Revolution Medicines, Inc. Q2 FY2024 Earnings Call

Good day and thank you for standing by. Welcome to Revolution Medicine's Q2 2024 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. 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.

Thank you, and welcome, everyone, to the second quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's 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. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly reports 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 Investors section of our website at revmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and CEO. Mark?

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. We disclosed recent data from the RMC6236-001 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 Investors section of our website at revmed.com. The data with a May 11, 2024 cutoff date reflects patients with previously treated pancreatic cancer across the RMC-6236 160-milligram to 300-milligram 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 in 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 milligrams 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 Revolution Medicines. 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, our 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 prelaunch 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 Revolution Medicines' 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 Revolution Medicines. 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?

Thank you, Mark. We ended 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. 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 15, 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 noncash 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.

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, advising shareholders, and the tireless efforts of Revolution Medicines 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.

Our first question comes from Marc Frahm from TD Cowen. Please go ahead.

Hey thanks for taking my questions. Maybe just to start off, when you think about the PFS data you released in pancreatic cancer the other day, it looks a little bit better than what was achieved with the G12C inhibitors in that subpopulation of pancreatic patients. Do you think that similar gap should be expected when we look at monotherapy data in other settings where we 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?

Thanks, Marc. I appreciate your question. I think at this point, given that data will be rolling out in coming months and over the next year, I think it's best just to let the data speak for themselves. There are obviously 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.

Okay. That's helpful. Regarding the first line in pancreatic cancer, how much more data do you need to collect to formulate a plan, rather than just expressing the intention to pursue it? For instance, will you require a significant amount of combination data with chemotherapy or the G12D inhibitor to determine the design for moving to the first line?

Yes. I mean I think we said before, and I know you and I talked about that, the monotherapy RMC-6236 already qualifies to be included in such a trial. And 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? And 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. Chemotherapy is typically replete with side effects. And so when you combine these two, we need to have confidence that the combination will not pose significant risks for patients. That’s really what we're doing is trying to figure that out.

Thanks a lot.

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

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 one-to-one 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 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 feasible, in your opinion?

Thanks, Michael. Maybe I'll just say something brief about it. If either Steve or Wei wants to add something, they can do that. My general comment is G12C is clearly the most complicated part of the lung cancer trial for RMC-6236. 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 prototype last October, but we've not laid that out in our expectations to do that in conjunction with the 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 Steve or Wei wants to add to that, feel free to.

I think the only thing I want to add is I think there will end up being a consideration from the FDA, if they were to approve KRAZATI, do they need a 1.6-month PFS improvement if perhaps 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 dosage has also to be acceptable. So that would be something we need to consider.

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

Okay. So the first question is the eligibility for the trial. Maybe Wei can answer that and then maybe I can comment on the second part of the question. Combination of 6236 plus 6291, what types of patients and tumors are being accounted?

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

And so that second line plus, given that they have to have been previously treated with a G12C inhibitor. And then your second question was what's the efficacy bar?

Yes.

Well, it's a fairly subtle topic here. Really, to compare two things and prove that they are different requires a randomized controlled trial with hundreds of patients. So there's not going to be a number that's going to come out of this that will allow us to declare victory at that level, of course. What we're looking for though is can we see some level of differentiation as qualitatively informative. And what that is will emerge over time. We'll see what we see, and we'll communicate it at that time. But there's not a preset response rate, PFS, or OS number that we can associate with it and ever ascribe it to this particular combination in and of itself.

Okay, great. Thank you.

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

Hi, thanks for taking the questions. I'm hoping you could just help us level set expectations into the Phase I non-small cell lung cancer update in the fourth quarter in terms of patient numbers. 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 to 300 milligrams? And then, just as a follow-up in pancreatic cancer, Mark, how should we be thinking about additional updates, either within the data set that you presented in July, perhaps at medical meetings or sort of follow-on updates as that trial matures? Thank you.

Yes. Thanks, Eric. Nice to talk with you. On the second question of PDAC, I think we've made a pretty clear commitment to provide 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 new to add to that today. With regard to the lung cancer data, it's hard really to go into that level of forecasting what we'll communicate. I think generally speaking, we're going to be in the ballpark with the kinds of numbers that we've enrolled previously for pancreatic cancer, but the analysis will just have to speak for itself at the time.

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 a scenario where you conduct two Phase III trials, one in sort of G12X minus C and then another that's focused in G12C patients? Thank you.

There are many potential scenarios to consider. I can't provide specifics today about which scenario we'll follow, but we will move forward. This will be clearer when we share the data and explain it. Wei's earlier comment was more of a conceptual point related to the FDA's role in determining what will be considered the standard of care. The question is whether KRAZATI, if approved, would be recognized as the standard-of-care for G12C patients, or if we would have a range of acceptable treatments, in which case docetaxel would remain a good comparator. This is definitely a discussion we need to have with the FDA. It's not really a matter of choosing between options A, B, or C; rather, it's a conceptual framework to consider. Additionally, the timing of KRAZATI's approval in relation to that study will also be an important factor.

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

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

Hi, guys, thanks for taking the questions. Given that there are multiple data updates now expected in Q4, 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.

Yes. Thanks, Jonathan. The answer to your question is yes. So you get 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 at least narrow it down to a quarter. That's a step forward. But beyond that, we'll save the format for the right moment.

Understood. Thank you.

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

Hi, 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 in censorship, just the level of censorship in an expected range, is there something that might have accounted in some idiosyncratic way potentially investigation 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.

Yes. Thanks, Chris. Thanks for the question. Yes, 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 to indicate anything? And does it affect our view of how to translate that information to Phase III?

There was nothing unusual about the censoring. The censoring was standard due to the fact that some patients will enroll later than other patients. At the time of the data cutoff, they have not had a progression event. And so that's the reason for the censoring that you saw for the patients that occurred throughout both the Kaplan-Meier curve for the PFS and the OS. As we follow through and have later data cuts with more maturity to the data, many of the censoring will move out, and hopefully even beyond the median PFS as an estimate. Furthermore, if they happen to have a PFS event, then obviously that censoring will be removed. In terms of translation to the ultimate registrational trial, in an early line study, we can observe the data in real time and can cut the data continuously, 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 registrational trial, this will no longer be an issue because there will be a prespecified number of PFS and OS events that we define that would actually be used to date, at which time we read out the study. Therefore, we will not be looking at the data in real time, and we won't be presenting data in an immature state as we have in this case. So we were not expecting these. Therefore, 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 that's not fully matured.

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. The general consensus was they're not different patients. They're just patients who enrolled later into dose cohorts and hence forced to be censored at a certain point in time.

That's reassuring clarification. Appreciate it.

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

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?

Yes, 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 in our view of those data from that. We, of course, have target product profiles that are internal and proprietary, but nevertheless 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've previously considered sufficient, and investors have had opinions about that, and everybody is having an opinion about it, and we'll present ours in the context of the data that we have and let everybody to the dogfight if needed.

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?

Yes. We haven't offered any guidance on timing for that yet. We'll approach it on an ad-hoc basis. One key point that Steve and Wei have mentioned several times is that we view colorectal cancer primarily as a combination strategy play. This has historically been the case and will continue to be so. Therefore, that's more the timeframe to keep in mind, although we may still present some monotherapy data. However, we strongly believe that the biology of colorectal cancer necessitates a combination approach.

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 G13S, 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.

Yes. Maybe Steve wants to comment on the non-G12X versus G12X. And I would speak about the data nesting.

Yes, well, as we think about it in the nesting is that the proposal is that if it isn't G12, it isn't an immuno-cohort, 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 the disease, I think is something that we don't really know yet. 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. 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 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 just don't have the full clarity.

Yes. 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 looking at the whole group. And also keep 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 one.

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 in the next 12 months or so, how do you plan to move forward with the earlier Wave 2 pipeline in order to realize the ultimate potential of the RAS(ON) approach? Thanks.

So we define Wave 1 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 2, but I think that would be a natural progression. 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's enough. That's a lot of a story for people to digest, and we've allocated capital largely accordingly, 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 1 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 continues to deliver 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 earlier 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 perform in order to understand where the gaps are. And that's not something that's just a matter of designing it preclinically, but we want to see in the clinic where the gaps are or what sorts of combinations are best used, what next-generation compounds make sense and how to develop that. So stay tuned. We'll all be learning as we go.

Appreciate the color. Thank you.

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

This is Alex on for Peter. Thanks for taking our questions. I just had one on the combination data with pembrolizumab in lung cancer in the second half for 6236. So I understand that safety data for the combination is going to help you inform 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 Revolution Medicines. Thank you.

Yes. Thanks a lot, Alex. I think Dr. Lin can answer that question.

Yes. I think absolutely, we have thought about this, and I think you're absolutely correct. I think the current regimen of pembrolizumab plus chemotherapy is used both in the first line as well as the adjuvant setting. So by starting with safety and clinic activity 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 the line.

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

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

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

Tumor types with 9805.

Yes, it's a G12D solid tumor study, which will include a variety of G12D solid tumors. G12D is most commonly found in gastrointestinal tumors, though it also appears in lung cancer and other types, albeit less frequently. To my knowledge, the representation in the study reflects its presence globally. These tumors are aggressive regardless of their type, so they will likely respond to targeted therapy given its availability. Therefore, I expect a mix. Regarding your second question about 6236 in non-small cell cancer, are all the patients in the study previously treated, or are there second-line and later patients, or are there also first-line patients included?

Yes. The trial design includes an initial dose escalation where we enroll previously treated patients and expand from there. Once we determine the safe and tolerable dose after this escalation, we will move on to later lines of treatment.

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

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 the combination of your molecules with ADCs. And then I had a follow-up question.

Yes, there are many possibilities, nearly limitless. If we successfully establish RMC-6236 as a foundational targeted therapy, we expect numerous combinations to emerge, including those we prioritize, those that investigators prefer, and others developed externally. Currently, we have no announced plans related to ADCs. We intend to continue monitoring the ADC landscape to identify which compounds may complement ours and have appropriate tolerability profiles that would warrant combining them with 6236. While we remain open and interested in this area, we do not have any plans to share at this time.

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

That's possible at some point. There are a lot of combinations that we're talking about. We really have to establish 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, sometimes that are BID. So those aren't exactly amenable to a fixed-dose combination. So I don't know that that's going to be a major part of our commercial 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.

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

Hey congrats on the progress. I was curious, some KOLs did note that the deepening of response over time seen with the PDAC patients was interesting to them. And 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 going to translate to other indications or other RAS inhibitors? Any color there would be helpful.

Thank you, Laura. That's an interesting question. Who wants to take that question?

The observation that the responses deepen 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. 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 of different cell types, 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 as 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. Moreover, responses can be a bit complex: a patient can go from no tumor reduction to significant tumor reduction and they are considered responders. If they go from a small reduction to a slightly larger reduction, they might not be counted as a response. Therefore, the deepening of responses over time is really, in our data set, has only been observed in the transition of patients from non-response to response and from a response to a deeper response, which can happen in all patients irrespective of whether they respond to RAS 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 mechanism of action of the drug, and it isn't quite as obvious in lung cancer.

Thank you. And just to add to it, the responses we see deepening could potentially offer some hope for translation into other avenues. However, the biology we're dealing with may not present an exact fit across different tumor types. Overall, more research is needed to clarify this.

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

Hey thanks for taking my question. I had a quick one here on 6236 and its combinability with pembrolizumab. And maybe even with other combination approaches you're looking at, primarily as it relates to 6236 mediated rash. When you look at historical data sets 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 the rate and severity of rash when you start combining?

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

Yes. I think the immune-mediated type of rash is slightly different than the type of rash that we even observe more commonly. Ours is more predominantly acne form and fully responsive to antibiotic treatment. So that's quite different than the other synergistic rashes that are more common. It's always a mix when trying to find out what's actually more predominant, and I think whether we're talking about BRAC inhibitor, MAP inhibitor, et cetera. So when we combine the two, it's possible we may observe some distinct rashes, but past experience did not indicate combining the two would mutually enhance their respective rash.

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

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

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

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