Revolution Medicines Q4 2023 Earnings Call Transcript

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Provided by Quartr
February 26, 2024

There are 14 speakers on the call.

Operator

Good day, and thank you for standing by. Welcome to Revolution Medicine's 4th Quarter and Full Year 2023 Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer session. Please be advised that today's conference is being recorded.

Operator

I would now like to hand the conference over to your first speaker today, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.

Speaker 1

Thank you, and welcome, everyone, to the Q4 and full year 2023 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. Wei Lin, our Chief Medical Officer, will join us for the Q and A portion of today's call.

Speaker 1

As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks and uncertainties. Actual results may differ materially from these statements and except as required by law, the company undertakes no obligation to revise or update any forward looking statements. I encourage you to review the legal disclaimer in our corporate presentation and our earnings press release as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Doctor.

Speaker 1

Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Speaker 2

Thanks, Erin. Good afternoon, everyone, and thank you for joining us. We will keep our prepared remarks brief today in light of the corporate presentation we provided at the JPMorgan Healthcare Conference in January. Today, I'll review highlights of our company progress and lay out several important 2024 milestones for our pioneering RAS ON inhibitor pipeline and Jack Anders will provide highlights of our financial results. 2023 was a transformative year for Revolution Medicines.

Speaker 2

First, we disclosed the preliminary clinical profiles of 2 unprecedented targeted RASON inhibitors, RMC-six thousand two hundred and thirty six, a RASON multi selective inhibitor and RMC 6291, a RASON G12C selective inhibitor as evaluated in Phase 1, 1b trials in patients with RAS mutated cancers. Initial safety, tolerability and antitumor activity data reported at the Triple Meeting and ESMO Congress showed that both investigational drugs have highly differentiated clinical profiles suggesting substantial promise for patients and supporting their continued development. We also announced in September that we had dosed our first patient in the Phase 1, 1b trial of RMC-nine thousand eight hundred and five, an oral and covalent G12D selective inhibitor, our 3rd distinguished RASon inhibitor in clinical development. As I'll summarize momentarily, this important progress with our 1st wave of RAS ON inhibitors provides significant momentum heading into this year's plans and we believe serves as validation of the RASon inhibitor platform and deep pipeline more broadly. 2nd, we ended 2023 with a particularly strong balance sheet bolstered by the EQRx acquisition that fuels our ambitious plans aiming to maximize clinical impact and drive shareholder value.

Speaker 2

With a strong pipeline and financial position, we have 3 strategic priorities for 2024. 1st, building on strong clinical momentum with our boldest and most mature investigational drug with broad potential, our highest priority in 2024 is to propel single agent RMC6236 into its first pivotal trials. We are currently working toward the goal of launching randomized controlled trials against standard of care chemotherapy for patients with RAS mutated non small cell lung cancer or pancreatic ductal adenocarcinoma and we expect that these efforts will command the largest share of our resources this year. Encouragingly, at the JPMorgan conference, we disclosed that with ongoing follow-up since ESMO, the RMC6236 safety profile had remained relatively stable, including at 300 milligrams per day with relatively few dose interruptions or discontinuations. In the non small cell lung cancer cohort, we reported favorable trends for aggregate objective response rate across doses into the low to mid-40s range and that were trending even higher in the 300 milligram cohort.

Speaker 2

In the pancreatic ductal adenocarcinoma cohort, we reported favorable trends for aggregate ORR into the mid-20s and that were trending even higher in the 300 milligram cohort. We are now focused on the 300 milligram dose and below for both lung and pancreatic cancer and continue to follow these patients as we develop a more mature data set to determine progression free survival or PFS. We've begun preparing our regulatory packages for dose selection and monotherapy pivotal trials that we plan to initiate in the second half of twenty twenty four. Beyond advancing into late stage development in second line lung and pancreatic cancers, our second strategic priority for 2024 is to expand the reach of RMC-six the impact of single agent 6,236 in patients with tumors harboring RAS mutations beyond the G12X mutations that had been the focus of the dose escalation, mainly G13x and Q61x mutations. Likewise, we're studying 6236 in patients with tumor types beyond lung and pancreatic cancer, including colorectal cancer, melanoma and gynecologic cancers.

Speaker 2

We anticipate disclosing initial clinical PK, safety, tolerability and activity data from the genotype and tumor type cohorts in the 2nd or Q3 of 2024. In addition, we've initiated combination drug cohorts to examine options for reaching into first line treatment settings. For example, we've begun evaluating RMC6236 in combination with a checkpoint inhibitor, a combination that is likely required for advancing into first line treatment for lung cancer. We anticipate disclosing initial data in the second half of twenty twenty four with establishing safety of these combinations as the main focus. Our third priority for the year is to qualify our RAS on mutant selective inhibitors for late stage development, RMC-six thousand two hundred and ninety one, our G12C selective inhibitor and RMC-nine thousand eight hundred and five, our G12 D selective inhibitor.

Speaker 2

At the triple meeting in October, we reported preliminary results with RMC-six thousand two hundred and ninety one monotherapy supporting clinically meaningful differentiation at doses that were generally well tolerated. Based on dose optimization work that has been completed, further study of RMC-six thousand nine hundred and one as a single agent continues at 200 milligrams BID. As a major next step for RMC-six thousand nine hundred and one, we have initiated our first RASAN inhibitor doublet trial with RMC6236 in patients with advanced KRAS G12C mutated cancers. Patients are currently being treated in the dose escalation portion of the trial and we anticipate disclosing initial clinical PK, safety, tolerability and activity data in the second half of twenty twenty four. We've also begun treating patients with RMC6,291 and a checkpoint inhibitor to assess the safety of this combination.

Speaker 2

For our G12D selective inhibitor, RMC-nine thousand eight hundred and five, we shared at the JPMorgan conference that oral bioavailability of RMC9805 has been confirmed in patients. We've seen pharmacokinetics consistent with expectations from our preclinical data, including dose dependent increases in plasma exposure on once daily dosing. We've cleared several dose levels with good tolerability and no dose limiting toxicities have been reported thus far. We anticipate disclosing initial safety and activity data in the second half of twenty twenty four. Finally, these ambitious clinical development priorities for advancing our first wave of RASon inhibitors are made possible by our strong balance sheet, which now includes approximately $1,100,000,000 of cash from the acquisition of EQRx that closed in November.

Speaker 2

With our compelling pipeline, innovation engine and financial position, we aim to continue building and solidifying our position as an industry leader in developing targeted medicines for patients living with RAS addicted cancers for many years to come. I'd like to now turn the call over to Jack Anders, our Chief Financial Officer, to provide the Q4 and full year financial update. Jack? Thank you, Mark.

Speaker 3

We are pleased to strengthen our balance sheet with the acquisition of EQRx, which added approximately $1,100,000,000 in net cash proceeds after estimated post closing wind down and transition costs. We ended the year with $1,850,000,000 in cash and investments, which is expected to fund planned operations into 2027 based on our current operating plan. Q4 full year 2023 financial results included $26,900,000 in operating expenses associated with the wind down of EQRx, which primarily consisted of non recurring accounting charges associated with employee related termination expenses and stock based compensation expense resulting from the acceleration of EQRx equity awards in conjunction with the closing of the transaction. These were mostly one time accounting charges specific to the close of the transaction in 2023 and are not expected to repeat in 2024. Collaboration revenue was $700,000 for the Q4 of 2023 compared to $15,300,000 for the prior year quarter and $11,600,000 for full year 2023 compared to $35,400,000 for the prior year.

Speaker 3

Decrease in revenue was due to the termination of the company's collaboration agreement with Sanofi in 2023. Total operating expenses for the Q4 of 2023 increased to $188,700,000 largely driven by R and D expenses, which totaled $148,500,000 Total operating expenses for full year 2023 increased to $498,800,000 with R and D expenses increasing to $423,100,000 As noted earlier, our Q4 and full year 2023 operating expenses included $26,900,000 in expenses associated with the wind down of EQRx. The remaining increase in total operating expenses for Q4 and full year 2023 was primarily due to an increase in clinical supply manufacturing and clinical trial expenses for our ongoing clinical development programs. Increase in personnel related expenses related to additional headcount and an increase in stock based compensation expense. Net loss for the Q4 of 2023 was $161,500,000 or $1.14 per share.

Speaker 3

For the full year, net loss was $436,400,000 or $3.86 per share. Turning to financial guidance for 2024. We expect full year GAAP net loss to be between $480,000,000 $520,000,000 which includes estimated non cash stock based compensation expense of $70,000,000 to $80,000,000 The increase in expected GAAP net loss for 2024 is a result of increased expenses associated with the progression of our ongoing clinical development programs. I'll now turn the call back over to Mark.

Speaker 2

Thank you, Jack. In summary, in 2024, we at RevMed have ambitious plans to deliver on clear priorities for our pioneering RAS1 inhibitor portfolio, building on tremendous momentum coming out of 2023 and enabled by a strong balance sheet and a highly talented and motivated team. We remain committed to discovering, developing and delivering innovative targeted therapies for patients living with RAS addicted cancers. On behalf of our organization, I'd like to extend our deep appreciation to our patients, clinical investigators, scientific and business collaborators, advisors and shareholders. This concludes our prepared remarks for today.

Speaker 2

And I'll now turn the call over to the operator for the Q and A session.

Operator

Thank you. Our first question comes from the line of Mark Frahm with TD Cowen. Your line is now open.

Speaker 4

Hi, Tim. This is Ernie Rodriguez for Mark. Congrats on all the progress and thanks for taking our questions. My question is on the combinations with pembro for 6,291, 6,236. What would you like to see on those on that early data in the combinations for you to feel comfortable to make a decision to move those combinations into pivotal development?

Speaker 5

Hi, Ernie. Thanks very much for your question. Primarily, what we're looking for is to validate safety. As you know, the biggest challenge so far in moving into first line has been for other RAS inhibitors has been combined hepatotoxicity signals. And while we have early reason to believe that this is less likely to happen with either 6,236 or 6,291 compared to the earlier compounds, that's something we just have to evaluate.

Speaker 5

And so that's really the main thing we'll be looking for is establishing a safety profile that can support moving into first line.

Speaker 4

Thank you. That's helpful. And then just a quick one. Do you remind me if you mentioned before, I don't remember the potential or how you think about the potential for combining 9,805 with 6,236?

Speaker 5

Sure. We haven't said much about that other than we considered the 6,291 plus 6,236 combination to be sort of a key test case. And if those combined comfortably as we have seen preclinically, if that carries through into patients, then it will certainly be encouraging with regard to combining other mutant selective inhibitors with 6,236 and of course, 9,805 would be early on that list.

Speaker 4

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

Operator

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

Speaker 6

Hey, good afternoon. Thanks for taking my questions. Yes, Mark, I think we really appreciate the maturing Phase I data for 6,236. I think you've made comments on how the data has been improving or changing over time now. But just curious if you could comment a bit more on how much more data do you need to support initiation of Phase III and also to fulfill Project OPTIMA's requirement before launching the pivotal studies as a monotherapy?

Speaker 6

Thanks so much.

Speaker 5

Thank you, Michael. Appreciate the question. Right. So the update that we provided in January that you're referring to has to do with response rates and that information is helpful for guiding dose selection. And of course, we're incorporating that updated information into our analyses and into packages for the FDA.

Speaker 5

So that's really for dose selection. I think for moving into the pivotal trials, we're actually making the go decision on those. We're looking for a mature PFS assessment or estimate that can come from more mature observation, which obviously we're developing now. And that really leads to finalization of the trial design, the statistical power and so on. And accompanying all that, of course, is FDA input.

Speaker 5

So I think those are the key elements for making a final go decision associated with each of those trials.

Speaker 6

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

Speaker 6

Could you help us understand the cadence of data disclosed in the second half a bit better?

Speaker 5

I wish I knew. I'd be able to tell you. We have some ideas about how things might roll out, but I think it's too early to really set out a schedule. We're not engineering it for a particular disclosure methodology, just as the information becomes available and as it becomes appropriate to disclose it, we'll do so. I think clearly what people are most anxious to hear about is the timing.

Speaker 5

It's a go decision and timing and details about the final plan for those pivotal trials. So that's clearly what we would highlight as the most important event in the second half of the year, but it is also true there will be other information coming out as we outlined in the milestones.

Speaker 6

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

Speaker 5

Thank you.

Operator

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

Speaker 7

Yes, good evening. Thanks for taking the questions. Maybe just following up on Mike's question regarding regulatory buy in and the finalization of the pivotal studies. Is visibility on sort of activity in the context of G12X and Q61 mutations

Speaker 5

needed at all to sort

Speaker 7

of get buy in on the nested efficacy analysis as part of your proposed design? And then I have a follow-up to that question.

Speaker 5

Okay. Thanks, Eric. Thanks for joining us today. Clearly, we're trying to make decisions in collaboration ultimately with the FDA about what to include in that final trial design. And to the extent that we have any activity information that can guide it, we'll include that information in conversations with the FDA.

Speaker 5

We do of course have preclinical data that suggests that supports the notion that really all mutant forms of RAS, certainly all that we've ever tested, showed some degree of sensitivity to RC6236. And the elevation of the G12X population, you might recall, came out of a large cell line panel that shows that statistically greater sensitivity of the G12X population of tumor lines to 6,236 than the others, but did not distinguish them as yes versus no. It was more quantitative signal that highlighted them and therefore we prioritize them in the dose escalation study. So the bulk of the data that we have is around the G12X group, but we are working to gather additional information that extends into these other genotypes as you alluded to. And to the extent that we can include that in our final determination of what's the best design, we'll certainly discuss that with the FDA as well.

Speaker 4

Okay,

Speaker 7

great. And maybe just a follow-up on planned combination studies with 6,236. Specifically, can you talk about what the gating steps are to starting a frontline pancreatic combination study with chemo? Is there a particular chemo regimen you're looking to combine with between either Fulferidox or gem paclitaxel? And beyond adequate tolerability, is there an efficacy signal that you'd want to see in a combination setting to warrant pursuit of a frontline opportunity?

Speaker 5

Thanks for that question. I really appreciate your enthusiasm. You're moving us to first line. That's terrific. There is, I think, growing interest in the first line space with RC6236 given what investigators have experienced so far.

Speaker 5

Maybe, Doctor. Lin, our Chief Medical Officer, who's joining us today can comment on what we're looking for to help us make the decision about launching and designing and launching such a trial.

Speaker 8

Yes. How do you do that, Mark? Hi, Andy. I think you did mention the 2 current regimens that are currently the center care. 1 is modified Fulferonox, the other is gemabraxane and both are wide in wide clinical use.

Speaker 8

So we would be exploring the combination with both of these regimens in early phase study. And the benchmark for those are gembrasane typically response rate in the 30 20% to 30% range and then MOSFET, fulferonox in the 30% to 40% range. So that's really being superior to either one of these would enable us to really move forward into a first line setting. Obviously, that's just the response rate. Ultimately, we'd like to provide survival benefit and so PFS, another metric we will keep.

Speaker 7

Okay, great. Thanks again for taking the question.

Operator

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

Speaker 9

Hi, guys. Thanks for taking my questions. First question was an enviable year end cash balance of about $1,850,000,000 can you discuss your high level thought process around how one spends that capital effectively within the context of all the moving parts in your pipeline? And then second question on RMC 6,236, what is your latest thinking on what a development path forward in second line pancreatic cancer could look like? Would the Phase 3 primary endpoint of that study be OS or PFS?

Speaker 9

Thank you.

Speaker 5

Thanks, Johnson. I think on the first question, which was capital allocation, given all the competing opportunities that we have, I think we've been pretty clear about this that our number one strategic priority is to advance 6,236 into pivotal trials in second line pancreatic and lung cancer. And no question that from our bandwidth perspective and even direct spending that supports it that the allocation of capital is made accordingly. So that's going to take the lion's share of our effort. So then beyond that, we've identified these 2 additional corporate priorities for 2024, which is expand the reach of 6,236, and you've heard the various ways in which we're doing that.

Speaker 5

And that requires a certain amount of capital and a certain amount of bandwidth and then qualifying our mutant selective inhibitors 6,291 and 9,805 to advance into late stage development that requires a certain amount of capital too. So those are clearly kind of ring fenced and elevated in priority for 2024. That doesn't account for the entire budget, of course, because we have programs that go beyond those assets. Those are earlier stage programs either defined development stage assets of which we have several that we've identified and talked about. And then we have a robust discovery effort that leverages years of accumulated know how to build out 2nd later generation, RAS inhibitors and so on.

Speaker 5

So we're going to continue to allocate according to those priorities, but we are thinking about not just the near term. So when we're making these investments in 2024, we have to meet our 2024 goals, but we also are trying to build our strategy, our data set and our asset pool that would sustain and protect the franchise once we're able to create a commercial franchise from the first from the earliest assets that move forward. So lots of things to invest in. It seems like we have a lot of capital today. At some point, it won't feel like that much capital, but we're managing according to a very strategic plan.

Speaker 9

Understood. And then just on the 6,236 development path in pancreatic cancer?

Speaker 5

The 6,236 monotherapy second line pancreatic cancer clinical trial design, Phase 3 design?

Speaker 9

Yes. Exactly, exactly. And what is your latest thinking on what that primary endpoint could look like? Thank you.

Speaker 5

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

Speaker 8

on that. Yes. I think on the endpoint front, we're looking at is really going to do end from the PFS and overall survival OS.

Operator

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

Speaker 10

Hey guys, thanks so much for taking the question. Just heading into the initial KRAS combo data later this year, I guess, what would you consider good data from this, from the 6,236, 6,291 combo? And what are you focused on, from this initial data? Thanks.

Speaker 5

Okay. Thanks for joining us and thanks for your question. Yes, the RAS doublet is really kind of another differentiating angle of RefMed's portfolio and strategy. I think at the moment, we're really the only organization that could attempt such a combination and the preclinical data strongly supported and do support evaluating 6,236 in combination with 6,291 in G12C cancers. What we don't know is exactly how that will play out translationally in humans.

Speaker 5

We know in the animal models, which are generally relatively short term models and don't have the same evolution characteristics as a true human cancer, heterogeneous human cancer. We know what that looks like and again look like increased depth of response and increased durability response or increased frequency response. So really everything you can measure, you can see in the preclinical studies, but it's very hard to try to tie a direct line from those into the human studies. So I think a fair amount of this will be keeping our eyes wide open and looking for early signals that we then want to chase down and have to validate further. But I do think the very first question is simply is a safe combination, is it safe and tolerated?

Speaker 5

And the 2 components of that seem to be safe and well tolerated today. But putting the 2 together, we just need to verify first that that doesn't create any drug interactions or other manifestations that could compromise the strategy going forward. And then after that, we'll be thinking about and looking for the clinical activity signal that I just alluded to, whether it's frequency response, depth of response or durability response.

Speaker 10

Great. Thanks so much. And just a quick follow-up, I guess, which indication should we expect data on in the expansion cohorts from 6,236 and the data update later this year? And then more broadly, I guess, in the CRC cohort, what are you looking to see to make a go, no go decision thinking longer term for a potential pivotal study start there? Thanks.

Speaker 5

Okay. I think you managed to squeeze in. I think it's the third question, nicely done. So in terms of the data that we've committed to communicating later this year, let's just start with the pivotal trials. There are 2 separate trials under contemplation here, pancreatic cancer and lung cancer.

Speaker 5

And so there's a data set associated with each of those. And I think those would be sort of headline data sets to come out later in the year as we announce plans, go forward plans. But then I think you were asking about going beyond pancreatic cancer and lung cancer and Expansion cohorts. And expansion cohorts that go beyond pancreatic and lung cancer. We've indicated that there are several different directions for those.

Speaker 5

One is different RAS unit size beyond G12X, and we've indicated we'll provide some preliminary view of that sometime in the mid year range, I think we said Q2 to Q3 timeframe. The second is tumor types beyond lung and pancreatic cancer and that includes colorectal cancer and we've indicated we'll provide some information on that in the second half of the year. And then 3rd is combinations that help us to begin to enable optionality for going into first line and the 6236-6291 combination we just spoke about and then combinations of 6236 with pembro, 6291 with pembro. And then, Way alluded to a few other things that one would consider for ultimately moving into first line, particularly in pancreatic cancer with chemotherapy. So there's a wide range of things that are going to happen.

Speaker 5

A good number of those we could read out in the second half of this year.

Speaker 1

CRCs are really well.

Speaker 5

Yes. Did you have did you want to follow-up on that?

Operator

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

Speaker 11

Hi, good evening. Thanks for taking my question. I've got one follow-up and a question. Just on the PDAC data that you'll be presenting from the ongoing study data this year in second line. Could you tell us what you see as the bar in terms of PFS that you would like to see?

Speaker 11

And with regards to your program or what you're pursuing in first line, you're developing 6236 in second line or at least you're planning to initiate a pivotal study there. What is the clinical rationale or the hypothesis in terms of what will be the right combination partner with pembro plus minus chemo, whether it would be 6,236 or 6,291? If you could sort of share your thinking there, that would be helpful. Thanks.

Speaker 5

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

Speaker 11

That's right.

Speaker 5

Yes, I don't think we've really specified a particular number. Of course, we have our own internal benchmarks, but we've not publicly discussed, those no go, no go decisions. But we're clearly looking to be superior to second line chemotherapy and we know what median PFS is in virtually every second line study that's ever been done. It's really around 3 to 3.5 months at best in true second line patients. Keep in mind, our population is not truly second line.

Speaker 5

Our population for the 2nd, 3rd and potentially even some beyond that, people had multiple different previous treatments. So our population probably isn't going to perform as well as the peer second line population will perform. But nonetheless, we've said what we're trying to do with our current patients population is to be superior to the well accepted benchmark for 2nd line. But how much superior, I think is a question that goes beyond what we've come in on today. If you want to repeat your second question, then we can figure out who's the best person to comment on it.

Speaker 11

Sure. Just from a mechanistic perspective, I can understand if 6,236 as a monotherapy makes sense in the second line, I understand the logic behind exploring a combination of that with pembro in first line. But why would someone treat with 6 to 9 months plus pembro in first line and then move to 6 to 36 in second line, just hypothetically?

Speaker 5

So your question is in pancreatic cancer, if you received Pharmacy 6,236 as part of a first line regimen, why would you continue why would you repeat 6,236 as part of a second line regimen? Is that what you're asking?

Speaker 11

Well, or why would you start with 6,291, which is more targeted as a first line treatment and then move to 6,236, which is broader.

Speaker 5

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

Speaker 11

Correct. You're

Speaker 8

talking about

Speaker 5

lung cancer. And your question was, if we combine 6,236 with 6,291 in first line, no? I'm not following it. So maybe you can interpret the question and then

Speaker 8

you can answer it. Let me interpret your question. So I think what I'm hearing you say is, if we were able to succeed in developing 6,291 plus pembro with 6,291 plus pembro in chemo and that becomes a new standard care for G12C patients in the first time lung, why would patients get 6,236 with a second line? Is that your question?

Speaker 11

Yes, yes. That's helpful. Thanks.

Speaker 8

Yes. So I think

Speaker 5

some thoughts on

Speaker 8

it. Yes. I'll take a stab at that. I mean that's certainly one scenario we could develop it using a 6,291 purely based regimen plus either pembro mono for the PD-one high or pembro plus chemo for all patients. There's another scenario where we could be developing 6,291 plus 6,236 plus pembro without kebop, right?

Speaker 8

That would be another option. Just want to put that out there. But let's take the what you put on the table, which is 691 plus pembro with 699 plus pembro plus chemo, if that became the standard care in first line. I think we still do believe that there could be such a rationale for 6,236 to remain as an option in the second line setting. And the reason is the following, I think it really has to do with the way that DABRAF's redidicate tumor behaves in development resistance against any G12 C inhibitor.

Speaker 8

I think there's a wealth of data from sotorasib, atagracis and debaracib. I think one really emerging sign is number 1, 80%, 90% of those tumors retain original T12C mutation, they don't lose it. Number 2, the vast majority of the resistant mutation involve some type of either another RAS mutation or another mutation in the RAS pathway to reactivate the RAS pathway. So what we call it a RAS rescue mechanism. So resting or reactivating the RAS seems to be the predominant mechanism and hence it goes along, I think, with how Mark is really describing these tumors as RAS addicted.

Speaker 8

I think the fact that they're addicted means that they are really relying on turning the tumor pathway back on in RAS. And hence the broad spectrum activity of 6,236 involving not only other RAS mutations that can potentially cover. So if a tumor were to develop a GcalD mutation to bypass the Gcaldc that 6,236 can remain active. And furthermore, even if the patient were to activate a receptor targeting kinase like EGFR and the signal goes through a well type RAS that 6236 can also cover. So there are so many resistant mutations that are well characterized for the current G12C inhibitors that potentially 6236 can be acted against.

Speaker 8

So I think still we like to provide rationale. Obviously, we need to generate current data to support that for 446,236 remains the standard of care in the second line setting, even if 6,291 is not resolved as a first line treatment of choice.

Speaker 5

So you guys yourself are very scholarly and you answered that question. I just want to circle back

Speaker 10

to the That

Speaker 11

was very helpful.

Speaker 5

Yes. If I could just go back to the first thing that Wei said that was it's really important. It might have gone by a little bit quickly, which is that although we're testing 6,291 plus pembro and we're also evaluating 6,236 plus pembro, we're also evaluating 6,291 plus 6,236 and all three of those are a way of triangulating potentially on a triplet combination of 6,291 plus 6,236 plus pembro, which would be as Way said, a chemo free regimen for first line. We do it's not the only outcome of that. It's not the only possible outcome, but that would be one way in which all those get rationalized.

Speaker 5

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

Speaker 11

That makes sense. Thanks.

Operator

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

Speaker 12

Hi, guys. This is John on. I'm on for Alex. Thanks for taking our question. Just a quick one from us.

Speaker 12

In terms of second half data updates, what could be the venue that we would be expecting? Would it be like a medical conference or should we just be expecting like a press release or like an Investor Day? So any color on that, that would be great if you can share.

Speaker 5

Thanks, John. Hard to answer that question because there's so many different data sets that we've listed there that could come out in the second half of the year. Although our preference is to disclose such information in the context of peer reviewed medical conferences, It's not always up to us. It just depends on the timing and availability. Often these things require abstracts that are submitted long ahead of when we might have the information.

Speaker 5

So we'll pick a forum for each of the disclosures that suits it to make sure that we're not holding on to data that investors need to know about.

Speaker 12

Okay. Thank you for the color.

Operator

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

Speaker 13

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

Speaker 5

Hi, Jay. Thanks for joining us and thanks for your question. I think again, we've been pretty consistent about this, which is that in the U. S, we really believe this is a serious opportunity for RedMed to build its own franchise, and to use the RAS portfolio to create a very strong and leading franchise. So I don't think we're particularly keen on sharing any of that with a partner.

Speaker 5

And I don't think there's any reason to do so at least as we see things today. Outside the U. S, it's pretty clear that we don't have much opportunity there. That's a much more complex context in which to think about commercializing. We can't do development outside the U.

Speaker 5

S. We already do development outside the U. S, but doing pivotal late stage global development typically takes a real appreciation of the nuances in different country settings and different geographies. So that can be done. That can be enhanced by working with a partner that already has that infrastructure.

Speaker 5

And then of course, commercialization per se is not something that we have any near term plan to pursue on our own. So I think it's pretty clear that an ex U. S. Partner or partners could be in the offering for us at some point in the future. We're open to that possibility.

Speaker 5

And when the right opportunity presents itself and it makes sense for us to do it, I'm sure we would do so.

Speaker 13

Super helpful. Thank you very much. And if I could ask one follow-up. As you look ahead to the potential tumor agnostic setting for 6,236, can you just talk about the regulatory path that you're thinking about there?

Speaker 5

Doctor. Wainwright, it's Jonathan.

Speaker 8

Yes. Happy to address that. I think we already present probably activity in non small cell lung cancer as well as pancreatic cancer. So those are probably going to be served as anchor in our approach to tissue agnostic. Right now, we're actually rolling patients with colorectal cancer, melanoma as well as chronic plastic cancers as well as other solid tumor.

Speaker 8

And obviously, it could be very much data driven, but it's our aspiration given the broad activity we've seen frequently that this molecule could potentially help as many as 30% of patients with solid tumor with BRAF mutations. So we certainly like to test that hypothesis to the fullest and then the data will drive our decision about how much of the tissue mass can be as large.

Speaker 13

Okay, great. Thanks again for taking the questions. Thank

Operator

Our next question comes from the line of Laura Prentiss Gast from Raymond James. Your line is now open.

Speaker 10

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

Speaker 5

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

Speaker 8

Yes. I think that

Speaker 5

the results should reflect fairly well what we've seen so far

Speaker 8

in terms of the autoimmune patients and the Hennepin were addressing, I think, just really highlight. This is a usual situation. This is the biggest driver in all of oncology. And then by enabling the drug this, I can really unbox a huge unmet need. So all the patients coming in interest in our trial is reflection there.

Speaker 10

Great. Very helpful. Thank you very much.

Operator

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

Speaker 10

Hi, this is Kaylee Riza on for Ben Burnett. Thanks for taking our questions.

Speaker 1

I just had one quick question about RMC6236. I was wondering if you could give us any additional color on how the confirmed response rates for non small cell lung and PDAC are trending post ESMO? Thank you.

Speaker 5

Yes. Thanks for your question. As we mentioned in January and reiterated here, we've seen favorable trends in the response rates. You're asking specifically about confirmation. And I think generally what I can say is that most responses do confirm, most of the responses that have been un previously have been subsequently confirmed, except in those instances where somebody progressed in the interim or had to come off of drug and will never have the opportunity to confirm.

Speaker 5

So most of these do confirm. I'm not going to be able to give you specific confirmed rates today in part because these are ongoing trials. And so what happens is you're always enrolling new patients wait until later in the year when we'll try to give more precise information.

Speaker 10

Okay. Thank you very much.

Operator

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

Speaker 5

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

Operator

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

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Earnings Conference Call
Revolution Medicines Q4 2023
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