Revolution Medicines Q2 2024 Earnings Call Transcript

Quartr
Provided by Quartr
August 7, 2024

There are 16 speakers on the call.

Operator

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 speakers' presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 11 on your telephone.

Operator

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 Asey, Senior Vice President of Corporate Affairs. Please go ahead.

Speaker 1

Thank you, and welcome everyone to Q2 2024 earnings call. Joining me on today's call are Doctor. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer and Jack Anders, our Chief Financial Officer Doctor. Steve Kelsey, our President of R and D and Doctor. Wei Lin, our Chief Medical will join us for the Q and A portion of today's call.

Speaker 1

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 ks and our quarterly report on Form 10 Q that are filed with the U. S. Securities and Exchange Commission.

Speaker 1

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 atrevmed.com. With that, I'll turn the call over to Doctor. Mark Goldsmith, Revolution Medicine's Chairman and CEO. Mark?

Speaker 2

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.

Speaker 2

We have made meaningful progress with our pioneering RAS ON inhibitor pipeline, notably preparing RMC6236, our RAS ON multi selective inhibitor to move into its 1st 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 RMC6236. 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 RMC6236 monotherapy. These data have increased our confidence in the promise of this program and reinforce our commitment to initiate our 1st 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.

Speaker 2

The full detail of these results can be found on the Investors section of our website at revnet.com. The data with a May 11, 2024 cut off date reflects patients with previously treated pancreatic cancer across the RMC6236 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 events.

Speaker 2

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 3 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.

Speaker 2

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-six thousand two hundred and thirty six 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 3 study.

Speaker 2

Additional metrics in more detail regarding these data can be found on our website. Given the strength of 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 1st global registrational Phase III study this year. This Phase III study called RASOLUT-three zero two will evaluate RMC6236 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 RMC6236 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 RMC6236 monotherapy study continue to mature.

Speaker 2

In the Q4, we expect to provide updated safety and antitumor activity, including durability data and to initiate a second registrational study evaluating RMC6236 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-six thousand two hundred and thirty six into earlier lines of therapy, including first line metastatic, locally advanced unresectable and resectable disease. Exploratory studies evaluating RMC6236 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 RMC6236 with pembrolizumab with or without chemotherapy in patients with advanced RAS mutated non small cell lung cancer.

Speaker 2

We expect to report initial data for this combination in the Q4 of 2024. While there is substantial focus and investment in RMC6236 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, RMC6291, our G12C selective inhibitor and RMC9805, our G12D selective inhibitor for late stage development. First, we continue to make progress in our combination studies with the goal of moving RMC-six thousand two hundred and ninety one into early lines of therapy for patients with RAS G12C tumors. The RAS on inhibitor doublet of RMC6,291 in combination with RMC6,236 in thousand two hundred and thirty six 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 Q4 of this year.

Speaker 2

Another combination approach with KRAS G12C non small cell lung cancer is RMC6291 with pembrolizumab with or without chemotherapy. A study of this combination is ongoing and we anticipate disclosing initial data for RMC-six thousand two hundred and ninety one with Pembrolizumab in the first half of twenty twenty five. 2nd, the first in human monotherapy study of RMC-nine thousand eight hundred and five, 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 Q4. Overall, we have a busy and exciting road ahead with the anticipated initiation of 2 RMC6236 monotherapy registrational studies, a number of important exploratory combination study data updates and additional data maturation that may validate the potential to advance 2 clinical stage RAS on mutant selective inhibitors into late stage development.

Speaker 2

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.

Speaker 2

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 2 individuals who have joined RevMed's senior leadership team. First, Ryan Aasi, 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. 2nd, Doctor. Mary Pindershank has joined the organization as our Senior Vice President and Head of Medical Affairs.

Speaker 2

In addition to being a well respected board certified medical oncologist, Doctor. Pindershank 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.

Speaker 2

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 Andrews, our Chief Financial Officer, to provide a financial update. Jack?

Speaker 3

Thank you, Mark. We ended the Q2 of 2024 with $1,590,000,000 in cash and investments. This compares to $1,700,000,000

Speaker 4

at the

Speaker 3

end of Q1. The decrease in cash and investments during the Q2 was primarily due to net loss for the quarter. Turning to expenses, R and D expenses for the Q2 of 2024 were $134,900,000 compared to $98,000,000 for the Q2 of 2023. The increase in R and D expenses was primarily due to increases in clinical trial expenses for our 1st wave of RASON inhibitors, preclinical portfolio expenses, personnel related expenses associated with additional headcount and stock based compensation expense. G and A expenses for the Q2 of 2024 were $21,700,000 compared to $14,600,000 for the Q2 of 2023.

Speaker 3

The increase in G and 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 Q2 of 2024 was $133,200,000 compared to $98,300,000 for the Q2 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 $560,000,000 $600,000,000 which includes estimated non cash stock based compensation expense of between $70,000,000 $80,000,000 That concludes the financial update. I'll now turn the call back over to Mark.

Speaker 2

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-six thousand two hundred and thirty six 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 RedMed employees on behalf of patients.

Speaker 2

This concludes our prepared remarks for today. And I'll now turn the call over to the operator for the Q and A session.

Operator

Thank you. At this time, we will conduct a question and answer to ask a question during this session, you will need to press star 11 on your telephone and wait for your name to be announced. Our first question comes from Mark Fromm from TD Cowen. Please go ahead.

Speaker 5

Yes. Thanks for taking my questions. Maybe just to start off, when you think about the PFS80 you released in pancreatic cancer the other day, It looks a little bit better than the what was achieved kind of the G12C inhibitors in that subpopulation of pancreatic patients. Do you think that similar gap should kind

Speaker 6

of be expected when we

Speaker 5

look at monotherapy data in other settings where we 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 just way too different across tumors?

Speaker 2

Thanks, Mark. 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'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.

Speaker 5

Okay. Thanks. That's helpful. And then if you maybe thinking about first line in pancreatic cancer, just how much more data do you need to gather to kind of know what the plan is there, rather than just saying 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 design looks like to move to first line?

Speaker 2

Yes. I mean, I think we said before, and I know you and I talked about that the monotherapy RM6236, I think already qualifies to be included in such a trial. And really the question is around what 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-six thousand six hundred and thirty six clearly is a broad based inhibitor of RAS.

Speaker 2

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 we put those 2 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.

Speaker 2

There are many combinations as you point out that we couldn't pursue. I wouldn't consider RMC-nine thousand eight hundred and five specifically part of that determination for 6,236 going into frontline is its own entity and how we'll deal with that we'll describe over time as we reveal data about that interesting compound.

Speaker 7

Okay. Thanks a lot.

Operator

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

Speaker 6

Hey, thanks for taking my questions. I had one on the potential Phase 3 study in second line non small cell lung cancer for 6,236. I mean, one would think that the easiest of the simplest design would just be a 1 to 1 randomization compared to docetaxel. But I'm just curious there may be a scenario where Crevasati has full FDA approval in G12C positive patients at some point in the future and based on the CRISPR12 study. And I was just wondering to what degree that might factor into the potential trial design?

Speaker 6

Would you, for example, allow CRISPRT 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?

Speaker 2

Thanks, Michael. Good to hear from you. Maybe I'll just say something brief about it. And then if either Steve or Whitewa said something, we can do that. Maybe my general comment is G12C is clearly the most complicated part of the lung cancer trial for RMC6236.

Speaker 2

There are subtleties associated with that as you just alluded to. We've not described our plan yet for lung cancer.

Speaker 7

We put forth a sort of

Speaker 2

a prototype last October, but we've not laid that out in our expectations 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 of our skis to emit today. But whether there are any principles that Steve or Wayne wants to add to that, feel free to.

Speaker 8

I think the only thing I want to add is, I think will end up being a consideration from the FDA. If they were to prove PERSOTI to basically the 1.6 month PFS improvement, that DASK PERSATI as the standard care for G12C patients or just another standard care in addition to docetaxel and that would dictate whether PERSATI is required to be the comparator for docetaxel was to be acceptable. So that would be a regulatory view issue.

Speaker 6

Okay. Okay. Thank you. And then, yes, very curious about the combination of 6,236 with 6,291 where I think you committed to presenting data later in the Q4. And yes, just want to understand a bit better what types of patients are enrolled in your study?

Speaker 6

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 that dual combination into more registration directed studies?

Speaker 2

Okay. So the first question is one of sort of eligibility for the trial. Maybe Wei can answer that and then maybe I can comment on the second part of the question.

Speaker 8

This combination of 6,236 plus 6,291, what types

Speaker 2

of patients and tumors are being in the trial?

Speaker 8

Yes. So, if the patient that are eligible is any patient with a T12C treated tumor, predominantly so far we'll be enrolling TCLC patients who have a lung cancer or a cochlear cancer just given the predominance of those tumor types. I think if you look at 100 patients with solid tumor T12C mutations, 70 of them will probably be lung cancer and the other 20 will be colorectal cancer, remaining chambrosanct 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.

Speaker 8

And so that second line plus given that they have to

Speaker 2

have been previously treated with gtosidibular. And then your second question was what the efficacy bar? Yes. Well, it's a fairly subtle topic here. Really to compare 2 things and prove that they're different requires a randomized controlled trial with hundreds of patients.

Speaker 2

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 could associate with this and ever ascribe it to this particular combination in and of itself.

Speaker 6

Okay, great. Thank you.

Operator

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

Speaker 9

Hi. Thanks for taking the questions. I'm hoping you could just help us level set expectations into the Phase 1 non small cell lung cancer update in Q4 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, 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 sort of follow on updates as that trial matures?

Speaker 9

Thank you.

Speaker 2

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. And but we've not been able to share a specific timeline or setting in which that would happen.

Speaker 2

So

Speaker 8

I don't think

Speaker 2

we have anything 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

Speaker 8

in the ballpark of the

Speaker 2

kinds of numbers that we've enrolled previously for pancreatic cancer. But the analysis will just have to speak for itself at the time.

Speaker 9

Okay, thanks. Maybe just one follow-up in lung cancer, if I could. Just picking up on a prior question about the Phase 3 strategy. It sounds sort of like one option that you're contemplating as an integrated trial where G12C patients can go on to either a G12C or can be compared to a G12C inhibitor or taxane. I just wonder operationally, is there sort of a scenario where you conduct 2 Phase III trials, 1 in sort of G12X minus C and then another in G12 another that's focused in G12C patients?

Speaker 9

Thank you.

Speaker 2

Well, yes, 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 done at the time that we share the data and describe it. I think that Wade's comment earlier was more one concept that has an FDA ultimately that's an FDA question, what will they treat as the standard of care and will would CRISADE, if it's approved, be declared as the standard of care for G12C patients or just want several treatments that are acceptable, in which case docetaxel would be a good comparator. That's a topic really for discussion with the FDA.

Speaker 2

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 if Grizoni gets approved, when does it get approved relative to that study.

Speaker 9

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

Operator

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

Speaker 4

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? Do you have an order in mind or could these be bundled together in a combined way?

Speaker 5

Thank you.

Speaker 2

Yes. 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.

Speaker 2

We're glad that we can give you at least narrow it down to a quarter. That's a step forward, but beyond that, it will save the format for the right moment.

Speaker 4

Understood. Thank you.

Operator

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

Speaker 10

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 2nd line PDAC readout, thinking about dropouts and censorship, is 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 of 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 3 multi institutional trial? Thanks.

Speaker 2

Yes. Thanks, Chris. Nice to talk to you. Thanks for the question. Yes, there was some censorship that went some censoring that went on in both PFS and OS analyses and maybe Wei can address both of

Speaker 7

your questions. What type of

Speaker 2

censorship was it? Was it unusual to indicate anything? And does it how does it affect our view of how

Speaker 8

to translate that information to Phase 3? There were nothing unusual about the sensory, the sensory or the standard sensory due to the fact that some patients were enrolled later than other patients. And at the time of the data cut off, they have not had a progression event. And so that's the reason for the sensing that you saw for the patients that occurred throughout the both the cap marker for the PFS and OS. And as we follow through and have later data cut with more maturity to the data, immunosensory will move out and hopefully even beyond the median PFS estimate.

Speaker 8

And furthermore, if they have the PFS event and obviously that sensor will be removed. In terms of translation to the AUGMENT retrational trial, in a because in a early line study, we can observe the data in real time and we can cut the data continuously. And so you do see a early data cut, which we presented with some censoring due to the maturity, lack thereof of the data. In a setting of a registration trial, this will 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 at the data in real time and we'll be not presenting data in an immature state we have in this case.

Speaker 8

So we were not expecting these. And so 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 should be at a earlier immature data cutoff. So that's where the question is from.

Speaker 2

Thanks, Wayne. If I could send one point to the first part of the question, which is those patients who are censored because they have 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 have 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 enroll later into dose cohorts and hence forced to be censored at

Speaker 7

a certain point in time.

Speaker 10

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

Operator

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

Speaker 11

Hi, this is Elliot Bosco on for Eliana Merrell, UBS. First one, what's your view on what would be a competitive PFS data for the upcoming 6,236 non small cell lung cancer update? In particular, could you clarify what would be competitive when thinking about both CRAS and non CRAS targeted therapies?

Speaker 2

Yes. Elliot, 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.

Speaker 2

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. We, of course, have target product profiles that are internal and proprietary, but unless 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.

Speaker 2

And we'll present ours in the context of the data that we have and with everybody to the dogfight if needed.

Speaker 11

Okay. And then just one more for the ongoing 6,236 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?

Speaker 2

Yes. We haven't provided any guidance on timing for that. So it tends to just do it off the cuff here. I think the one concept that I think Steve has communicated a number of times and we 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.

Speaker 2

So that goes that's more of the horizon to be thinking about, not to say we may not present some monotherapy data, but we do believe that fundamentally the

Speaker 8

biology of colorectal cancer requires.

Speaker 11

Okay. Thanks for taking the question. Sure.

Operator

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

Speaker 12

Hey, guys. Thanks for taking our questions. First one from us, just on the nested trial design in RASOLUT-three zero two, any signals you'd highlight from either your Phase 1 or preclinical work for the activity of 6,236 specifically in the 16 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.

Speaker 8

Yes, maybe Steve wants to comment about

Speaker 2

the non G12X versus G12x

Speaker 8

and how we think about that in the past.

Speaker 2

Vesting? Yes.

Speaker 7

Well, how we think about it

Speaker 8

in the vesting is that the proposal is that it is in Q12, it is in the inner core, obviously, describe it.

Speaker 7

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 rats driving the disease, I think, is something that we don't really know yet. I mean, the assessment of any of our compounds, including RMC6236 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. Making. And so we're a little less confident there.

Speaker 7

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 answers to the question, but at the moment, we are unable to

Speaker 2

do that. 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 RAS G12X mutation. So the majority of the disease that we're trying to treat here is still in the core population.

Speaker 2

But we'd like to offer something more broadly than that if it's just about.

Speaker 12

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 2 pipeline in order to realize the ultimate potential of the RASM approach?

Speaker 12

Thanks.

Speaker 2

So we thanks for that question. I mean, we define wave 1 RASM 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. And we have not declared any sort of public guidance about what, where, when and how.

Speaker 2

There's so much to chew on with the first three assets, both as monotherapy, combinations, multiple lines of therapy, multiple tumor types.

Speaker 8

That's enough that's a lot

Speaker 2

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 RMC6236. 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.

Speaker 2

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 performing in order to understand where the gaps are. And that's not something that's just a matter of defining it pre clinically, but we want to see in the clinic where the gaps are, what source of combinations like best to use, what next generation compounds make sense and how to develop that. So stay tuned. We'll all be learning as we go.

Operator

Our next question comes from Peter Lawson from Barclays. Please go ahead.

Speaker 13

Hi, good afternoon. This is Alex on for Peter. Thanks for taking our questions. Just had one on the combination data with pembro in lung cancer in the second half for 6,236. So I understand that safety data for the combination is going to help you inform your strategy in the first line metastatic setting.

Speaker 13

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.

Speaker 2

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

Speaker 8

Yes. I think, absolutely, we have thought about this And I think you're absolutely correct. I think the current regimen of tango plus chemotherapy is used both in the first line as well as the actual perioperative setting. So by stopping the safety and putting activity of that combination in the first time setting, that would also enable us to move into our early access setting. So that is something very much on my mind.

Operator

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

Speaker 4

Thank you for taking my questions. So for the G12D data in Q4, what tumor types would be included in this first data this quarter? And also for the 6,236 pembro combo in lung, for the data this quarter, do we expect only second line class settings? Thank you.

Speaker 2

I didn't quite understand the first question. I didn't somebody catch exactly what was being asked about the 9805. Tumor types, I'm sorry, I just didn't hear that word. Yes, I mean, it's a solid it's a G12D solid tumors study. So it will have a mix of G12D solid tumors.

Speaker 2

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

Speaker 8

to show up for targeted therapy as it's available. So I think there'll be a mix.

Speaker 2

And then the second question about 6,236 in non small cell lung cancer was whether those patients are all previously treated or not? Are they second line and later? Or are they first line patients as well?

Speaker 8

Yes. So the trial is diagnosed that in initial dose escalation, we enrolled previously treated an expansion, then once we establish a safe and tolerable dose, after dose escalation will be spending for the 1st month.

Speaker 4

Thank you.

Speaker 8

Thank

Operator

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

Speaker 14

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

Speaker 2

Yes, there's I mean, there are a lot of possibilities. It's almost infinite. And if we're successful in establishing RMC6236 as a backbone targeted therapy, we would mention a lot of things will be combined, both things that we prioritize, things that investigators prioritize and things that who knows who else ultimately decides to study things that are done outside of the context of the company. We have no plan to disclose today relating to ADCs. And I think we'll want to keep watching the ADC space and to see which compounds emerge as potentially being complementary and having tolerability profiles that justify wanting to combine 6,236 with it.

Speaker 2

So we're open to it. We're interested in your plans to disclose that.

Speaker 14

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

Speaker 8

That's possible at some point.

Speaker 2

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, some compounds that are BID. So those aren't exactly amenable to fixed dose combinations.

Speaker 2

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 we'll move when it makes sense to do something like that when it really is going to add convenience and not just add complexity.

Speaker 14

Great. Thanks for taking the questions.

Operator

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

Speaker 15

Hey, guys. 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 refer to that as a phenomenon. Do you think this could be due to the unique mechanism of action of the drug?

Speaker 15

And do you think it's going to translate to other indications or other RAS inhibitors? Any color there would be helpful.

Speaker 2

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

Speaker 7

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 2 diseases with which we have the most experience right now with RMC6236.

Speaker 8

And

Speaker 7

so having said that, it's clearly more obvious with RMC6 236 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 the 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 a pleiotropic 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 could 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 optimizations that we apply to that to take effect. And I superimposed on top of that, of course, is the dichotomization of responses is lack of response.

Speaker 7

A patient can go from 0% tumor reduction to 31% tumor reduction in their call a response. So 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 data set has only been applied to the dichotomous conversion of patients from lack of response to response and from a response to a response with a higher percentage of gene reduction. But in fact, this is happening in the linear continuum in all patients irrespective of whether they qualify for restis response or not. So the answer is we don't know, but I suspect it's a fifty-fifty mixture of the biology of pancreatic cancer and the act mechanism action of the drug.

Speaker 7

And it isn't quite as obvious in lung cancer, which makes me say that.

Speaker 15

That's really helpful. Thanks for all the color.

Operator

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

Speaker 14

Hey, thanks for taking my question. I had a quick one here on 6,236 and combinability with pembrolizumab and maybe even with other combination approaches you're looking at and then primarily as it relates to 6,236 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 or not the rate and severity of rash when you start combining? Thanks.

Speaker 2

Yes, I'm 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, probably due to direct effects on the epidermal cells. And that has to do with inhibiting RAS. I don't know that has anything to do with chemotherapy, but Wade, do you want to comment on that?

Speaker 8

Yes. I think the immune mediated type of rash are slightly different than the type of rash that we observed more commonly. Ours is more predominantly acne form and then fully responsive to antibiotic treatment. So that's quite different than the macular pathways that are more commonly here. There's always it's always a mix, but I need to talk about what's actually more predominant and the I think whether you talk about BRAF inhibitor, MET inhibitor, HFR inhibitor or RAS inhibitors, active drug tend to be the dominant form.

Speaker 8

So that when we combine the 2, it may be true to related. You're probably going to see each creating its own type of rash, but classic spread did not indicate combining the 2 mutually enhance their respective rash.

Speaker 14

Okay. Thanks. That's helpful. Thanks for taking the question.

Operator

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

Speaker 2

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

Operator

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

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Earnings Conference Call
Revolution Medicines Q2 2024
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