Revolution Medicines - Q4 2023

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to Revolution Medicines' Q4 and full year 2023 conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there'll be a Q&A 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. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Erin Graves (Senior Director of Corporate Communications and Investor Relations)

Thank you, and welcome everyone to the Q4 and full year 2023 earnings call. Joining me on today's call are Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Wei Lin, our Chief Medical Officer, will 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 in our corporate presentation and our 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 Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer. Mark Goldsmith?

Mark Goldsmith (Chairman and CEO)

Thanks, Erin Graves. Good afternoon, everyone, and thank you for joining us. We will keep our prepared remarks brief today in light of the corporate presentation we provided at the J.P. Morgan Healthcare Conference in January. Today, I'll review highlights of our company progress and lay out several important 2024 milestones for our pioneering RAS(ON) inhibitor pipeline, and Jack Anders will provide highlights of our financial results. 2023 was a transformative year for Revolution Medicines. First, we disclosed the preliminary clinical profiles of two unprecedented targeted RAS(ON) inhibitors, RMC-6236, a RAS(ON) multi-selective inhibitor, and RMC-6291, a RAS(ON) G12C selective inhibitor, as evaluated in phase I/I-B trials in patients with RAS-mutated cancers.

Initial safety, tolerability, and antitumor activity data reported at the Triple Meeting and ESMO Congress showed that both investigational drugs have highly differentiated clinical profiles, suggesting substantial promise for patients and supporting their continued development. We also announced in September that we had dosed our first patient in the phase I/I-B trial of RMC-9805, an oral and covalent G12D selective inhibitor, our third distinguished RAS(ON) inhibitor in clinical development. As I'll summarize momentarily, this important progress with our first wave of RAS(ON) inhibitors provides significant momentum heading into this year's plans, and we believe serves as validation of the RAS(ON) inhibitor platform and deep pipeline more broadly. Second, we ended 2023 with a particularly strong balance sheet, bolstered by the EQRx acquisition that fuels our ambitious plans, aiming to maximize clinical impact and drive shareholder value.

With a strong pipeline and financial position, we have three strategic priorities for 2024. First, building on strong clinical momentum with our boldest and most mature investigational drug with broad potential, our highest priority in 2024 is to propel single-agent RMC-6236 into its first pivotal trials. We are currently working toward the goal of launching randomized controlled trials against standard of care chemotherapy for patients with RAS-mutated non-small cell lung cancer or pancreatic ductal adenocarcinoma, and we expect that these efforts will command the largest share of our resources this year. Encouragingly, at the J.P. Morgan conference, we disclosed that with ongoing follow-up since ESMO, the RMC-6236 safety profile had remained relatively stable, including at 300 mg per day, with relatively few dose interruptions or discontinuations.

In the non-small cell lung cancer cohort, we reported favorable trends for aggregate objective response rate across doses into the low- to mid-40s range and that were trending even higher in the 300 mg cohort. In the pancreatic ductal adenocarcinoma cohort, we reported favorable trends for aggregate ORR into the mid-20s and that were trending even higher in the 300 mg cohort. We are now focused on the 300 mg dose and below for both lung and pancreatic cancer and continue to follow these patients as we develop a more mature data set to determine progression-free survival, or PFS. We've begun preparing our regulatory packages for dose selection and monotherapy pivotal trials that we plan to initiate in the second-half of 2024.

Beyond advancing into late-stage development in second-line lung and pancreatic cancers, our second strategic priority for 2024 is to expand the reach of RMC-6236. We've begun evaluating the impact of single agent RMC-6236 in patients with tumors harboring RAS mutations beyond the G12X mutations that had been the focus of the dose escalation, mainly G13X and Q61X mutations.... Likewise, we're studying RMC-6236 in patients with tumor types beyond lung and pancreatic cancer, including colorectal cancer, melanoma, and gynecologic cancers. We anticipate disclosing initial clinical PK, safety, tolerability, and activity data from the genotype and tumor type cohorts in the second or Q3 of 2024. In addition, we've initiated combination drug cohorts to examine options for reaching into first-line treatment settings.

For example, we've begun evaluating RMC-6236 in combination with a checkpoint inhibitor, a combination that is likely required for advancing into first-line treatment for lung cancer. We anticipate disclosing initial data in the second-half of 2024, with establishing safety of these combinations as the main focus. Our third priority for the year is to qualify our RAS(ON) mutant-selective inhibitors for late-stage development, RMC-6291, our G12C selective inhibitor, and RMC-9805, our G12D selective inhibitor. At the Triple Meeting in October, we reported preliminary results with RMC-6291 monotherapy, supporting clinically meaningful differentiation at doses that were generally well tolerated. Based on dose optimization work that has been completed, further study of RMC-6291 as a single agent continues at 200 mg BID.

As a major next step for RMC-6291, we have initiated our first RAS(ON) inhibitor doublet trial with RMC-6236 in patients with advanced KRAS G12C mutated cancers. Patients are currently being treated in the dose escalation portion of the trial, and we anticipate disclosing initial clinical PK, safety, tolerability, and activity data in the second-half of 2024. We've also begun treating patients with RMC-6291 and a checkpoint inhibitor to assess the safety of this combination. For our G12D selective inhibitor, RMC-9805, we shared at the JP Morgan conference that oral bioavailability of RMC-9805 has been confirmed in patients. We've seen pharmacokinetics consistent with expectations from our preclinical data, including dose-dependent increases in plasma exposure on once-daily dosing.

We've cleared several dose levels with good tolerability, and no dose-limiting toxicities have been reported thus far. We anticipate disclosing initial safety and activity data in the second-half of 2024. Finally, these ambitious clinical development priorities for advancing our first wave of RAS(ON) inhibitors are made possible by our strong balance sheet, which now includes approximately $1.1 billion of cash from the acquisition of EQRx that closed in November. With our compelling pipeline, innovation engine, and financial position, we aim to continue building and solidifying our position as an industry leader in developing targeted medicines for patients living with RAS-addictive cancers for many years to come. I'd like to now turn the call over to Jack Anders, our Chief Financial Officer, to provide the Q4 and full year financial update. Jack Anders?

Jack Anders (CFO)

Thank you, Mark Goldsmith. We are pleased to strengthen our balance sheet with the acquisition of EQRx, which added approximately $1.1 billion in net cash proceeds after estimated post-closing wind down and transition costs. We ended the year with $1.85 billion in cash and investments, which is expected to fund planned operations into 2027, based on our current operating plan. Q4 and full year 2023 financial results included $26.9 million in operating expenses associated with the wind down of EQRx, which primarily consisted of non-recurring accounting charges associated with employee-related termination expenses and stock-based compensation expense, resulting from the acceleration of EQRx equity awards in conjunction with the closing of the transaction. These were mostly one-time accounting charges specific to the close of the transaction in 2023 and are not expected to repeat in 2024.

Collaboration revenue was $0.7 million for the Q4 of 2023, compared to $15.3 million for the prior-year-quarter, and $11.6 million for full-year 2023, compared to $35.4 million for the prior-year. Decrease in revenue was due to the termination of the company's collaboration agreement with Sanofi in 2023. Total operating expenses for the Q4 of 2023 increased to $180.7 million, largely driven by R&D expenses, which totaled $148.5 million. Total operating expenses for full year 2023 increased to $498.8 million, with R&D expenses increasing to $423.1 million.

As noted earlier, our Q4 and full year 2023 operating expenses included $26.9 million in expenses associated with the wind down of EQRx. The remaining increase in total operating expenses for Q4 and full year 2023 was primarily due to an increase in clinical supply manufacturing and clinical trial expenses for our ongoing clinical development programs, increases in personnel-related expenses related to additional headcount, and an increase in stock-based compensation expense....Net loss for the Q4 of 2023 was $161.5 million, or $1.14 per share. For the full year, net loss was $436.4 million, or $3.86 per share.

Turning to financial guidance for 2024, we expect full year GAAP net loss to be between $480 million and $520 million, which includes estimated non-cash stock-based compensation expense, $70 million-$80 million. The increase in expected GAAP net loss for 2024 is a result of increased expenses associated with the progression of our ongoing clinical development programs. I'll now turn the call back over to Mark Goldsmith.

Mark Goldsmith (Chairman and CEO)

Thank you, Jack Anders. In summary, in 2024, we at RevMed have ambitious plans to deliver on clear priorities for our pioneering RAS inhibitor portfolio, building on tremendous momentum coming out of 2023 and enabled by a strong balance sheet and a highly talented and motivated team. We remain committed to discovering, developing, and delivering innovative targeted therapies for patients living with RAS-addicted cancers. On behalf of our organization, I'd like to extend our deep appreciation to our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.

Operator (participant)

Thank you. As a reminder, to ask a question, you'll need to press star one, one on your telephone. To withdraw your question, please press star one, one again. Please wait for your name to be announced. We ask that you please limit your questions to one and one follow-up until all have had a chance to ask a question, after which we'll be able to answer any additional questions from you as time permits. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from the line of Marc Frahm with TD Cowen. Your line is now open.

Ernie Rodriguez (Biotech Analyst)

Hi, team, this is Ernie Rodriguez for Mark Goldsmith. Congrats on all the progress and thanks for taking our question. The question is on the combinations with pembro for RMC-6291, RMC-6236. What would you like to see on that early data in the combinations for you to feel comfortable to make a decision to move those combinations into pivotal development? Thanks.

Mark Goldsmith (Chairman and CEO)

Hi, Ernie Rodriguez. Thanks very much for your question. Primarily, what we're looking for is to validate safety. As you know, the biggest challenge so far in moving into first line has been, for other RAS inhibitors, has been, combined hepatotoxicity signals. And, while we have early reason to believe that this is less likely to happen with either RMC-6236 or RMC-6291 compared to the earlier compounds, that's something we just have to evaluate. And so that's really the main thing we'll be looking for, is, establishing a safety profile that can support moving into first line.

Ernie Rodriguez (Biotech Analyst)

Thank you. That's helpful. And then just a quick one: Did you remind me if you mentioned before, I don't remember, the potential or how you're thinking about the potential for combining RMC-9805 with RMC-6236?

Mark Goldsmith (Chairman and CEO)

Sure. We haven't said much about that other than we consider the RMC-6291 + RMC-6236 combination to be sort of a key test case. And if those combine comfortably, as we have seen preclinically, if that carries through into patients, then it'll certainly be encouraging with regard to combining other mutant selective inhibitors with RMC-6236, and of course, RMC-9805 would be, would be early on that list.

Ernie Rodriguez (Biotech Analyst)

Got it. Thank you. Thanks again for taking our question.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Michael Schmidt with Guggenheim Partners. Your line is now open.

Michael Schmidt (Senior Managing Director and Biotech Analyst)

Hey, good afternoon, thanks for taking my questions. Yeah, Mark Goldsmith, we, I think, really appreciate some of the, the maturing phase 1 data for RMC-6236. I think you've made comments on how the data has been improving or changing over time now. But just curious if you could comment a bit more on, you know, how much more data do you need to support initiation of phase III and also to fulfill Project Optimus requirements before launching the pivotal studies as a monotherapy? Thanks so much.

Mark Goldsmith (Chairman and CEO)

Thank you, Michael Schmidt. Appreciate the question. Right, so the update that we provided in January that you're referring to had to do with response rates, and that information is helpful for guiding, dose selection. And of course, we're incorporating that updated information, into our, into our analyses and into packages for the FDA. So that's really for dose selection. I think, for moving into the pivotal trials, for actually making the go decision on those, we're looking for a mature, PFS assessment or estimate that can come from more mature, observation, which obviously we're developing now. And, that really leads to finalization of a trial design, the statistical power and so on, and accompanying all that, of course, is FDA, input. So I think those are the key elements for, making a final go decision.

Michael Schmidt (Senior Managing Director and Biotech Analyst)

Okay, thanks. And then you've highlighted a number of potential data disclosures in the second-half of this year, including additional monotherapy and then also early combination data from all three of your programs. Can you just help us understand the sequence of events? You know, will this all come at the same time? Is there some of the data might come before we see other data? Could you help us understand the cadence of data disclosed in the second-half a bit better?

Mark Goldsmith (Chairman and CEO)

I wish I knew. I'd be able to tell you. You know, we have some ideas about how things might roll out, but I think it's too early to really set out a schedule. We're not engineering it for a particular disclosure methodology. Just as the information becomes available and as it becomes appropriate to disclose it, we'll do so. I think clearly what people are most anxious to hear about is the timing, is a go decision and timing, and details about the final plan for those pivotal trials. So that's clearly what we would highlight as the most important events in the second-half of the year. But it is also true there will be other information coming out as we outlined in the milestones.

Michael Schmidt (Senior Managing Director and Biotech Analyst)

Great. Well, thanks so much, and congrats on the progress.

Mark Goldsmith (Chairman and CEO)

Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Eric Joseph with JP Morgan. Your line is now open.

Eric Joseph (Equity Research Analyst)

Good evening. Thanks for taking the questions. Maybe just following up on Michael Schmidt question regarding regulatory buy-in and the finalization of the pivotal studies. Is visibility on sort of activity in the context of G12X and Q61X mutations needed at all to sort of get buy-in on the nested efficacy analysis as part of your proposed design? That's and then I have a follow-up to that question.

Mark Goldsmith (Chairman and CEO)

Okay. Eric Joseph. Thanks for joining us today. You know, clearly, we're trying to make decisions in collaboration ultimately with the FDA about what to include in that final trial design, and to the extent that we have any activity information that can guide it, we'll include that information in conversations with the FDA. We do, of course, have preclinical data that suggests that supports the notion that really all mutant forms of RAS, certainly all that we've ever tested, showed some degree of sensitivity to RMC-6236.

The elevation of the G12X population, you might recall, came out of a large cell line panel that shows a statistically greater sensitivity of the G12X population of tumor lines to RMC-6236 than the others, but did not distinguish them as yes versus no. It was more a quantitative signal that highlighted them, and therefore, we prioritized them in the dose escalation study. So the bulk of the data that we have is around the G12X group. But we are working to gather additional information that extends into these other genotypes, as you alluded to. And to the extent that we can include that in our final determination of what's the best design, we'll certainly discuss that with the FDA as well.

Eric Joseph (Equity Research Analyst)

Okay, great. And maybe just a follow-up on planned combination studies with RMC-6236. Specifically, can you talk about what the gating steps are to starting a frontline pancreatic combination study with chemo? Is there a particular chemo regimen you're looking to combine with, you know, between either FOLFIRINOX or gemcitabine Taxol? And, you know, beyond adequate tolerability, is there an efficacy signal that you'd want to see in a combination study to warrant pursuit of a frontline opportunity?

Mark Goldsmith (Chairman and CEO)

Yeah, thanks for that question. I really appreciate your enthusiasm. You're moving us to first line. It's terrific. You know, there, there is, I think, growing interest in, in the first line space with RMC-6236, given, given what investigators have experienced so far. Maybe, Dr. Wei Lin, our Chief Medical Officer, who's joining us today, can comment on, what we're looking for to help us make the decision about launching and, designing and launching such a trial.

Wei Lin (Chief Medical Officer)

Yeah, happy to do that, Mark Goldsmith. Hi. I think you did mention the two current regimens that are currently the standard care. One is modified FOLFIRINOX, the other is gemcitabine, and both are in wide clinical use. So, we would be exploring the combination with both of these regimens in an early phase study. And, the benchmark for those are gemcitabine typically response rate in a 20%-30% range, and then modified FOLFIRINOX in a 30%-40% range. So, that's really being superior to either one of these would enable us to really move forward into a first-line setting.

Obviously, that's just the response rate, and ultimately, we'd like to provide survival benefit, and so PFS is another metric to be looking at.

Eric Joseph (Equity Research Analyst)

Okay, great. Thanks again for taking the question.

Operator (participant)

Thank you. Our next question comes from the line of Jonathan Chang with Leerink Partners. Your line is now open.

Jonathan Chang (Senior Research Analyst Covering Emerging Oncology)

Hi, guys. Thanks for taking my questions. First question: With an enviable year-end cash balance of about $1.85 billion. Can you discuss your high-level thought process around how one spends that capital effectively within the context of all the moving parts in your pipeline? And then second question, on RMC-6236, what is your latest thinking on what a development path forward in second-line pancreatic cancer could look like? Would the phase III primary endpoint of that study be OS or PFS? Thank you.

Mark Goldsmith (Chairman and CEO)

Thanks, Jonathan Chang. I think on the first question, which was capital allocation, given all the competing opportunities that we have, you know, I think we've been pretty clear about this, that our number one strategic priority is to advance RMC-6236 into pivotal trials in second-line pancreatic and lung cancer. No question that from our bandwidth perspective and, you know, even direct spending that supports it, that the allocation of capital is made accordingly. So that's going to take the lion's share of our effort.

So then, beyond that, we've identified these two additional corporate priorities for 2024, which is expand the reach of RMC-6236, and you've heard the various ways in which we're doing that, and that requires a certain amount of capital and a certain amount of bandwidth. Then, qualifying our mutant-selective inhibitors, RMC-6291 and RMC-9805, to advance into late-stage development, that requires a certain amount of capital, too. So those are clearly kind of ring-fenced, and elevated in priority for 2024. That doesn't account for the entire budget, of course, because we have programs that go beyond those assets.

Those are earlier stage programs, either defined development stage assets, of which we have several that we've identified and talked about, and then we have a robust discovery effort that leverages, you know, years of accumulated know-how to build out second, you know, later generation RAS inhibitors and so on. So, you know, we're gonna continue to allocate according to those priorities, but we are thinking about not just the near term. So when we're making these investments in 2024, we have to meet our 2024 goals, but we also are trying to build our strategy, our data set, and our asset, you know, pool that would sustain and protect a franchise once we're able to create a commercial franchise from the earliest assets that move forward. So lots of things to invest in.

It seems like we have a lot of capital today. At some point, it won't feel like that much capital, but we're managing according to a very strategic plan.

Jonathan Chang (Senior Research Analyst Covering Emerging Oncology)

Understood. And then just on the RMC-6236 development path in pancreatic cancer.

Mark Goldsmith (Chairman and CEO)

The RMC-6236 monotherapy, second-line pancreatic cancer clinical trial design, phase III design?

Jonathan Chang (Senior Research Analyst Covering Emerging Oncology)

Yeah. Exactly, exactly. And

Mark Goldsmith (Chairman and CEO)

So we-

Jonathan Chang (Senior Research Analyst Covering Emerging Oncology)

What is your latest thinking on what that primary endpoint could look like? Thank you.

Mark Goldsmith (Chairman and CEO)

Well, I think, yes, I think we can clarify what we've stated so far, and then anything else that adjusts that based on conversations with the FDA will update in the second-half of the year, but I think Wei Lin can comment more strictly on that.

Wei Lin (Chief Medical Officer)

Yeah. I think that on the endpoint currently we're looking at is really a dual endpoint of PFS and overall survival, OS.

Operator (participant)

Thank you. One moment for our next question, please. Our next question comes from the line of Eliana Merle with UBS. Your line is now open.

Eliana Merle (Managing Director and Equity Research Analyst)

Hey, guys. Thanks so much for taking the question. Just heading into the initial KRAS combo data later this year, I guess, what would you consider good data from this, from the RMC-6236, RMC-6291 combo, and what are you focused on from this initial data? Thanks.

Mark Goldsmith (Chairman and CEO)

Okay, thanks for joining us, and thanks for your question. Yeah, the RAS doublet is really kind of another differentiating angle of Revolution Medicines' portfolio and strategy. I think at the moment, we're really the only organization that could attempt such a combination, and the preclinical data strongly supported and do support evaluating RMC-6236 in combination with RMC-6291 in G12C cancers. What we don't know is exactly how that will play out translationally in humans. We know in the animal models, which are generally relatively short-term models and don't have the same evolution characteristics as a true human cancer, heterogeneous human cancer, we know what that looks like, and it can look like increased depth of response and increased durability of response, or increased frequency of response.

So really, everything you can measure, you can see in the preclinical studies, but it's very hard to try to tie a direct line from those into the human studies. So, I think a fair amount of this will be keeping our eyes wide open and looking for early signals that we then wanna chase down and have to validate further. But I do think the very first question is simply, is this a safe combination? Is it safe and tolerated? And the two components of that seem to be safe and well tolerated to date, but putting the two together, we just need to verify first that that doesn't create any drug interactions or other manifestations that could compromise the strategy going forward. And then after that-...

We'll be thinking about and looking for the clinical activity signal, that I just alluded to, whether it's frequency of response, depth of response, or durability response.

Eliana Merle (Managing Director and Equity Research Analyst)

Great, thanks so much. And just a quick follow-up, I guess, which indication should we expect data on in the expansion cohorts from RMC-6236 in the data update later this year? And then more broadly, I guess, in the CRC cohort, what are you looking to see to make a go, no-go decision thinking longer term for a potential pivotal study start there? Thanks.

Mark Goldsmith (Chairman and CEO)

Okay, I think you managed to squeeze in a third question. Nicely done. So in terms of the data that we've committed to communicating later this year, let's just start with the pivotal trials. There are two separate trials, you know, under contemplation here, pancreatic cancer and lung cancer, and so there's a data set associated with each of those, and I think those would be sort of headline, you know, data sets to come out later in the year, as we announce plans, you know, go forward plans. But then I think you were asking about going beyond pancreatic cancer and lung cancer and,

Wei Lin (Chief Medical Officer)

Expansion cohorts.

Mark Goldsmith (Chairman and CEO)

Expansion cohorts, but that go beyond pancreatic and lung cancer.

Eliana Merle (Managing Director and Equity Research Analyst)

Mm-hmm.

Mark Goldsmith (Chairman and CEO)

We've indicated that there are several different directions for those. One is different RAS genotypes beyond G12X, and we've indicated we'll provide some preliminary view of that sometime in the mid-year range. I think we said Q2-Q3 timeframe. The second is tumor types beyond lung and pancreatic cancer, and that includes colorectal cancer. We've indicated we'll provide some information on that in the second-half of the year. And then third is combinations that help us to begin to enable optionality for, for going into first line, and the RMC-6236, RMC-6291 combination we just spoke about, and then combinations of RMC-6236 with pembro, RMC-6291 with pembro.

And then, Wei Lin alluded to a few other things that one would consider for ultimately moving into first line, particularly in pancreatic cancer, with chemotherapy. So there's a wide range of things that are gonna happen. A good number of those we could read out in the second-half of this year.

Eliana Merle (Managing Director and Equity Research Analyst)

CRC. Great, thanks.

Mark Goldsmith (Chairman and CEO)

Yes. Did you wanna follow up on that?

Operator (participant)

Thank you. Our next question comes from the line of Ami Fadia with Needham and Company. Your line is now open.

Ami Fadia (Senior Analyst)

Hi, good evening. Thanks for taking my question. I've got one follow-up and a question, just on the PDAC data that you'll be presenting, from the ongoing study later this year in second line. Could you tell us what you see as the bar in terms of PFS that you would like to see? And with regards to your program, or what you're pursuing in first line, you're developing RMC-6236 in second line, or at least you, you know, you're planning to initiate a pivotal study there. What is the, you know, clinical rationale or the hypothesis in terms of what would be the right combination partner with pembro + minus chemo, whether it would be RMC-6236 or RMC-6291? If you could sort of share your thinking there, that would be helpful. Thanks.

Mark Goldsmith (Chairman and CEO)

Let me comment on the first question, then I might ask you to repeat the second question because I'm not sure that I completely tracked it. Your question was in second line PDAC, what is the bar that would compel us to move forward from a PFS perspective?

Ami Fadia (Senior Analyst)

That's right.

Mark Goldsmith (Chairman and CEO)

Is what you're asking. Yeah, I don't think we've really specified a particular number. Of course, we have our own internal benchmarks, but we've not publicly discussed those no-go decisions. But we're clearly looking to be superior to second-line chemotherapy, and we know what median PFS is in virtually every second-line study that's ever been done. You know, it's really around three months and three and 1/2 months at best in true second-line patients. Keep in mind, our population is not truly second line. Our population for the second and third and potentially even some beyond that, people who had multiple different previous treatments. So our population probably isn't going to perform as well as the second, a pure second-line population would perform.

But nonetheless, we've said what we're trying to do with our current patient population is to be superior to the well-accepted benchmark for second line, but how much superior, I think, is a question that goes beyond what we've commented on today. If you want to repeat your second question, then we can figure out who's the best person to comment on that.

Ami Fadia (Senior Analyst)

Sure. You know, just from a mechanistic perspective, I can understand, you know, if RMC-6236 as a monotherapy makes sense in second line, I understand the logic behind exploring a combination of that with pembro in first line. But why would someone treat with RMC-6291 + pembro in first line and then move to RMC-6236 in second line? Just hypothetically.

Mark Goldsmith (Chairman and CEO)

So your question is, in pancreatic cancer, if you received RMC-6236 as part of a first-line regimen, why would you repeat RMC-6236 as part of a second-line regimen? Is that, is that what you're asking?

Ami Fadia (Senior Analyst)

Well, or why would you start with RMC-6291, which is more targeted, you know, as a first-line treatment, and then move to RMC-6236, which is broader?

Mark Goldsmith (Chairman and CEO)

Okay. Now I understand. So we're talking about in KRAS G12C cancers, specifically.

Ami Fadia (Senior Analyst)

Correct.

Mark Goldsmith (Chairman and CEO)

You're talking about lung, and you're talking about lung cancer. Your question was, if we combine RMC-6236 with RMC-6291 in first line? No? I'm not following you. Maybe you can interpret the question, and you can answer it.

Wei Lin (Chief Medical Officer)

Let me interpret your question. So I think, what I'm hearing you say is, if we were able to succeed in developing RMC-6291 + pembro, or RMC-6291 + pembro and chemo, and that becomes the new standard care for G12C patients in first-line lung, why would patients get RMC-6236 as a second line? Is that your question?

Ami Fadia (Senior Analyst)

Yeah. that's helpful. Thanks.

Mark Goldsmith (Chairman and CEO)

Yeah. So I think, go ahead. Go ahead. Now I have some thoughts on it.

Wei Lin (Chief Medical Officer)

Yeah, I'll take a stab at it. I mean, that's certainly one scenario we could develop it using a RMC-6291 purely based regimen, + either pembro mono for the PD-L1 high, or pembro + chemo for all patients. There's another scenario where we could be developing RMC-6291 + RMC-6236, + pembro, without key chemo, right? That'd be another option. Just want to put that out there. But let's take the what you put on the table, which is RMC-6291 + pembro, with RMC-6291, + pembro, + chemo.

If that became the standard care in first line, I think we, we still do believe that there could be sense of rationale for RMC-6236 to remain as an option in the second line setting. The reason is the following: I think it really has to do with the way that the KRAS G12C tumor behaves in developing resistance against any G12C inhibitor. [I think there is sotorasib, adagrasib, divarasib]. I think one really emerging sign is, number one, 80%-90% of those tumors retain the original G12C mutation. They don't lose it.

Number two, the vast majority of the resistant mutations involve some type of either a RAS, another RAS mutation, or another mutation in the RAS pathway to reactivate the RAS pathway.

So what we call a RAS rescue mechanism. So rescuing or reactivating the RAS seems to be the predominant mechanism, and hence, it goes along, I think, with how Mark Goldsmith was describing these tumors as RAS addicted. I think the fact that they're addicted means that they are really relying on turning the tumor pathway back on in RAS. And hence, the broad spectrum activity of RMC-6236, involving not only other RAS mutations that can potentially cover, so if a tumor were to develop a G12D mutation to bypass the G12C, that RMC-6236 can remain active. And furthermore, if even if the patient were to activate a receptor tyrosine kinase like EGFR, and the signal goes through a wild-type RAS, that RMC-6236 can also cover.

So there are so many resistant mutations that are well characterized for the current G12C inhibitors that potentially RMC-6236 can be active against. So I think it still provides rationale. Obviously, we need to generate clinical data to support that for RMC-6236 to remain the standard of care in the second-line setting, even if RMC-6291 establishes itself as a first-line treatment of choice.

Mark Goldsmith (Chairman and CEO)

You got yourself a very scholarly, complete answer, thank you. I just want to circle back to the first thing.

Ami Fadia (Senior Analyst)

That was very helpful.

Jack Anders (CFO)

Yeah, if I could just go back to the first thing that Wei Lin said, that was—it's really important. It might have gone by a little bit quickly, which is that although we're testing RMC-6291 + pembro, and we're also evaluating RMC-6236 + pembro, we're also evaluating RMC-6291 + RMC-6236, and all three of those are a way of triangulating, potentially, on a triplet combination of RMC-6291 + RMC-6236 + pembro, which would be, as, as Wei Lin said, a chemo-free regimen for first line. We don't—It's not the only outcome of that. It's not the only possible outcome, but that would be one way in which all those get rationalized.

One shouldn't assume today that we will or would not move forward with the doublet of PD-1 + either one of those agents. We'll see. We'll let the data tell us what makes sense to do.

Ami Fadia (Senior Analyst)

Hmm. That makes sense. Thanks.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Alec Stranahan with Bank of America. Your line is now open.

John Chang (Managing Director and Equity Research Analyst)

Hey, guys, this is John Chang. I'm on for Alec Stranahan. Thanks for taking our question. Just a quick one from us. In terms of second-half data updates, what could be the venue that we would be expecting? Would it be at, like, a medical conference, or should we just be expecting, like a press release or like an investor day? So any color on that, that'd be great if you can share it.

Mark Goldsmith (Chairman and CEO)

Thanks, John Chang. Hard to answer that question because there's so many different data sets that we've listed there that could come out in the second-half of the year. Although our preference is to disclose such information in the context of peer-reviewed, you know, medical conferences, it's not always up to us. It just depends on the timing and availability. Often, these things require abstracts that are submitted long ahead of .... We'll pick a forum for each of the disclosures that suits it to make sure that we're not holding on to data that investors need to know about.

Wei Lin (Chief Medical Officer)

Okay. Thank you for the call.

Thank you. One moment for our next question. Our next question comes from the line of Jay Olsen with Oppenheimer. Your line is now open.

Jay Olson (Managing Director and Senior Analyst Covering Biotechnology)

Oh, hey, congrats on the progress, and thank you for taking the question. As you look ahead to the potential for multiple pivotal trials, can you just talk about how you're thinking about partnering opportunities both in the U.S. and outside the U.S.?

Mark Goldsmith (Chairman and CEO)

Hi, Jay Olson. Thanks for joining us, and thanks for your question. I think, again, we've been pretty consistent about this, which is that, in the U.S., we really believe this is a serious opportunity for RevMed to build its own franchise, and to use the RAS portfolio, to create a very strong and, and leading franchise. So I, I don't think we're, we're particularly keen on, sharing any of that with a partner, and I don't think there's any reason to do so, at least as we see things today. Outside the U.S., it's pretty clear that we don't have much opportunity there. That's a much more complex, context in which to think about commercializing. We can do development outside the U.S.

We already do development outside the U.S., but doing pivotal late-stage global development typically takes a real appreciation of the nuances in different country settings and, you know, different geographies. So that can be done, that can be enhanced by working with a partner that already has that infrastructure. And then, of course, commercialization per se is not something that we have any near-term plan to pursue on our own. So I think it's pretty clear that an ex-U.S. partner or partners could be in the offing for us at some point in the future. We're open to that possibility. And when the right opportunity presents itself and it makes sense for us to do it, I'm sure we would do so.

Jay Olson (Managing Director and Senior Analyst Covering Biotechnology)

Super helpful. Thank you very much. If I could ask one follow-up. As you look ahead to the potential tumor agnostic setting for RMC-6236, can you just talk about the regulatory path that you're thinking about there?

Mark Goldsmith (Chairman and CEO)

Dr. Wei Lin is probably best to answer that question.

Wei Lin (Chief Medical Officer)

Yeah, happy to address that. I think we already presented publicly activity in non-small cell lung cancer as well as pancreatic cancer. So those are probably gonna serve as anchor in our approach with tissue agnostic. Right now, we're actually enrolling patients with colorectal cancer, melanoma, as well as chronic lymphatic cancers, as well as other solid tumor. And obviously, to be very much data driven, but it's our aspiration, given the broad activity we've seen preclinically, that this molecule could potentially help as many as 30% of patients with solid tumor with RAS mutations.

So, we certainly like to test that hypothesis to the fullest, and then that will drive our decision about how much the tissue agnostic we aspire to.

Jay Olson (Managing Director and Senior Analyst Covering Biotechnology)

Okay, great. Thanks again for taking the questions.

Operator (participant)

Thank you. As a reminder, to ask a question, you'll need to press star one one, and please wait for your name to be announced. Our next question comes from the line of Laura Prendergast from Raymond James. Your line is now open.

Laura Prendergast (VP of Biotechnology Equity Research)

Hey, guys, thanks for taking the questions, and look forward to seeing all these data updates later in the year. Just one for me. You know, curious, since you're running, you know, at the same time, this pan-RAS trial and then, RAS selective clinical trials, have you gotten any feedback from trial investigators on, you know, how they make the decision on whether to enroll patients on a pan-RAS trial or a RAS selective trial? You know, assuming that you probably have some trials going on at the same locations. I'm just curious if you've gotten any insight there.

Mark Goldsmith (Chairman and CEO)

Yeah, I'll just make a general comment. In most of the indications we're talking about, the need for these compounds is so high that there are more patients than we can possibly support in these early stage clinical trials, where the size of the trial just is inherently limited. So, I don't think there's really any sort of near-term issue associated with that, but maybe, maybe Wei Lin wants to comment further about when you're into pivotal trials, how might that affect, if any?

Wei Lin (Chief Medical Officer)

Yeah, I think the clinical trial should reflect fairly well what we've seen so far in terms of recruiting patients and the unmet need we're addressing. I think just really highlight this is an unusual situation. This is the biggest driver in all of oncology, and then by enabling the drug this can really unlock a huge unmet need. So, all the patients coming in interest in our trial is reflection of that.

Laura Prendergast (VP of Biotechnology Equity Research)

Great, very helpful. Thank you very much.

Operator (participant)

Thank you. One moment for our final question, please. Our final question comes from the line of Ben Burnett with Stifel. Your line is now open.

Speaker 14

Hi, this is Kelly Breazeale with Ben Burnett. Thanks for taking our questions. I just had one quick question about RMC-6236. I was wondering if you could give us any additional color on how the confirmed response rates for non-small cell lung and PDAC are trending post ESMO. Thank you.

Mark Goldsmith (Chairman and CEO)

Yeah, thanks for your question. You know, we, as we mentioned, in January and reiterated, here, we've seen favorable trends in the response rates. You're asking specifically about confirmation, and I, I think generally what I can say is that most responses do confirm. Most of the responses that have been unconfirmed previously have been subsequently confirmed, except in those instances where somebody progressed in the interim or had to come off of drug and will never have the opportunity to, to confirm. So, most of these do confirm. I'm not gonna be able to give you specific, confirmed rates today, in part because these are ongoing trials. And so what happens is you're always enrolling new patients and getting unconfirmed responses while we're being asked about what's the confirmed response rate.

So I say you'll have to hang on and wait until later in the year when we'll try to give more precise information.

Speaker 14

Okay, thank you very much.

Operator (participant)

Thank you. I'm currently showing no further questions in the queue at this time. I'd like to hand the conference back over to Mark Goldsmith for closing comments.

Mark Goldsmith (Chairman and CEO)

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

Operator (participant)

This concludes today's conference call. Thank you for your participation. You may now disconnect everyone. Have a wonderful day.