outcome from a Phase I dose escalation study.

Chris Shibutani joins us from Goldman Sachs.

This is Charlie 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 that cause 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 these compounds get 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. I have a quick question about 6236, which is still developing. Are you seeing any specific combination partners that might be more or less suitable for 6236 at this stage? Or do you find that the current profile is acceptable enough to consider all potential combination partners?

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 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 non-overlapping 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 an 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 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 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 that there was a question about access to patients, which we sometimes get asked about. There are an estimated 55,000 new U.S. cases of KRAS G12D cancers each year. Even considering multiple companies' studies that may be happening concurrently, we're talking about dozens or at most hundreds of patients. I don't believe there will be any significant impact from competition to the extent that there is any compared to competition from RMC-6236. We will 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 types of patients recruited. So given the complexity of colorectal cancer in general, other than screening for KRAS suppression of KRAS G12D, are you also going to be screening for the absence of other mutations?

To elaborate on Steve's comments, the initial step for the compound is a Phase I dose escalation, which usually does not involve imposing many restrictions. Such limitations are typically considered later, once we understand its behavior and determine our priorities. Steve noted that there will be relatively few restrictions aside from standard exclusion criteria, and the inclusion will focus on patients with a KRAS G12D mutation. However, I don't anticipate adding any significant additional 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 it's 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 three molecules by design? Or is there a particular reason for the high CNS activity?

So I was thinking about your second question, but could you remind me what the first question was?

Any feedback from physicians following AACR?

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 Revolution Medicines 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 three of these have this property and all three 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 the support of many others was able to do that. Whether or not they designed 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.

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.

I appreciate your questions. To clarify how the selection process works, there's a dose selection committee comprised of all the investigators. They review all activity, tolerability, and safety data in a comprehensive package before a meeting is scheduled. They analyze that data, look at the pharmacokinetics, and if we have cleared the dose-limiting toxicity window, they move forward with a dose escalation. They also consider input from Revolution Medicines to decide on the increase amount, such as the 220-milligram increase compared to the 160-milligram dose. This explains how we arrive at those numbers. Regarding the exposure level we will achieve at 220 milligrams, we will determine that after dosing the patients and analyzing their blood samples to understand pharmacokinetics. Therefore, we do not currently know that information; we have projections, but projections are not definitive, so I cannot answer that question at this time. What would your next question be?

How important is it to keep going up?

Yes, I think we've indicated in various ways that more is generally better. This seems true for most compounds, not just ours but for many antitumor drugs. We aim to increase our dosage as high as is safe and tolerable. Your question reflects the same concern as project optimist, which is how much is sufficient. Currently, we are not facing that issue since, as Steve mentioned, we are still observing good tolerability. We haven’t reached a point where this is a concern. However, at some point, there will inevitably be side effects; it's hard to believe there won't be, and they could be more significant than what we've experienced so far. Nonetheless, we are satisfied with the exposures we've had at other dose levels up to 160 mg, and we are beyond what we think corresponds to a 10 milligrams per kilogram mouse exposure, which was a noticeably effective dose level in mice. We're well above that and have been for some time, but it's challenging to determine exactly what our exposure is at 220 mg.

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?

I believe your follow-up question was about whether we expect response rates to improve over time as patients remain on the medication. Yes, we made that statement back in February, and we stand by it. We are continuing to gather evidence of the clinical activity against tumors, and we will see over time if that assertion holds true as we increase the dosage. When we report the data set, we will provide a more definitive answer rather than a preliminary one. Regarding ON versus OFF, RMC-6236 may not be the optimal candidate for that comparison, as it has a unique profile among compounds currently in or approaching clinical trials due to its activity against a wide variety of genotypes. Thus, it essentially defines its own class and will be compared to standard care in each histological context. In the case of RMC-6291, the treatment regimen will need to demonstrate differentiation from standard care, which currently includes a targeted KRAS G12C(OFF) inhibitor in the second line. Ultimately, we expect this differentiation will emerge from our combination strategies, which is our vision for the RMC-6291 program. We aim to have the best RAS inhibitor available, and we believe RMC-6291 has the potential to be the leading KRAS G12C inhibitor, primarily because of its ON mechanism. This will complement whatever combination strategy is developed when tested in a Phase II setting.

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.

Thank you for your participation. This does conclude the program. You may now disconnect.