Revolution Medicines, Inc. (NASDAQ:RVMD) Q4 2023 Earnings Call Transcript

Revolution Medicines, Inc. (NASDAQ:RVMD) Q4 2023 Earnings Call Transcript February 26, 2024

Revolution Medicines, Inc. misses on earnings expectations. Reported EPS is $-1.14 EPS, expectations were $-0.86. Revolution Medicines, Inc. isn’t one of the 30 most popular stocks among hedge funds at the end of the third quarter (see the details here).

Operator: Good day and thank you for standing by. Welcome to Revolution Medicine’s Fourth Quarter and Full Year 2023 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. [Operator Instructions] Please be advised that today’s conference is being recorded. I would now like to hand the conference over to your first speaker today, Erin Graves, Senior Director of Corporate Communications and Investor Relations, please go ahead.

Erin Graves: Thank you, and welcome, everyone, to the Fourth Quarter and Full Year 2023 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. Wei Lin our Chief Medical Officer will join us for the Q&A portion of today’s call. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

I encourage you to review the legal disclaimer in our corporate presentation and our earnings press release, as well as all of the company’s filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine’s Chairman and Chief Executive Officer. Mark?

Mark Goldsmith: 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 Morgan Healthcare Conference in January. Today, I’ll review highlights of our company progress and lay out several important 2024 milestones for our pioneering RAS(ON) inhibitor pipeline, and Jack Anders will provide highlights of our financial results. 2023 was a transformative year for Revolution Medicine. First, we disclosed the preliminary clinical profiles of two unprecedented targeted RAS(ON) inhibitors, RMC-6236, a RAS(ON) multi-selective inhibitor, and RMC-6291, a RAS(ON) G12C-selective inhibitor as evaluated in Phase 1/1b trials in patients with RAS-mutated cancers.

Initial safety, tolerability, and anti-tumor 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-9805, an oral and covalent oral G12D selective inhibitor, our third distinguished RAS(ON) inhibitor in clinical development. As I’ll summarize momentarily, this important progress with our first wave of RAS(ON) inhibitors provide significant momentum heading into this year’s plans and we believe serves as validation of the RAS(ON) inhibitor platform and deep pipeline more broadly.

A scientist in a white lab coat measuring liquid in a beaker in the biotechnology lab.

Second, we ended 2023 with a particularly strong balance sheet, bolstered by the EQRx acquisition that fuels our ambitious plans, aiming to maximize clinical impact and drive shareholder value. With a strong pipeline and financial position, we have three strategic priorities for 2024. First, building on strong clinical momentum with our boldest and most mature investigational drug with broad potential. Our highest priority in 2024 is to propel single agent RMC-6236 into its first pivotal trial. 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 RMC-6236 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. 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 began preparing our regulatory packages for dose selection and monotherapy pivotal trials that we plan to initiate in the second half of 2024. Beyond advancing into late stage development in second-line lung and pancreatic cancers, our second strategic priority for 2024 is to expand the reach of RMC-6236. We began evaluating the impact of single agent 6236 in patients with tumors harboring RAS mutations beyond the G12X mutations that had been the focus of the dose escalation, mainly G13X and Q61X mutations. Likewise, we’re studying 6236 in patients with tumor types beyond lung and pancreatic cancer, including colorectal cancer, melanoma, and gynecologic cancers. We anticipate disclosing initial clinical PK safety, tolerability, and activity data from the genotype and tumor type cohorts in the second or third quarter of 2024.

In addition, we’ve initiated combination drug cohorts to examine options for reaching into first-line treatment settings. For example, we began evaluating RMC-6236 in combination with a checkpoint inhibitor, a combination that is likely required for advancing into first-line treatment for lung cancer. We anticipate disclosing initial data in the second half of 2024 with establishing safety of these combinations as the main focus. Our third priority for the year is to qualify our RAS(ON) mutant selective inhibitors for late stage development, RMC-6291, our G12C selective inhibitor, and RMC-9805, our G12D selective inhibitor. At the Triple Meeting in October, we reported preliminary results with RMC-6291 monotherapy supporting clinically meaningful differentiation at doses that were generally well-tolerated.

Based on dose optimization work that has been completed, further study of RMC-6291 as a single agent continues at 200 milligrams bid. As a major next step for RMC-6291, we have initiated our first RAS(ON) inhibitor doublet trial with RMC-6236 in patients with advanced KRASG12C mutated cancers. Patients are currently being treated in the dose escalation portion of the trial and we anticipate disclosing initial clinical PK, safety, tolerability, and activity data in the second half of 2024. We’ve also begun treating patients with RMC-6291 and a checkpoint inhibitor to assess the safety of this combination. For our G12D selective inhibitor, RMC-9805, we shared at the JP Morgan conference that oral bioavailability of RMC-9805 has been confirmed in patients.

We’ve seen pharmacokinetics consistent with expectations from our preclinical data, including dose-dependent increases in plasma exposure on once daily dosing. We’ve cleared several dose levels with good tolerability and no dose-limiting toxicities have been reported thus far. We anticipate disclosing initial safety and activity data in the second half of 2024. Finally, these ambitious clinical development priorities for advancing our first wave of RAS(ON) inhibitors are made possible by our strong balance sheet, which now includes approximately $1.1 billion of cash from the acquisition of EQRx that closed in November. With our compelling pipeline, innovation engine, and financial position, we aim to continue building and solidifying our position as an industry leader in developing targeted medicines for patients living with RAS-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 fourth quarter and full-year financial update. Jack?

Jack Anders: Thank you, Mark. We are pleased to strengthen our balance sheet with the acquisition of EQRx, which added approximately $1.1 billion in net cash proceeds after estimated post-closing winddown and transition costs. We ended the year with $1.85 billion in cash and investments, which is expected to fund planned operations into 2027 based on our current operating plan. Q4 and full year 2023 financial results included $26.9 million in operating expenses associated with the winddown of EQRx, which primarily consisted of non-recurring accounting charges associated with employee-related termination expenses and stock-based compensation expense resulting from the acceleration of EQRx equity awards in conjunction with the closing of the transaction.

These were mostly one-time accounting charges specific to the close of the transaction in 2023 and are not expected to repeat in 2024. Collaboration revenue was $0.7 million for the fourth quarter of 2023 compared to $15.3 million for the prior year quarter and $11.6 million for full year 2023 compared to $35.4 million for the prior year. Decrease in revenue was due to the termination of the company’s collaboration agreement with Sanofi in 2023. Total operating expenses for the fourth quarter of 2023 increased to $180.7 million, largely driven by R&D expenses, which totaled $148.5 million. Total operating expenses for full year 2023 increased to $498.8 million with R&D expenses increasing to $423.1 million. As noted earlier, our Q4 and full year 2023 operating expenses included $26.9 million in expenses associated with the winddown 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 fourth quarter of 2023 was $161.5 million or $1.14 per share. For the full year, net loss was $436.4 million or $3.86 per share. Turning to financial guidance for 2024, we expect full year GAAP net loss to be between $480 million and $520 million, which includes estimated non-cash stock-based compensation expense of $70 million to $80 million. The increase in expected GAAP net loss for 2024 is a result of increased expenses associated with the progression of our ongoing clinical development programs. I’ll now turn the call back over to Mark.

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

See also 44 Countries With Hot and Wet Equatorial Climate and 15 Best Dividend Stocks to Buy According to Warren Buffett.

Q&A Session

Operator: Thank you. [Operator Instructions] Our first question comes from the line of Marc Frahm with TD Cowen. Your line is now open.

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

Mark Goldsmith: 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 6236 or 6291 compared to the earlier compounds, that’s something we just have to evaluate, and so that’s really the main thing we’ll be looking for, is establishing a safety profile that can support moving into first-line.

Ernie Rodriguez: 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 9805 with 6236?

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

Ernie Rodriguez: Got it. Thank you. Thanks again for taking our questions.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Michael Smith with Guggenheim Partners. Your line is now open.

Michael Smith: Hey, good afternoon. Thanks for taking my questions. Yes, Mark, I think we really appreciate the maturing Phase 1 data for 6236. I think you’ve made comments on how the data has been improving or changing over time now, but just curious if you could comment a bit more on how much more data do you need to support initiation of Phase 3 and also to fulfill project Optimus requirements before launching the pivotal studies as a monotherapy? Thanks so much.

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

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

Mark Goldsmith: 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 — is the 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.

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

Mark Goldsmith: Thank you.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Eric Joseph with JP Morgan. Your line is now open.

Eric Joseph: 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 needed at all to sort 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.

Mark Goldsmith: 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 will include that information and conversations with the FDA. We do, of course, have pre-clinical data that suggests — that supports the notion that really all mutant forms of RAS, certainly all that we’ve ever tested, showed some degree of sensitivity to RMC-6236. And the elevation of the G12X population, you might recall, came out of a large cell line panel that shows a statistically greater sensitivity of the G12X population of tumor lines to 6236 than the others, but did not distinguish them as yes versus no, it was more a quantitative signal that highlighted them and therefore we prioritized them in the dose escalation study.

So the bulk of the data that we have is around the G12X group. But we are working to gather additional information that extends into these other genotypes, as you alluded to, and to the extent that we can include that in our final termination of what’s the best design, we’ll certainly discuss that with the FDA as well.

Eric Joseph: Okay, great. And maybe just a follow-up on planned combination studies with 6236. Specifically, can you talk about what the gating steps are to starting a frontline pancreatic combination study with chemo? Is there a particular chemo regimen you’re looking to combine with — between the FOLFIRINOX or gem-paclitaxel? And beyond adequate tolerability, is there an efficacy signal that you’d want to see in a combination setting to warrant pursuing the frontline opportunity?

Mark Goldsmith: Yes. Thanks for that question. I really appreciate your enthusiasm. You’re moving us to first-line, it’s terrific. There is, I think, growing interest in the first-line space with RMC-6236 given what investigators have experienced so far. Maybe Dr. 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 — designing and launching such a trial.

Wei Lin: Yes. Happy to do that, Mark. Hi. I think you did mention the two current regimens that are currently the standard of care. One is modified FOLFIRINOX, the other is gem-ABRAXANE, and both are in wide clinical use. So we would be exploring the combination with both of these regimens in an early phase study, and the benchmark for those are, gem-ABRAXANE typically response rate in the 20% to 30% range and then modified FOLFIRINOX in the 30% to 40% range, so that’s really being secure 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.

Eric Joseph: 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.

Jonathan Chang: Hi, guys. Thanks for taking my questions. First question, with an enviable year end cap balance of about $1.85 billion, can you discuss your high-level thought process around how one spends that capital effectively within the context of all the moving parts in your pipeline? And then second question, on RMC-6236, what is your latest thinking on what a development path forward and second-line pancreatic cancer could look like? Would the Phase 3 primary endpoint of that study be OS or PFS? Thank you.

Mark Goldsmith: Thanks, Jonathan. 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 6236 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 two additional corporate priorities for 2024, which is to expand the reach of 6236, and you’ve heard the various ways in which we’re doing that, and that requires a certain amount of capital and a certain amount of bandwidth, and then qualifying our mutant selective inhibitors, 6291 and 9805, to advance into late stage development, that requires a certain amount of capital too.

So those are clearly kind of ring-fenced and elevated in priority for 2024. That doesn’t account for the entire budget, of course, because we have programs that go beyond those assets. Those are earlier stage programs, either defined development stage assets, of which we have several that we’ve identified and talked about, and then we have a robust discovery effort that leverages years of accumulated know-how to build out second later generation RAS inhibitors and so on. 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 a 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.

Jonathan Chang: Understood. And then just on the 6236 development path in pancreatic cancer.

Mark Goldsmith: The 6236 monotherapy second-line pancreatic cancer clinical trial design, Phase 3 design?

Jonathan Chang: Yes, exactly. What is your latest thinking on what that primary endpoint could look like? Thank you.

Mark Goldsmith: Well, 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 on that.

Wei Lin: Yes, I think on the endpoint currently we’re looking at is really a due endpoint of PFS and overall survival OS.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Ellie Merle with UBS. Your line is now open.

Ellie Merle: 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 6236, 6291 combo? And what are you focused on from this initial data? Thanks.

Mark Goldsmith: Okay. Thanks for joining us, and thanks for your question. Yes, the RAS doublet is really kind of another differentiating angle of Rev Med’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 6236 in combination with 6291 in G12C cancers. What we don’t know is exactly how that will play out translationally in humans. We know in the animal models, which are generally relatively short term models and don’t have the same evolution characteristics as a true human cancer, heterogeneous human cancer, we know what that looks like, and it can look like increased depth of response and increased durability of response, or increased frequency of response, so really everything you can measure, you can see in the preclinical studies, but it’s very hard to try — to tie a direct line from those into the human studies.

So I think a fair amount of this will be keeping our eyes wide open and looking for early signals that we then want to chase down and have to validate further. But I do think the very first question is simply, is it a safe combination? Is it safe and tolerated? And the two components of that seem to be safe and well tolerated to date, but putting the two together, we just need to verify first that that doesn’t create any drug interactions or other manifestations that could compromise the strategy going forward. And then after that, we’ll be thinking about and looking for the clinical activity signal that I just alluded to, whether it’s frequency response, depth of response, or durability response.

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

Mark Goldsmith: Okay, I think you managed to squeeze in at least 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 two separate trials under contemplation here, pancreatic cancer and lung cancer, and so there’s a data set associated with each of those, and I think those would be sort of headline 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…

Ellie Merle: Expansion cohorts?

Mark Goldsmith: Expansion cohorts that go beyond pancreatic and lung cancer, we’ve indicated that there are several different directions for those. One is different RAS genotypes beyond G12X. And we’ve indicated we’ll provide some preliminary view of that sometime in the mid-year range, I think we said Q2 to Q3 time frame. 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 third 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, Wei alluded to a few other things that one would consider for ultimately moving into first-line, particular in pancreatic cancer with chemotherapy.

So there’s a wide range of things that are going to happen. A good number of those we could read out in the second half of this year. Yes, did you have — did you want to follow up on that?

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

Ami Fadia: 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? 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 would be the right combination partner with pembro plus-minus chemo, whether it would be 6236 or 6291? If you could sort of share your thinking there, that would be helpful. Thanks.

Mark Goldsmith: 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 PDAC, what is the bar that would compel us to move forward from a PFS perspective?

Ami Fadia: That’s right.

Mark Goldsmith: That’s what you’re asking? 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 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 three to three and a half months at best in true second-line patients. Keep in mind, our population is not truly second-line. Our population includes second, third, and potentially even some beyond that. People have had multiple different previous treatments. So our population probably isn’t going to perform as well as the pure second-line population would perform.

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

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

Mark Goldsmith: So your question is, in pancreatic cancer, if you received RMC-6236 as part of a first-line regimen, why would you continue — why would you repeat 6236 as part of a second-line regimen, is that what you were asking?

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

Mark Goldsmith: Okay, now I understand. So we’re talking about, in KRASG12C cancers specifically.

Ami Fadia: Correct.

Mark Goldsmith: [Technical Difficulty] And talking about lung cancer, and your question was if we combine 6236 with 6291 in first-line? No, I’m not following it. So maybe you can interpret the question and you can answer it.

Wei Lin: Let me interpret your question, so I think what I’m hearing you say is if we were able to succeed in developing 6291 plus pembro, or 6291 plus pembro and chemo, and that becomes a new standard of care for G12C patients in first-line lung, why would patients get 6236 with a second-line? Is that your question?

Ami Fadia: Yes, that’s helpful. Thanks.

Mark Goldsmith: Yes. [Technical Difficulty] some thoughts on it.

Wei Lin: I’ll take a stab there. I mean, that’s certainly one scenario we could develop it using a 6291 purely based regimen, plus either pembro mono for the poly or pembro plus chemo for all [Technical Difficulty]. There’s another scenario where we could be developing 6291 plus 6236 plus pembro without chemo, right? That’d be another option. Just want to put that out there. But let’s take what you put on the table, which is 6291 plus pembro with 6291 plus pembro plus chemo, if that became the standard of care in first-line, I think we still do believe that there could be scientific rationale for 6236 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 the RAS mutated tumor behaves in development resistance against any G12C inhibitor.

I think there’s wealth of data from sotorasib, adagrasib, and ivarasib. I think one really emerging sign is; number one, 80%, 90% of those tumors retain original G12C mutation, they don’t lose it. Number two, 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 a RAS rescue mechanism. So rescuing or reactivating the RAS seemed to be the predominant mechanism and hence it goes along, I think, with how Mark is really describing these tumors as RAS-addicted, I think the fact that they’re addicted means that they are really relying on turning the tumor pathway back on in RAS. And hence the broad spectrum activity of 6236 involving not only other RAS mutations that can potentially cover, so if a tumor could develop a G12D mutation to bypass the G12C, that 6236 can remain active.

And furthermore, even if a patient were to activate a receptor tyrosine 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 active against. So I think it still provides rationale. Obviously, we need to generate clunk data to support that for 6236 to remain the standard of care in the second-line setting, even if 6291 establish itself as first-line treatment of choice.

Mark Goldsmith: So you got yourself a very scholarly answer to that question. I just want to circle back…

Ami Fadia: That was very helpful.

Mark Goldsmith: Yes. If I could just go back to the first thing that Wei said, though, it’s really important, it might have gone by a little bit quickly, which is that although we’re testing 6291 plus pembro, and we’re also evaluating 6236 plus pembro, we’re also evaluating 6291 plus 6236, and all three of those are a way of triangulating potentially on a triplet combination of 6291 plus 6236 plus pemro, which would be, as Wei said, a chemo-free regimen for first-line. It’s not the only outcome of that. It’s not the only possible outcome, but that would be one way in which all those get rationalized. One shouldn’t assume today that we will or would not move forward with the doublet of a PD1 plus — plus either one of those agents. We’ll see. We’ll let the data tell us what makes sense to do.

Ami Fadia: That makes sense. Thanks.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Alec Stranahan with Bank of America. Your line is now open.

Unidentified Analyst: Hey, guys, this is John on — I’m on for Alec. Thanks for taking our question. Just a quick one from us. In terms of second-half data updates, what could be the venue that we would be expecting? Would it be like a medical conference or should we just be expecting a press release or like an Investor Day, so any color on that would be great if you can share it?