Revolution Medicines - Q2 2024

Executive Summary

• RVMD reported Q2 2024 net loss of $133.2M (-$0.81/share) as R&D spend ramped for multiple RAS(ON) programs; revenue was $0 following the 2023 Sanofi collaboration termination.
• Management reiterated plans to initiate the first registrational Phase 3 trial (RASolute 302) of RMC‑6236 in 2L metastatic pancreatic cancer in 2024 and to launch an NSCLC registrational study in 4Q 2024, positioning late‑stage transition catalysts in 2H24–2025.
• Updated July guidance raised full‑year GAAP net loss to $560–$600M (from $480–$520M in May), reflecting accelerated development; cash, cash equivalents and marketable securities were $1.59B at 6/30, supporting runway into 2027.
• S&P Global consensus estimates for Q2 2024 could not be retrieved due to API limits, so beat/miss vs Street could not be assessed (see Estimates Context) [GetEstimates: limit exceeded].

What Went Well and What Went Wrong

What Went Well

• Strong clinical momentum for RMC‑6236 in PDAC: preliminary median PFS 8.1 months in KRAS G12X and 7.6 months in all RAS‑mutated tumors; OS not estimable at cutoff, underpinning Phase 3 start in 2024.
• Clear regulatory and development path: FDA feedback aligned on high‑level Phase 3 design and 300mg daily dose for PDAC; management also on track for an NSCLC registrational study in 4Q 2024.
• Organizational scaling for late stage/commercial: appointment of Frank Clyburn (ex‑Merck oncology/Keytruda) to the board and key leadership hires in medical affairs, corporate affairs, drug safety, and program leadership.
  • “We have made meaningful progress… preparing RMC‑6236… to move into its first pivotal monotherapy studies… These data have increased our confidence… and reinforce our commitment to initiate our first registrational study this year.” — CEO Mark Goldsmith.

What Went Wrong

• Operating loss widened y/y as R&D spend increased (R&D $134.9M vs $98.0M; G&A $21.7M vs $14.6M), driving net loss of $133.2M vs $98.3M in Q2 2023.
• FY24 GAAP net loss guidance raised to $560–$600M (from $480–$520M), reflecting higher development costs and program breadth.
• No collaboration revenue following Sanofi termination (revenue $0 vs $3.8M y/y), reducing reported top line and increasing reliance on financing runway.

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Revolution Medicines Q2 2024 Earnings Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will 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, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.

Ryan Asay (VP of Corporate Affairs)

Thank you, and welcome everyone to the second quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D, and Dr. Wei Lin, our Chief Medical Officer, will join us for the Q&A portion of today's call. I'll note that certain statements we make during this call will be forward-looking, because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements.

Alec Stranahan (VP of Equity Research)

For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report on Form 10-Q that are filed with the U.S. Securities and Exchange Commission. This afternoon, we released financial results for the quarter ended June 30, 2024, and recent corporate updates. This press release is available on the investor section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicines Chairman and CEO. Mark?

Mark Goldsmith (Chairman and CEO)

Thanks, Ryan. It's good to be with you this afternoon. Given our recent webcast in which we provided an update on our clinical progress in pancreatic cancer, we will keep our remarks relatively brief today. I'll share a quick summary of the data we presented last month, highlight recent progress we've made across the rest of our pipeline, and discuss several corporate updates. I'll then turn the call over to Jack, who will provide highlights of our financial results before we open the line for questions. We have made meaningful progress with our pioneering RAS(ON) inhibitor pipeline, notably preparing RMC-6236, our RAS(ON) multi-selective inhibitor, to move into its first pivotal monotherapy studies in common, difficult-to-treat cancers driven by oncogenic RAS variants. We kicked off the second half of the year with an important clinical milestone for RMC-6236.

Alec Stranahan (VP of Equity Research)

We disclosed recent data from the RMC-6236-001 trial, showing compelling preliminary progression-free survival and overall survival for patients with metastatic pancreatic cancer receiving RMC-6236 monotherapy. These data have increased our confidence in the promise of this program and reinforce our commitment to initiate our first registrational study this year. I'll take a few minutes to walk through some of the key findings from the pancreatic cancer results we shared last month. The full detail of these results can be found on the investor section of our website at revmed.com. The data, with a May 11th, 2024 cutoff date, reflects patients with previously treated pancreatic cancer across the RMC-6236 160 mg to 300 mg daily dose cohorts. The safety findings were promising.

The most common adverse events are believed to be on target and associated with the inhibition of wild-type RAS in normal tissue. Most adverse events were low grade, with approximately 22% of patients experiencing a grade 3 or higher treatment-related adverse event. The most common treatment-related adverse events observed were rash and gastrointestinal-related toxicities. There were no discontinuations due to treatment-related adverse events, and dose modifications of any kind occurred in only 28% of patients. The antitumor durability data were quite compelling as well. Historical progression-free survival benchmarks in pancreatic cancer are poor overall and deteriorate with advancing lines of therapy.

In a progression-free survival analysis of second-line patients, which is consistent with the patient population we plan to evaluate in our phase III study, we observed an initial median progression-free survival of 8.1 months in patients with KRAS G12X tumors and 7.6 months in patients with RAS-mutated tumors broadly. While these data continue to mature with longer patient follow-up, these preliminary findings compare favorably to standard of care in this patient population. We also showed an early interim look at overall survival in these patients.

As of the cutoff date, the median overall survival had not been reached for patients with either KRAS G12X mutations or other RAS mutations, and importantly, the lower bound of the 95% confidence interval for the median overall survival estimate is above the standard of care benchmark for median overall survival in second-line metastatic pancreatic cancer. As we noted in July, while early overall survival estimates represent a relatively immature data set, in the context of the strong progression-free survival data, we believe these observations provide a meaningful complement to the overall efficacy story of RMC-6236 in metastatic pancreatic cancer. We anticipate that these two measures, progression-free survival and overall survival, will be dual primary endpoints in our planned phase III study. Additional metrics and more detail regarding these data can be found on our website.

Given the strength of these data and based on initial feedback from the Food and Drug Administration, including alignment around high-level study design and the selection of 300 mg as our go-forward dose for pancreatic cancer, we plan to initiate our first global registrational phase III study this year. This phase III study, called RASolute 302, will evaluate RMC-6236 as a second-line therapy for patients with metastatic pancreatic cancer. Of course, while we are excited to initiate this study shortly on behalf of patients, our ambitions for RMC-6236 go well beyond second-line pancreatic cancer as we explore or plan to explore other tumor types in earlier lines of therapy. Data from the non-small cell lung cancer portion of the RMC-6236 monotherapy study continue to mature.

In the fourth quarter, we expect to provide updated safety and antitumor activity, including durability data, and to initiate a second registrational study evaluating RMC-6236 monotherapy for patients with previously treated non-small cell lung cancer. The strength of the data we've presented also enhances our commitment to expand the reach of RMC-6236 into earlier lines of therapy, including first-line metastatic, locally advanced unresectable, and resectable disease. Exploratory studies evaluating RMC-6236 in combination with current standard of care chemotherapy in first-line pancreatic cancer and colorectal cancer are currently enrolling and will yield important insights that should inform dosing paradigms for potential first-line registrational paths. This area remains a significant focus for RevMed. Another important combination study in progress is evaluating RMC-6236 with pembrolizumab, with or without chemotherapy, in patients with advanced RAS-mutated non-small cell lung cancer.

We expect to report initial data for this combination in the fourth quarter of 2024. While there is substantial focus and investment in RMC-6236 as our most advanced RAS(ON) inhibitor in the clinic, we also continue to prioritize investment in qualifying our first two RAS(ON) mutant-selective inhibitors, RMC-6291, our G12C selective inhibitor, and RMC-9805, our G12D selective inhibitor, for late-stage development. First, we continue to make progress in our combination studies with the goal of moving RMC-6291 into early lines of therapy for patients with RAS G12C tumors. The RAS(ON) inhibitor doublet of RMC-6291 in combination with RMC-6236 in patients with KRAS G12C solid tumors, primarily non-small cell lung cancer, is a vanguard study of this sort of combination regimen. This study is ongoing, and we expect to share initial data in the fourth quarter of this year.

Another combination approach with KRAS G12C non-small cell lung cancer is RMC-6291 with pembrolizumab, with or without chemotherapy. A study of this combination is ongoing, and we anticipate disclosing initial data for RMC-6291 with pembrolizumab in the first half of 2025. Second, the first-in-human monotherapy study of RMC-9805, a RAS(ON) G12D selective inhibitor, continues to enroll well. Dose optimization is ongoing, and we are on track to share initial safety, tolerability, and antitumor activity in the fourth quarter. Overall, we have a busy and exciting road ahead with the anticipated initiation of two RMC-6236 monotherapy registrational studies, a number of important exploratory combination study data updates, and additional data maturation that may validate the potential to advance two clinical-stage RAS(ON) mutant-selective inhibitors into late-stage development. In addition to advancing our studies, we are also preparing the organization for the next phase of growth.

We are pleased to announce that we have appointed Frank Clyburn to our board of directors. Frank is a distinguished commercial pharmaceutical leader who brings a wealth of experience to help Revolution Medicines advance toward late-stage clinical development and pre-launch commercial readiness. Notably, he was instrumental in building Merck's modern oncology business, leading the successful global launch and commercialization of Merck's Keytruda to create the dominant immuno-oncology franchise. His insights and experience will be invaluable as we move forward. We've also made several strategic leadership hires across medical affairs, research and development, program management, and corporate affairs to help scale our organization as we move closer to becoming a fully integrated commercial organization. In particular, I'd like to highlight two individuals who have joined RevMed's senior leadership team.

First, Ryan Asay, who is hosting today's call, brings extensive business experience in the biopharmaceutical industry to his new role as our Senior Vice President for Corporate Affairs. Second, Dr. Mary Pinder-Schenck has joined the organization as our Senior Vice President and Head of Medical Affairs. In addition to being a well-respected board-certified medical oncologist, Dr. Pinder-Schenck brings extensive U.S. and global medical affairs leadership experience to RevMed.

I'm highly confident in the strength of our team and the collective depth and breadth of experience we can apply to this transformative stage of the company. We continue to build the capabilities needed to drive the long-term sustainable growth of our business. This team, along with our robust pipeline of innovative programs and one of the most productive drug discovery organizations in the industry, position us well for what lies ahead. Now I'd like to turn the call over to Jack Anders, our Chief Financial Officer, to provide a financial update. Jack?

Jack Anders (CFO)

Thank you, Mark. We entered the second quarter of 2024 with $1.59 billion in cash and investments. This compares to $1.7 billion at the end of Q1. The decrease in cash and investments during the second quarter was primarily due to net loss for the quarter. Turning to expenses, R&D expenses for the second quarter of 2024 were $134.9 million, compared to $98.0 million for the second quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial expenses for our first wave of RAS(ON) inhibitors, preclinical portfolio expenses, personnel-related expenses associated with additional headcount, and stock-based compensation expense. G&A expenses for the second quarter of 2024 were $21.7 million, compared to $14.6 million for the second quarter of 2023.

Alec Stranahan (VP of Equity Research)

The increase in G&A expenses was primarily due to increases in personnel-related expenses associated with additional headcount, commercial preparation activities, and stock-based compensation expense. Net loss for the second quarter of 2024 was $133.2 million, compared to $98.3 million for the second quarter of 2023. As previously disclosed on July 15th, we have updated our 2024 financial guidance and expect full year 2024 GAAP net loss to be between $560 million and $600 million, which includes estimated non-cash stock-based compensation expense of between $70 million and $80 million. That concludes the financial update. I'll now turn the call back over to Mark.

Mark Goldsmith (Chairman and CEO)

Thank you, Jack. Revolution Medicines entered the second half of the year by fulfilling one of many important clinical milestones for our organization. We are well capitalized and remain focused on delivering key data and actions to advance RMC-6236 into its first registrational studies, while evaluating several opportunities to move into earlier lines of treatment for patients living with RAS-addicted cancers. We are also laying the groundwork to move our first two RAS(ON) mutant selective inhibitors into late-stage development. This important work and the progress we've made would not be possible without the support of our patients and caregivers, clinical investigators, scientific and business collaborators, advisors, shareholders, and the tireless efforts of RevMed employees on behalf of patients. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.

Operator (participant)

Thank you. At this time, we will conduct a question-and-answer session. As a reminder, to ask a question during this session, you need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We ask that you please limit your questions to one question and one follow-up. Please stand by while I compile the Q&A roster. Our first question comes from Marc Frahm from TD Cowen. Please go ahead.

Marc Frahm (Biotechnology Equity Research Analyst)

Yes, thanks for taking my questions. Let me just start off, when you think about the PFS data you released in pancreatic cancer the other day, you know, it looks a little bit better than what was achieved kind of with the G12C inhibitors in that subpopulation of pancreatic patients. Do you think that similar gap should kind of be expected, when we look at monotherapy data in other settings where we, you know, kind of have mature G12C inhibitor data, whether that's lung cancer or ultimately some other settings like colorectal cancer? Or is just the biology way too different across tumors?

Mark Goldsmith (Chairman and CEO)

Thanks, Mark. Appreciate your question. I think at this point, given that data will be rolling out, you know, in coming months and over the next year, I think it's best to still let the data speak for themselves. There's obviously there are many differences in the subtle aspects of biology comparing one tumor type to another. Whether or not that nets out in any particular direction, I think can just be determined empirically.

Marc Frahm (Biotechnology Equity Research Analyst)

Okay. Thanks. And then maybe thinking about first line in pancreatic cancer, just, you know, how much more data do you need to gather to kind of know what the, the plan is there, rather than just saying you, you want to do it, whether it's monotherapy? Do you need a fair amount of combo data with chemo or even with the G12D inhibitor, to just kind of figure out what the, what the design looks like to move to first line?

Mark Goldsmith (Chairman and CEO)

Yeah. I mean, I think we said before, and I know you and I talked about, that the monotherapy RMC-6236, I think, already qualifies to be included in such a trial. Really, the question is around how to play with chemotherapy. What role should that play? Should that be an arm in the study, and if so, how should that be done? That's principally a safety and tolerability question more than it is an efficacy question. RMC-6236 clearly is a broad-based inhibitor of RAS. It's by design. It's generally well tolerated and safe, but it does have some side effects.

Alec Stranahan (VP of Equity Research)

Chemotherapy is typically replete with side effects, and so when you put those two together, we need to have confidence going into the study, going into a registration study that that combination will not blow up for patients. So that's really what we're doing, is trying to figure that out. There are many combinations, as you point out, that we could pursue. I wouldn't consider RMC-9805 specifically part of that determination for RMC-6236 going into frontline. It's its own entity, and how we'll deal with that, we'll describe over time as we reveal data about that that interesting compound.

Marc Frahm (Biotechnology Equity Research Analyst)

Okay. Thanks a lot.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Michael Schmidt from Guggenheim. Please go ahead.

Michael Schmidt (Senior Biotech Analyst and Senior Managing Director of Equity Research)

Hey, thanks for taking my questions. I had one on the potential phase III study in second-line non-small cell lung cancer for 6236. I mean, one would think that the easiest or the simplest design would just be a 1:1 randomization compared to docetaxel. But, I'm just curious, there may be a scenario where Krazati has full FDA approval in G12C-positive patients at some point in the future and, based on the KRYSTAL-12 study. And I was just wondering, to what degree that might factor into the potential trial design. Would you, for example, allow Krazati in the control arm for G12C-positive patients, assuming that the trial obviously would include those patients, or is that something that is, not, you know, not feasible in your, in your opinion?

Mark Goldsmith (Chairman and CEO)

Thanks, Michael. Good to hear from you. Maybe I'll just say something brief about it, and then if either Steve or Wei wants to add something, they can do that. Maybe my general comment is G12C is clearly the most complicated part of the lung cancer trial for RMC-6236. There are, there are subtleties associated with that, as you just alluded to. We've not described our plan yet for lung cancer. We put forth a sort of a prototype last October, but we've not laid that out, and our expectation is to do that in conjunction with disclosure of the data that would support it. So I think we'd be getting out a little bit over our skis to commit today, but whether there are any principles that Steve or Wei wants to add to that, feel free to.

Wei Lin (CMO)

I think the only thing I want to add is that I think it will end up being a consideration from the FDA, if they were to approve Krazati, do they believe that 1.6-month PFS improvement is that Krazati as the standard of care for G12C patients, or just another standard of care in addition to docetaxel? And that would dictate whether Krazati is required to be the comparator, or docetaxel is to be acceptable. So that'd be a regulatory view issue.

Michael Schmidt (Senior Biotech Analyst and Senior Managing Director of Equity Research)

Okay. Okay, thank you. And then, yeah, very curious about the, the combination of 6236 with 6291, where I think you committed to presenting data later in the fourth quarter. And, yeah, just want to understand a bit better what types of patients are going in this study. Are these predominantly second line or later patients, or perhaps some treatment-naive patients included there as well? And what, what efficacy bar are you looking for to potentially advance that, that dual combination into more, you know, registration-directed studies?

Mark Goldsmith (Chairman and CEO)

Okay, so the first question is one of sort of eligibility for the, for the trial. Maybe Wei can answer that, and then I, maybe I can comment on the, the second part of the question. Combination 6236 + 6291, what types of patients and tumors are in the trial?

Wei Lin (CMO)

Yeah. So, the patients are eligible is any patient with a G12C previously treated tumor. Predominantly so far, we'll be enrolling G12C patients who have a lung cancer or a colorectal cancer, just given the predominance of those tumor types, or I think, if you look at 100 patients with solid tumor G12C mutations, 70 of them will probably be lung cancer, and the other 20 will be colorectal cancer, with the remaining 10% being the other. So that's kind of the distribution, and so just by that natural distribution, we end up enrolling predominantly colon and lung.

Mark Goldsmith (Chairman and CEO)

Yeah, so and, and so, that second line, plus given that they have to have been previously treated with, G12C inhibitor. And then your second question was what's the efficacy bar? Yeah. Well, it's a, it's a, it's a fairly subtle topic here. You know, really to compare two things and prove that they're different requires a randomized control trial with, you know, hundreds of patients. So there's not gonna be a number that's gonna come out of this that will allow us to declare, you know, victory at that level, of course.

Alec Stranahan (VP of Equity Research)

What we're looking for, though, is can we see some level of differentiation that's qualitatively informative? And, you know, what that is will emerge over time. You know, we'll see what we see, and we'll communicate it at that time. But there's not a, there's not a preset response rate, PFS or OS number that we could associate with this and ever ascribe it to this particular combination, in and of itself.

Michael Schmidt (Senior Biotech Analyst and Senior Managing Director of Equity Research)

Okay, great. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Eric Joseph from JPMorgan. Please go ahead.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Hi, thanks for taking the, the questions. I'm hoping you could just help us level set expectations into the, the phase I non-small cell lung cancer update in fourth quarter in terms of patient numbers. I, you know, just kind of drafting from the update that we saw in July in pancreatic, should we expect a similar ramp-up in the number of evaluable patients across, doses 160 mg-300 mg? And then, just as a follow-up, in pancreatic cancer, Mark, I guess how should we be thinking about sort of, additional updates, either kind of within the data set that you presented in July, perhaps at medical meetings or, so sort of, follow-on, updates, as, that trial, matures? Thank you.

Mark Goldsmith (Chairman and CEO)

Yeah. Thanks, Eric. Nice to talk with you. On the second question of PDAC, I think we've made a pretty clear commitment to providing an update to those data when we have a meaningful update. But we've not been able to share a specific timeline or setting in which that will happen. So I don't think we have anything to add to that today. With regard to the lung cancer data, you know, it's hard really to go into that level of forecasting what we'll communicate. You know, I think generally speaking, we're gonna be in the ballpark of the kinds of numbers that we've enrolled previously for pancreatic cancer, but the analysis will just have to speak for itself, you know, at the time.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Okay, thanks. Maybe just one follow-up in lung cancer, if I could, just picking up on a prior question, about the phase III strategy. It sounds sort of like one option that you're contemplating is an integrated trial where G12C patients can go on to either a G12C or can be compared to a G12C inhibitor or a taxane. I just wonder operationally, is there sort of a scenario where you conduct two phase III trials, one in sort of G12X minus C, and then another in G12, another that's focused in G12C patients? Thank you.

Mark Goldsmith (Chairman and CEO)

Well, yeah, there are a lot of possible scenarios. I don't think I can give any hints today about what the scenario is that we'll pursue. I think that's, that's, that's just done at the time that we share the data and describe it. I think that Wade's comment earlier was more one of concept, that that's an FDA question. Ultimately, that's an FDA question. What will they treat as the standard of care?

Alec Stranahan (VP of Equity Research)

And would Krazati, if it's approved, be declared as the standard of care for G12C patients, or just one of several treatments that are, that are acceptable, in which case, docetaxel still would be a good comparer. You know, that's, that's a topic, you know, really, really, for discussion with the FDA. It's not so much that we're considering A, B, or C, but just as a concept, that's how one would have to think about it. And also, I think the other factor that would go into that is the timing, as to, you know, if Krazati gets approved, when does it get approved relative to the, to that study.

Eric Joseph (VP and Branch Manager of Chase Private Client Branch)

Okay, got it. Appreciate the color, and thanks for taking the questions.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Jonathan Chang from Leerink Partners. Please go ahead.

Jonathan Chang (Senior Managing Director of Emerging Oncology)

Hi, guys. Thanks for taking the question. Given that there are multiple data updates now expected in 4Q, how should we be thinking about the cadence and venue of these disclosures? Will it happen sequentially? Do you have an order in mind, or could these be bundled together in a combined way? Thank you.

Mark Goldsmith (Chairman and CEO)

Yeah, thanks, Jonathan. The answer to your question is yes. So you gave a list of possibilities, and that is the list of possibilities. I think we won't be able to provide more clarity. We're glad that we can give you at least narrow it down to a quarter. That's a step forward, but beyond that, I think we'll save the format for for the right moment.

Jonathan Chang (Senior Managing Director of Emerging Oncology)

Understood. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Chris Shibutani from Goldman Sachs. Please go ahead.

Chris Shibutani (Senior Analyst and Managing Director of Biotechnology Equity Research)

Oh, thank you very much. I know that, Mark, you and the team had a discussion of the data, but perhaps if you could, just for the purposes of this audience at this point, for the second line, PDAC readout, thinking about dropouts and censoring, is the level of censoring in an expected range? Is there something that might have accounted in some idiosyncratic way, potentially, investigational site or trial or any aspect or treatment of the patients? And then how should we think about this as possibly being relevant at all as we think about the larger phase III multi-institutional trial? Thanks.

Mark Goldsmith (Chairman and CEO)

Yeah, thanks, Chris. Nice to talk to you. Thanks for the question. Yeah, there was some censoring that went on in both the PFS and OS analyses, and maybe Wei can address both of your questions. What type of censoring was it? Was it unusual? Did it indicate anything? And, how does it affect our view of how to translate that information to this setting, you know?

Wei Lin (CMO)

There were nothing unusual about the censoring. The censoring were just standard censoring due to the fact that some patients were enrolled later than other patients, and at the time of the data cutoff, they had not had a progression event. So that's the reason for the censoring that you saw for the patients that occurred throughout both the Kaplan-Meier for the PFS, the OS. As we follow through and have later data cutoff with more maturity to the data, many of those censoring will move out, and hopefully even beyond the median PFS as estimated. Furthermore, if they have a PFS event then obviously that censoring will be removed.

Alec Stranahan (VP of Equity Research)

In terms of translation to the ultimate registrational trial, in an early line study, we can observe the data in real time, and we can cut the data continuously, and so you do see an early data cut, which we presented with some censoring due to the maturity or lack thereof of the data. In a setting of a registration trial, this would not no longer be an issue because there'll be a pre-specified number of PFS and OS events that we define that would actually be used to date, at which time we read out the study.

And so we would not be looking the data in real time, and we'll be not presenting data in an immature state as we have in this case. So we were not expecting these.At that time, the PFS and OS, when we do read out, will be a fairly stable representation of the final analysis. So I don't think there's any sort of lack of translatability just because we're looking at the data sort of at an earlier immature data cut, if that's where the questions are. Yeah.

Mark Goldsmith (Chairman and CEO)

Thanks, Wei. And if I could just add one point to the first part of the question, which is those patients who were censored because they had started on the trial more recently. We did look at those patients, at their profiles, to determine whether they showed any different characteristics than patients who had been enrolled earlier. We also spoke with investigators, asked them about those patients, and the general consensus was, they're not different patients, they're just patients who enrolled later into those cohorts and forced to be censored at a certain point in time.

Chris Shibutani (Senior Analyst and Managing Director of Biotechnology Equity Research)

Thank you. That's reassuring clarification. Appreciate it.

Operator (participant)

Thank you. One moment for our next questions. Our next question comes from Eliana Merle from UBS. Please go ahead.

Elliott Bosco (Associate Director of Equity Research and US Biotech)

Hi, this is Elliott Bosco on for Ellie Merle, UBS. First one, what's your view on what would be a competitive PFS data for the upcoming 6236 non-small cell lung cancer update? In particular, could you clarify what would be competitive when thinking about both KRAS and non-KRAS targeted therapies?

Mark Goldsmith (Chairman and CEO)

Yeah, Elliott, thanks for your question. I mean, it's pretty straightforward. We think that the first thing we have to do is make sure that we clear the standard of care bar. And I know you're asking more than that, which is by how much does it have to be cleared? It's a little bit difficult for us to give you an answer to that while we're in the midst of gathering and analyzing data. It's very hard to separate then our view of those data from that.

Alec Stranahan (VP of Equity Research)

We, of course, have target product profiles that are internal and proprietary, but nonetheless, for a conversation like this, I think it's really a tricky question at this stage. So the best thing to do is to wait and see. We do have experience, of course, with RAS inhibitors as to what they previously considered sufficient, and investors have had opinions about that, and everybody's had an opinion about it. And we'll present ours in the context of the data that we have and with everybody through the dogfight, if needed.

Elliott Bosco (Associate Director of Equity Research and US Biotech)

Okay, and then just one more. For the ongoing 6236 monotherapy and combo studies in colorectal cancer, could you provide a sense of when we might see data? Is that likely to be a 2025 event?

Mark Goldsmith (Chairman and CEO)

Yeah, we haven't provided any guidance on timing for that, so I'll attempt to just do it off the cuff here. I think the one concept that I think Steve has communicated a number of times, and Wei has as well, is that we consider colorectal cancer to be primarily a combination strategy play. That's been the history of essentially forever, and it will be as well. So that does, you know, that's more the horizon to be thinking about. Not to say we may not present some monotherapy data, but we do, we do believe that fundamentally, the biology of colorectal cancer requires.

Elliott Bosco (Associate Director of Equity Research and US Biotech)

Okay, thanks for taking the question.

Mark Goldsmith (Chairman and CEO)

Sure.

Operator (participant)

Thank you. One moment before our next question. Our next question comes from Alec Stranahan from Bank of America. Please go ahead.

Alec Stranahan (VP of Equity Research)

Hey, guys. Thanks for taking our questions. First one from us, just on the nested trial design in RASolute 302, any signals you'd highlight from either your phase I or preclinical work for the activity of 6236, specifically in the G12X, the G13X, the G61X, and especially the RAS wild-type patients? Would you view these as maybe higher hanging fruit from a mechanistic perspective? I know you saw some preclinical activity in the RAS wild-type in your Nature paper earlier this year.

Mark Goldsmith (Chairman and CEO)

Yeah, maybe Steve wants to comment about the non-G12X versus G12X and how we think about that in the nesting.

Steve Kelsey (President of R&D)

Yeah. Well, how we think about it in the nesting is that the proposal is that if it isn't G12, it isn't in the inner core, as we describe it. Whether that is based on firm data or whether it is based on more of a conceptual approach to the whole disease and the concept of RAS driving, RAS driving the disease, I think is something that we don't really know yet.

Alec Stranahan (VP of Equity Research)

I mean, the assessment of any of our compounds, including RMC-6236 in RAS mutations outside of the G12 mutations, was a somewhat later event, and therefore, the emergence of data in those mutations is going to be somewhat behind the main body of data on which we base our decision making. And so we're a little less confident there. I think it's more about confidence than it is about science and medicine, and no doubt that will evolve in due course. So, I'd love to be able to give you a proper scientific answer to the question, but at the moment, we are unable to do that.

Mark Goldsmith (Chairman and CEO)

Yeah. And I would just add to that, that in the data we presented, we did show the overall RAS mutated group, and the PFS value for that was 7.6 months. So, if there are differences that we haven't yet developed clarity around, they don't seem to compromise, you know, looking at the whole group. You know, and also keeping in mind that 85% of pancreatic cancer is attributable to a G12 RAS G12X mutation. So the majority of the disease that we're trying to treat here is still in the core population, but we'd like to offer something more broadly than that if it's just about.

Alec Stranahan (VP of Equity Research)

Got it. That makes sense. And then one more, if I may. Obviously, launching and supporting your ongoing and planned studies is a top priority, but in terms of capital allocation, next 12 months or so, how do you plan to move forward with the earlier wave two pipeline in order to realize the ultimate potential of the RAS(ON) approach? Thanks.

Mark Goldsmith (Chairman and CEO)

So we thanks for that question. I mean, we define wave one RAS(ON) inhibitors as being the 6236, 6291, and 9805. And then we have lots of other inhibitors behind that. We haven't formally called them wave two, but I think that would be a natural progression. And we have not declared any sort of public guidance about what, where, when, and how. There's so much to chew on with the first three assets, both as monotherapy, combinations, multiple lines of therapy, multiple tumor types, that that's enough, that's a lot of story for people to digest. And we've allocated capital largely accordingly.

Alec Stranahan (VP of Equity Research)

Not that there is no money spent on other things, but really the drivers of our spending are just what we've identified as the wave one assets. And within that, most of that is actually RMC-6236. So all I can say is stay tuned. This is a company with an incredibly productive drug discovery organization that sort of delivers effectively more high quality, interesting assets than any organization could move forward in parallel. We've done some prioritizing, but we keep a very close eye on that productive early pipeline creation, and we'll move things forward as they make sense.

And by the way, we also want to understand how those first three assets performing in order to understand where the gaps are. That's not something that's just a matter of defining it preclinically, but we want to see in the clinic where the gaps are, or what sorts of combinations like best to use, what next generation compounds make sense, and how to develop them. Stay tuned. We'll all be learning as we go.

Appreciate the color. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Peter Lawson from Barclays. Please go ahead.

Speaker 17

Hi, good afternoon. This is, Alex on for Peter. Thanks for taking our questions. Just had one on the, on the combination data with pembro in lung cancer in the second half for, 6236. So I understand that, you know, safety data, for the combination is gonna help you inform your, your strategy in the first-line, metastatic setting. I'm wondering if that data would also enable, potential studies in earlier lines of therapy in lung cancer, like, the adjuvant setting, for example, and if that's something that's also of interest for, RevMed. Thank you.

Mark Goldsmith (Chairman and CEO)

.Yeah, thanks a lot, Alex. I think Dr. Lin can answer that question.

Wei Lin (CMO)

Yeah, I think absolutely, we have thought about this, and I think you're absolutely correct. I think the current regimen of pembro plus chemotherapy is used both in the first line as well as the outpatient curative setting. So by establishing the safety and efficacy of that combination in the first line setting, that would also enable us to move into earlier settings. So that is something very much on my mind.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Kelly Shi from Jefferies. Please go ahead.

Kelly Shi (VP and Senior Equity Analyst in Biotechnology)

Thank you for taking my questions. So for the G12D data in fourth quarter, what tumor types would be included in this first data disclosure? And also for the 6236 pembro combo in lung, for the data disclosure, do we expect only second line class settings? Thank you.

Mark Goldsmith (Chairman and CEO)

I didn't quite understand the first question. I can, did somebody catch exactly what was being asked about, the 9805?

Wei Lin (CMO)

Tumor types, 9805.

Mark Goldsmith (Chairman and CEO)

Ah, tumor types. I'm sorry, I just didn't hear that word. Yeah, I mean, it's a solid, it's a G12D solid tumors study, so it will have a mix of G12D solid tumors. G12D is most common in gastrointestinal tumors, although it does appear in lung cancer and others, but less frequently. And so I, to my knowledge, the representation in the study is sort of the representation in the world. And those tumors are nasty tumors no matter what type they are, so they're going to show up for targeted therapy as it's available. So I think it'll be a mix.And then the second question about RMC-6236 in non-small cell lung cancer was whether those patients are all previously treated or not, or are they second line and later, or are there first line patients as well?

Wei Lin (CMO)

Yeah, so the trial design says that, in the initial dose escalation, we enroll previously treated in expansion, then once we establish a safe and tolerable dose, after dose escalation, expanding to the first line.

Kelly Shi (VP and Senior Equity Analyst in Biotechnology)

Thank you.

Operator (participant)

Thank you. One moment before our next question. Our next question comes from Jay Olson from Oppenheimer. Please go ahead.

Jay Olson (Biotechnology Equity Research Analyst)

Well, hey, congrats on all the progress, and shout out to Ryan Asay. It's great to reconnect. We were curious about any long-term plans for combination studies and specifically accommodation of your molecules with ADCs, and then I had a follow-up question.

Mark Goldsmith (Chairman and CEO)

Yeah, there's. I mean, there are a lot of possibilities. It's almost infinite. And if we're successful in establishing RMC-6236 as a backbone targeted therapy, we would imagine a lot of things will be combined. Both things that we prioritize, things that investigators prioritize, and things that, who knows who else, ultimately, you know, decides to study, things that are done outside of the context of the company. We have no plans as of today relating to ADCs. And, you know, I think we'll wanna keep watching the ADC space and to see which compounds emerge, as potentially being complementary and having tolerability profiles that justify wanting to combine RMC-6236 with it. So we're open to it. We're interested, no plans to disclose today.

Jay Olson (Biotechnology Equity Research Analyst)

Great, thank you. And then, as a follow-up, for your internal combinations, are you planning to formulate any fixed dose, fixed dose combinations?

Mark Goldsmith (Chairman and CEO)

You know, that's possible at some point. You know, there are a lot of combinations that we're talking about. We really have to establish, you know, the doses first before you create those combinations. You have to allow for step downs, for dose modifications, which creates a little bit of complexity in the fixed dose realm. We also have some compounds that are, QD, some compounds that are BID, so those aren't exactly amenable to fixed dose combinations. So I don't know that that's going to be a major part of our commercial, you know, strategy, but, our team certainly has it on their radar and will move when it makes sense to do something like that, when it really is going to add convenience and not just add complexity.

Jay Olson (Biotechnology Equity Research Analyst)

Great. Thanks for taking the questions.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Laura Prendergast, from Raymond James. Please go ahead.

Laura Prendergast (Biotech Equity Research)

Hey, guys, congrats on the progress. I was curious, you know, some KOLs did note that, you know, the deepening of response over time seen with the PDAC patients was, you know, interesting to them, and, you know, I actually referred to that as a phenomenon. Do you think this could be due to the unique mechanism of action of the drug? And, do you think it's gonna translate to other indications or other RAS inhibitors? Any color there would be helpful.

Steve Kelsey (President of R&D)

Thank you, Laura. That's, that's an interesting question. Who wants to take that question? The observation that the response is deepened over time is much more evident in pancreatic cancer than it appears to be in non-small cell lung cancer, which are the two diseases with which we have the most experience right now with RMC-6236. And so, having said that, it's clearly more obvious with RMC-6236 than it is with chemotherapy. So I think it may be a combination of both the mechanism of action of the drug, which could include a multitude of different effects on both the tumor cells themselves and the immune microenvironment, and possibly also the particular biology and histology of pancreatic cancer, which traditionally is a very large mixture or a pleiotropic mixture of different cell types.

Alec Stranahan (VP of Equity Research)

Sometimes, which the dominant one is the epithelial tumor cell itself, and sometimes it isn't. It's a minority component of a mishmash of immune cells and fibrotic cells and a whole lot of other things. So you can imagine that, if your tumor is a very mixed histology and there's a lot of things going on, it may take quite some time for that remodeling to occur, such that when you look at it with a very crude imaging modality like CT scanning, which, let's face it, has been around for about 50 years, then it could take some time for the observations that we apply to that to take effect.

Superimposed on top of that, of course, is the dichotomization of responses as lack of response. You know, a patient can go from 0% tumor reduction to 31% tumor reduction, and they're called a response. If they go from 29% tumor reduction to 29.5% tumor reduction, they're not a response. And so the deepening of responses over time is really, in our dataset, has only been applied to the dichotomous conversion of patients from non-lack of response to response, and from a response to a response with a higher percentage of tumor reduction.

But in fact, this is happening in a linear continuum in all patients, irrespective of whether they qualify for RECIST response or not. So the answer is we don't know, but I suspect it's a 50/50 mixture of the biology of pancreatic cancer and the action, mechanism of action of the drug, and it isn't quite as obvious in lung cancer, which makes me say that.

Laura Prendergast (Biotech Equity Research)

That's really helpful. Thanks for the color.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Joe Catanzaro from Piper Sandler. Please go ahead.

Joe Catanzaro (Director and Senior Biotech Equity Analyst)

Hey, thanks for taking my question. I had a quick one here on 6236 and combinability with pembrolizumab, and maybe even with other combination approaches you're looking at, and it primarily as relates to 6236-mediated rash. When you look at historical datasets for other MAP kinase pathway inhibitors that also see rash, is there anything there that informs how the addition of pembrolizumab and/or chemotherapy could impact or not, the rate and severity of rash when you start combining? Thanks.

Steve Kelsey (President of R&D)

Yeah, I'm seeing shaking heads here. I don't think that we think there is much of a connection there. You know, the effect on RAS, the mechanism of RAS is probably due to direct effects on, you know, the epidermal cells. That has to do with inhibiting RAS. I don't know that it has anything to do with the chemotherapy, but Wei, do you want to comment on that?

Wei Lin (CMO)

Yeah. The immune-mediated type of rash are slightly different than the type of rash that we observe more commonly. Ours is more predominantly acneiform, and then fully responsive to antibiotic treatment. So, that's quite different than the maculopapular that are more commonly here. It's always a mix, but I'm talking about what's actually more predominant. And, I think the whether you talk about BRAF inhibitor, MEK inhibitor, EGFR inhibitor, or RAS inhibitors, acne don't tend to be the dominant form. So that, when we combine the two, it may be true to related. You're probably gonna see each creating its own type of rash, but past experience do not indicate combining the two mutually enhance their respective rash.

Joe Catanzaro (Director and Senior Biotech Equity Analyst)

Okay, thanks. That's, that's helpful. Thanks for taking the question.

Operator (participant)

Thank you. I am showing no further questions at this time. I will now turn it over to Mark Goldsmith for closing remarks.

Mark Goldsmith (Chairman and CEO)

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

Operator (participant)

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.