Revolution Medicines - Q3 2023
November 6, 2023
Transcript
Operator (participant)
Good day, and thank you for standing by. Welcome to the Revolution Medicines's Q3 2023 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone, and you will then hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Please go ahead.
Erin Graves (Senior Director of Corporate Communications and Investor Relations)
Thank you, and welcome everyone to the Third Quarter 2023 Earnings Call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines's Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D, 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 Revolution Medicines with respect to our business and the proposed acquisition of EQRx, including statements regarding our development plans and timelines for our portfolio and pipeline, and the expected timing and benefits of the proposed acquisition, all of which are intended to be covered by the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 for forward-looking statements. 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 slide of our corporate presentation, our earnings press release, and all of our filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicines's Chairman and Chief Executive Officer. Mark?
Mark Goldsmith (Chairman and CEO)
Thank you for joining us. I'd like to focus first on our remarkable headline investigational drug, RMC-6236, and try to paint the picture we see based on a couple important weeks of data updates and extensive dialogue with investigators and clinical experts. First, objectively and by hands-on investigator experience, treating over 131 patients so far, RMC-6236 is well-tolerated at clinically active doses, including 300 milligrams QD, as reported to us by investigators. These observations with the first-ever RAS multi inhibitor in the clinic are dogma-breaking and demonstrate clearly that this compound has a very sound therapeutic window. Second, this profile is enabling continuity of dosing, which we believe is critical in treating RAS-addicted cancers. Patients receiving RMC-6236 have required few dose interruptions and even fewer discontinuations for intolerability.
This differentiating feature of RMC-6236 is a core lever for evaluating meaningful clinical benefit. Third, despite the interpatient variability that is typical for oral anticancer agents, RMC-6236 showed dose-dependent increase in exposure at every dose escalation tested, up to and including 400 milligrams daily. Fourth, RMC-6236 has shown objective antitumor activity, both by radiographic imaging and ctDNA quantitation, against three oncogenic RAS genotypes for which no other targeted therapy is available: RAS G12D, G12V, and G12R. G12D and V alone account for more than half of all RAS solid tumors, and G12D, V, and R mutations are the three most common RAS drivers of pancreatic ductal adenocarcinoma, accounting for nearly 90%.
The results with each of these genotypes individually represent a first-in-class clinical validation for a direct RAS inhibitor, and the breadth of activity is simply unique, a true RAS multi inhibitor. It is not possible to discern any obvious relationship between dose and objective response rate by RECIST at this stage in the study, probably due to small numbers at each dose level and the bias towards short follow-up at the high dose levels. With increased numbers of patients now enrolled and ongoing maturation of the data, we expect to be able to conduct a robust exposure-efficacy analysis using several outcome measures. The blended objective response rate in non-small cell lung cancer is already solid, at 38% in the data we shared in October. Some patients are expected to develop a partial response after the first scan.
We anticipate this number settling out in the 40%-50% range at recommended phase II dose. Objective response rate in lung cancer generally correlates with progression-free survival. We plan to select a candidate dose to discuss with the regulators and execute the foundational work to enable a pivotal phase III trial in second-line RAS mutant non-small cell lung cancer to begin in 2024, while we continue collecting durability data. The blended objective response rate in pancreatic ductal adenocarcinoma in the data we shared in October was a respectable 20%, which may change as we gather more data at higher doses, follow patients on treatment longer, and hone in on a go-forward dose.
One relevant benchmark for comparison we've highlighted is the objective response rate for cytotoxic chemotherapy that has been reported across many studies in second-line pancreatic cancer, which hovers in the 7%-11% range. Notably, most patients treated in the RMC-6236 study so far have had two or more lines of treatment previously... making them third line or later by definition. In the context of third line or later, the reported objective response rate has been 0%-4%, while the response rate for such patients in our study was as high or higher than the overall 20% number. For all of these reasons, our expert advisors and we believe that RMC-6236 is performing well by this standard for patients who are facing grim prospects with standard of care.
While these objective response rate observations are encouraging, we continue to emphasize that objective response rate is not the key clinical endpoint for pancreatic ductal adenocarcinoma, since rapid progression with short overall survival is the norm, even in those who respond initially to established treatments. We expect that doctors, patients, regulators, and payers will be driven by durability of clinical benefit, as indicated by progression-free survival and overall survival. Median progression-free survival for standard second-line pancreatic ductal adenocarcinoma treatment consistently has been reported to be approximately three months and may be shorter for patients beyond second line. It's too early for us to project these parameters for RMC-6236, and it will take some time into 2024 for us to be able to establish a true median PFS. But here, there are also encouraging signs.
The disease control rate we shared in October was 87%, significantly higher than most reports for salvage chemotherapy in pancreatic cancer. Many patients on study have already crossed the median PFS threshold mentioned above and remain on treatment, including as far out as 48 weeks. This statement is true even for patients who have not yet shown an objective response. 20% of patients without a partial response were still on drug at 18 weeks, with many of these 20% having reached 21 or more weeks while continuing on drug, well past the short duration benchmark for second-line pancreatic ductal adenocarcinoma. Even the few patients with a partial response who progressed did so at 18 weeks or later. These are highly encouraging findings.
Finally, we believe we have a proposed recommended phase 2 dose for lung cancer in hand now, and expansions are underway to develop a robust data set we think is needed to satisfy Project Optimus. We have strong conviction about the potential clinical impact of RMC-6236 in serving the real unmet needs in lung cancer and with continuing consultation with advisors and engaging as appropriate with regulators. In 2024, we expect to initiate a pivotal phase 3 monotherapy, second-line, non-small cell lung cancer trial focused on achieving full regulatory approval and with a potential accelerated approval opportunity built in via an interim analysis. Investigators globally are highly interested in participating in this study. We are likewise excited about the potential for RMC-6236 in pancreatic cancer, where unmet needs are certainly profound.
Here, PFS is the gating parameter for advancing into late-stage development, since ORR is an unreliable predictor of durability. We expect to establish RMC-6236's durability profile via median PFS and identify a recommended phase 2 dose in 2024. With that in hand, and continuing consultation with advisors and engaging as appropriate with regulators, we are designing a pivotal monotherapy trial in pancreatic cancer, potentially to be initiated in 2024. Our base plan currently is a phase 3 randomized trial for second-line treatment, but we are also evaluating options that could accelerate our reach into first line. Investigators globally are highly interested in participating in this study or studies as well.
Next, I'd like to comment on our exciting second investigational drug to show clinical activity, RMC-6291, for RAS G12C cancers, and try to paint the picture we see based on the recent update and extensive dialogue with investigators and clinical experts. First, objectively, and by investigators who have treated more than 63 patients so far, RMC-6291 is well-tolerated across a wide range of clinically active doses, and so far, investigators report that it is well-tolerated. Asymptomatic prolongation of QTc on electrocardiogram has been seen in some patients, only infrequently exceeding the 500 millisecond threshold. Investigators broadly do not consider this laboratory finding a key limiter to clinical development of this compound. Second, good tolerability enables continuity of treatment, and patients receiving RMC-6291 have required few dose interruptions and even fewer discontinuations for intolerability.
Third, RMC-6291 has shown objective antitumor activity, both by radiographic imaging and ctDNA quantitation in both Non-Small Cell Lung Cancer and colorectal cancer. Notably, in lung cancer, the ORR in the data we shared in October was 50% in patients who had recently progressed on prior treatment with an approved KRAS G12C ON inhibitor. The only comparable reported data in similar patients using a G12C ON inhibitor showed an objective response rate of 7%. Similarly, the ORR for single-agent RMC-6291 was 43% in colorectal cancer patients who had not yet experienced a RAS inhibitor, similar to reported data from G12C ON inhibitors when used in combination with anti-EGFR antibodies. These results indicate two dimensions of clinically meaningful differentiation from other KRAS G12C inhibitors.
This differentiation is highly encouraging for the potential of RMC-6291 itself as a drug, and it supports our preclinical prediction that inhibition of the RAS(ON) state in a human tumor may be biologically differentiated relative to inhibition of the RAS(OFF) state. Further, we believe this paradigm likely applies across our portfolio of RAS(ON) inhibitors, boosting the probabilities of success across our entire deep pipeline. Fourth, based on these findings, we believe that RMC-6291 is an investigational drug with a profile that deserves to be evaluated in a late-stage development program. There remain several options to be considered, and strategic decisions will need to be made among them based on further data we are collecting.
These include monotherapy approaches built directly upon the differentiated response profile described above, and we are currently conducting monotherapy dose optimization with the goal of selecting the single agent recommended phase 2 dose with a Project Optimus data package that supports it. We are also committed to evaluating several compelling combination options very soon, and indeed, have already begun recruiting for the exciting pairing of RMC-6236 plus RMC-6291, based on compelling preclinical observations. In aggregate, these findings are highly encouraging and point to large opportunities ahead for these first two compounds. Based on this momentum, we look forward to completing the acquisition of EQRx. Let me summarize the status briefly.
We expect to acquire EQRx in an all-stock transaction to gain an estimated $1.1 billion in additional net capital after estimated post-closing EQRx wind down and transition costs, a significant quantum of capital that can be deployed for RevMed programs and more than we had estimated conservatively when we signed the deal. Our strength and balance sheet is intended to enable the larger investments needed to support the parallel data-driven, late-stage development for our RAS(ON) inhibitor pipeline, focused initially on RMC-6236, RMC-6291, and RMC-9805. Our shareholder meeting to vote on the transaction is scheduled for November eighth, 2023, at 11 A.M. Eastern Time, and the deal is expected to close shortly following the shareholder vote, subject to satisfaction of customary closing conditions.
The stock exchange ratio, determined and announced last week was as follows: Each common share of EQRx outstanding will be exchanged for 0.1112 common shares of RevMed. We estimate we will be issuing approximately 55 million new shares to EQRx shareholders as part of this merger, thus acquiring approximately $20 in estimated net capital per share of the common stock issued in connection with the merger, based on our updated net cash projection. Revolution Medicines will continue to focus on our mission to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. Now, let's hear from Jack Anders, our CFO, regarding our Q3 financials. Jack?
Jack Anders (CFO)
Thank you, Mark. Turning to our third quarter financials, we ended the quarter with $813.2 million in cash, cash equivalents, and investments. Please note this balance does not include any net proceeds from the anticipated acquisition of EQRx, which is expected to add approximately $1.1 billion in net cash proceeds should the transaction close. Total operating expenses for the third quarter of 2023 were $123.2 million. The increase in operating expenses over the prior year period was largely due to clinical trial and manufacturing expenses for RMC-6236 and RMC-6291, an increase in research expenses associated with our preclinical portfolio, and an increase in personnel-related expenses resulting from additional headcount.
GAAP net loss for the third quarter of 2023 was $108.4 million, or $0.99 per share. We are updating our financial guidance and expect full year 2023 GAAP net loss to be between $385 million and $415 million, which includes estimated non-cash stock-based compensation expense of $45 million-$50 million. The increase in GAAP net loss guidance is largely due to the anticipated acceleration of a portion of RMC-6236 manufacturing spend, originally planned for 2024. This spend was accelerated as a result of the progress in our RMC-6236 program. We reiterate cash runway guidance into 2025 based on our current plan. Please note that our current financial guidance excludes the impact of the proposed EQRx transaction. And with that, I'll now turn the call back over to Mark.
Mark Goldsmith (Chairman and CEO)
Thank you, Jack. We believe Revolution Medicines has an unprecedented opportunity to deliver high impact benefit to patients through our pipeline. Toward that goal, the deal with EQRx will markedly enhance our ability to bring the most out of these exciting compounds.
...We have heard broad and strong support for the RevMed portfolio, approach, and proposed transaction. The board and management of RevMed encourage all of our shareholders to vote in favor of the EQRX transaction. The employees of Revolution Medicines renew our deep commitment to outsmart cancer on behalf of patients and to build share value for our investors.
Operator (participant)
At this time, if you would like to ask a question, please press star one one on your touchtone telephone. Again, for any questions, please press star one one. One moment for our first question. Our first question will come from Marc Frahm of TD Cowen. Your line is open.
Marc Frahm (Biotechnology Equity Research Analyst)
Hi, thanks for taking my question. I recognize it's not been a lot of time since the data cuts that were presented back at ESMO and ENA, but there were a few patients who were unconfirmed but ongoing in partial responses at that time. I'm not sure if you're able to update if some of those have been able to have subsequent scans and that can actually confirm. And then maybe a bigger philosophical question. Just, you know, over those meetings, we also saw, and in the last few months, we've seen a handful of trials, you know, take on Docetaxel in the second-line setting lung cancer, a handful of different settings within lung cancer. And, you know, often drugs that look pretty promising have struggled a bit to, or even failed to beat Docetaxel.
Just philosophically, since the safety profile looks really good, you know, why be aggressive and take Docetaxel on straight on instead of trying to combine with Docetaxel, since that, you know, that would seem to be a much easier hurdle on an efficacy side?
Mark Goldsmith (Chairman and CEO)
Thanks a lot, Marc. Appreciate your questions. Let me comment first on the question of confirmations. You know, a number of those patients really had just squeaked in in the advanced period we required in order to report them, which means that they just had one scan, and it's only been a couple of weeks since then. So I think for most patients, we just don't have any more information, so I can't really provide an update today. The question of Docetaxel as a comparator versus for a monotherapy trial versus waiting for a combination. Well, I think in part the question answers itself a little bit, but maybe Steve Kelsey can give you a little bit more philosophy around that.
Steve Kelsey (President of R&D)
I think, Mark, the principle which we're trying to carry through the whole portfolio, irrespective of lines of therapy, is we'd like to get chemotherapy out of the equation if we possibly can. So a good starting point would be a single agent study against Docetaxel to try and beat it really. I think leaving chemotherapy like Docetaxel in the sort of therapeutic armamentarium for patients is suboptimal. I think that we would just rather try and beat it hands down and relegate the Docetaxel to a later line of therapy, frankly. I appreciate that it is certainly an option to do, to have Docetaxel in both arms, but that's not really the philosophical basis of our portfolio.
Marc Frahm (Biotechnology Equity Research Analyst)
Okay, thank you.
Operator (participant)
One moment for our next question. Our next question will be coming from Eric Joseph of JPMorgan. Your line's open.
Eric Joseph (Executive Director)
Hi, evening. Thanks for taking the question. I just wanted to try and get a little bit more incremental color on the tolerability profile that you're observing at the 400 milligram cohort and whether you see room to further dose escalate. I know that 500 milligrams was something that you were contemplating. Just as we think about your backfilling of some of the previous dose cohorts, can you just kind of elaborate a little bit on your sort of strategy there, what cohorts you're prioritizing, perhaps whether you're opening the criteria up for patients with G12C mutation, and perhaps also just sort of how colorectal cancer patients might sort of fall within that scope.
Is that a histology you're keen on sort of revisiting here within the phase 1 setting? Thank you.
Mark Goldsmith (Chairman and CEO)
Thanks a lot, Eric. I'll take the first question, and Steve can comment on the second. The first about tolerability. We don't really have any incremental information compared to what we just reported two weeks ago. And as you know, once we have the information, we'll submit it to the dose selection committee, and they'll determine where we are with it, whether or not it's a good dose, whether or not we should advance the dose. You know, those determinations will be made in the right timeframe with the right data. The second question, I think the question really was what's the range of options that we're looking at for combinations over the next 12 months, and how would we prioritize those?
Eric Joseph (Executive Director)
Really, more sort of, it's actually more about, as you are backfilling some of the prior dose cohorts, you know, to sort of, you know, take into, into consideration when thinking about or selecting the, the phase II recommended dose. I guess really it's a matter of what dose cohorts, which dose levels are you, perhaps accruing more aggressively, prioritizing? And whether, sort of the patient mix going in is, either perhaps being more concentrated to certain histologies or perhaps even being opened up as well.
Mark Goldsmith (Chairman and CEO)
Got it. Okay, so it's about monotherapy and dose selection.
Eric Joseph (Executive Director)
Yep.
Mark Goldsmith (Chairman and CEO)
Comment.
Steve Kelsey (President of R&D)
For pragmatic reasons, Eric, which are related to, firstly, the number of patients queuing up to get on the study, and secondly, the relative paucity of guidance coming from the FDA about the specific requirements to fulfill the Project Optimus initiative. We are aggressively backfilling most of the dose levels actually at 300 and below. The priority right now is to backfill them with patients who have non-small cell lung cancer and pancreatic cancer, because those are the ones that the FDA are going to be interested in in the exposure-response analysis that we submit to them for, so when we recommend a go-forward dose into phase III. There is an amendment to this protocol which has now been approved.
It's on clinicaltrials.gov, which allows us to expand in several different histologies, including colorectal cancer and other tumor types. And it also include, does include G12C mutant tumors. But that's completely separate from the exercise to select the recommended phase II dose for both non-small cell lung cancer and pancreatic cancer. The parallel activities at the moment.
Mark Goldsmith (Chairman and CEO)
Okay, great. Very helpful. I appreciate taking the question.
Operator (participant)
One moment for our next question. Our next question will be coming from Jonathan Chang of Leerink Partners. Your line's open.
Jonathan Chang (Senior Managing Director)
Hi, guys. Thanks for taking my questions. First question, how should investors be thinking about timelines for next data updates across your pipeline?
Mark Goldsmith (Chairman and CEO)
Yeah, I don't have much specificity on that right now. Obviously, we've been asked that a lot over the last couple of weeks. We just need to see how things play out. I think it's pretty clear what we're trying to do in the near term. It's largely around dose selection and acquiring more durability data and to some degree more ORR data at higher doses. So, you know, I don't think we're talking years out, but I can't give you specificity. The most, you know, sort of narrow question we get asked is, will we make a presentation at ASCO? I just don't know.
In order for us to do that, we'd have to submit an abstract in February, which means we have to know what it is we're going to present in May to do so. So we'll just have to see. But we'll try to provide more clarity once we sort of get past these next couple of months and give some more specificity about expected milestones in the coming year.
Jonathan Chang (Senior Managing Director)
Understood. And second question: What do you see as the duration of disease control and PFS benchmarks in previously treated PDAC? And what do you see as sufficiently good duration of disease control and PFS data relative to those benchmarks?
Mark Goldsmith (Chairman and CEO)
Yeah, I think Steve can comment mostly on the first part of that question because that's objective information. And then as to what we consider an improvement, you know, will be the subject of ongoing conversation with experts in the FDA.
Steve Kelsey (President of R&D)
Yeah, the benchmark right now is pretty universally set at around three months. There are a few series where the PFS is two months and one or two, where it's longer than that. But the vast majority of studies that have been done in that second-line salvage setting show a three-month PFS. Frankly, that's when the, that's when the scans are done, and there's a very dramatic drop-off in freedom from progression at the point at which that second scan is done. I think that's the key. That's definitely the benchmark to beat. Your, your question about how good is good, I mean, there are three constituencies that we have to satisfy here. There's the, the regulators, there's the prescribers, and then there's the payers, and those exist in multiple geographic jurisdictions.
I think the consultations that are ongoing with those constituencies will ultimately decide what is good enough, and then we'll be able to benchmark our actual data against that and decide if that's a meaningfully important improvement and decide whether to go forward and how.
Jonathan Chang (Senior Managing Director)
Understood. Thanks for taking my questions.
Operator (participant)
One moment for our next question. And our next question will come from Chris Shibutani of Goldman Sachs. Your line is open.
Charlie Ferranti (Biotech Equity Research)
Hi, everyone. This is Charlie on for Chris. Thank you so much for taking our questions. Just to start, wondering if you could provide some clarity on the 6236, 6291 combination trial that's enrolling. Who are you actively recruiting in terms of G12C experience versus naive patients in that study? And then my second question is just regarding the potential for tissue-agnostic approval. What does the team see as the clinical bar to reach there in terms of ORR? Thank you.
Mark Goldsmith (Chairman and CEO)
Just a clarification on your second question, Charlie. Were you asking about for the combination or for either of those compounds individually or just more generically?
Charlie Ferranti (Biotech Equity Research)
I guess more generically.
Mark Goldsmith (Chairman and CEO)
Okay. All right, thanks.
Steve Kelsey (President of R&D)
The 6236, 6291 combination protocol right now is enrolling both lung cancer and colorectal cancer patients. The colorectal cancer cohort will prioritize patients who have not had a G12C inhibitor. The lung cancer cohort right now allows either. We're not at the point where we're biasing in any one direction or the other right now because we're still in the dose escalation, dose finding, dose exploration mode, and it doesn't really matter, frankly, what disease or prior treatment the patient has for that, for that, for that purpose. As soon as we've got a dose for that combo, then I think we'll be a little bit more selective about the patients that we want to encourage into the study, and that will, to some extent, depend on what we've seen during the dose escalation period.
I think everybody knows, you know, accelerated approval is getting a little bit harder. The gloss is coming off it a little bit. The bar moves around depending on the indication, frankly. But, accelerated approvals traditionally have been given for, single agents with response rates in the sort of 25%-30% range, and I don't expect it to be any different for a RAS inhibitor and a RAS mutant, disease, particularly as the precedent has essentially been set by the accelerated approvals of, Sotorasib and Adagrasib.
Mark Goldsmith (Chairman and CEO)
He was, he was asking specifically about a tissue-agnostic, tumor-agnostic strategy.
Steve Kelsey (President of R&D)
Yeah, I think, though, but I think you know, in the core indications if you pursue a tissue-agnostic strategy, there's gonna be a couple of indications that are gonna dominate that cohort. And I think the response rate has to be, you know, in that sort of 30% range, I think, in order for anyone to take that seriously. Clearly, you know, the point of the tissue-agnostic strategy is there's gonna be some indications which are so uncommon, there's only gonna be a handful of patients, and you won't be able to compute a response rate with any degree of certainty. So we're really talking about the confidence intervals around the overall response rate for lead indications within that cohort.
Charlie Ferranti (Biotech Equity Research)
Great. That's very helpful. Thank you both very much.
Operator (participant)
We do have time for two more questions. One moment for our next question. It will be coming from Ami Fadia of Needham. Your line is open.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
Good evening, and thanks for taking my question. With regards to the pivotal trial you're planning in lung, do you believe that you need to generate data in G12C patients before you begin the trial? And perhaps, give us a sense of the number of patients you think you need to enroll for this type of a nested trial design. Thank you.
Mark Goldsmith (Chairman and CEO)
Thanks, Ami. I think Steve can comment on that.
Steve Kelsey (President of R&D)
I didn't quite understand the first part of your question. Is it-
Mark Goldsmith (Chairman and CEO)
Do we need to validate G12C in humans before-
Steve Kelsey (President of R&D)
Before we include them in a pivotal trial?
Mark Goldsmith (Chairman and CEO)
Yeah.
Steve Kelsey (President of R&D)
Validation is obviously a sort of a fairly hard-baked word. I think we want some experience in those patients before including them as a significant part of a pivotal trial. But everything that we have learned from the preclinical models would lead us to expect the activity in G12C mutant lung cancer to be very similar to the activity in G12D and G12V mutant lung cancer for RMC-6236. And so I don't think we'll validate, but we're gonna try and get some information that will help reassure us that what we've seen in the preclinical models is also true in the clinic. With regards to numbers, again, you know, we're still refining the study design.
We have, it's, you know, we obviously have to design that study. We have to discuss it with the, with the regulators, and we're still debating whether the G12C mutation should be in the, in the inner nest or the outer nest, frankly. So, as soon as we have finalized that study design, I think we'll be in a better position to, to explain what it is and what we've, and why we've done that. Right now, there are just a little too many moving parts to be able to be-
Jack Anders (CFO)
... as clear as we might like to be with you right now.
Mark Goldsmith (Chairman and CEO)
Yeah, and if I could, if I could add to that on that last point, you know, what Steve's alluding to is sort of regardless of our confidence in the activity against G12C, there still are operational issues associated with having approved G12C inhibitors available and, you know, dozens of, G12C inhibitors, G12C off inhibitors in clinical studies. And so there are risks associated with that cohort, you know, regardless of the performance of 6291. And so managing that is part of what we're thinking through, and that, that'll probably have more impact on whether G12C ends up in, in the cornerstone or, or on the periphery, because we want to make sure to protect, you know, the entirely unserved, the population that's entirely unserved by targeted therapy today, which is the G12X without C.
But we're interested in both, and we'll have to sort that out.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
If I may just ask a quick follow-up, and maybe if you could sort of just explain the concept of the nested trial design. The way I understood it was, you would power each subset,
Mark Goldsmith (Chairman and CEO)
No.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
To be able to-
Mark Goldsmith (Chairman and CEO)
No.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
Sort of...
Mark Goldsmith (Chairman and CEO)
No.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
Okay, if you could just clarify.
Mark Goldsmith (Chairman and CEO)
Yeah. No, the way it works is the core nest gets evaluated statistically first. So you enroll patients however they enroll. It has nothing to do with the sequence of enrollment, but then statistically, you test the core group that you predesignated as the core group. If that scores positively, then that permits you to go on to evaluating the larger group that still includes the core, but also now includes additional patients. And then you can keep... I mean, you could do that 100x if you wanted.
You can keep, you can keep recycling the statistical power, but it's if at any point you have to make sure you do it in the right order, because if at any point you don't see positivity, then you no longer can go on and test even larger groups because it would be, it would be futile to do so.
Ami Fadia (Managing Director and Senior Biotech Equity Research Analyst)
Got it. That's very helpful. Thank you.
Operator (participant)
One moment for our last question. Our last question will come from Alec Stranahan of Bank of America. Your line is open.
Alec Stranahan (VP)
Hey, guys. Thanks for taking my questions and for squeezing me in. Just a couple. At a high level, could you maybe talk about anticipated expense ramp to support the multiple mid and late-stage studies you have planned for 6236 and the new candidates from the RAS innovation engine? I guess, asked another way, how do you continue to be judicious in your spending, despite having almost $2 billion in cash on the balance sheet, assuming the EQRx deal closes? And just quickly to clarify for non-small cell, is it safe to assume that 500 mgs will not be pursued since you said that the pivotal monotherapy dose has been selected?
If so, is the reason just in terms of speed to start the registrational studies, or was there something in the clinical data that you think makes the 500 dose a non-starter? Thanks.
Mark Goldsmith (Chairman and CEO)
Thanks, Alec, for your questions. On the second question, let me just take care of that one and then come back to the expenses. The comment that we believe we have a recommended phase 2 dose, you know, candidate dose in hand, was specifically with regard to lung cancer, where we already have a response rate that's in the zone of where, you know, it needs to be and where that is generally better correlated with durability. So we can make some good assumptions now, continue planning and kind of pre-execution, and then allow the data to catch up with it, you know, in 2024.
The question about 500 milligrams and higher really, or 400 milligrams and higher, really has to do with pancreatic ductal adenocarcinoma, where we haven't really declared that we have a recommended phase 2 dose in hand. In fact, we've made it pretty clear we want to see what happens not only at 300, but at 400 milligrams. And then, as we commented earlier, if we clear that dose level and the dose selection committee wants to advance to 500 milligrams, well, then that's what we'll do. So just to separate, though, the two statements, they're really. They don't go together. They're on different concepts. Expense ramp. Jack, you want to comment on it?
Jack Anders (CFO)
Yeah, we haven't necessarily given out any specifics on forward-looking expense guidance outside of our 2023 GAAP net loss guidance. But it is fair to say that our expenses will increase from current levels. We are going to be making investments in these programs. We do need some more data in order to fully understand what those investments are. And I think your question is, you know, whether we're going to be judicious and with our spend. I mean, we obviously... we need to make investments, but we're gonna be wise about the spend on a go forward basis, but we haven't given any specifics.
Mark Goldsmith (Chairman and CEO)
Yeah. If I could just build on Jack's last comment there. The whole point of the transaction is to give us the capital to make the investments in 2024 and 2025, and beyond that we really need to make in order to maximize value creation by evaluating these first two, three compounds, in the right settings, and to evaluate them aggressively in a competitive environment, taking into account also all the downstream commercial considerations and regulatory context, exclusivity and pricing and so on. So, we will be increasing our spending, there's no doubt, but I think it will increase our productivity and maximize value creation.
Our focus is not immediately on hoarding the capital, but at the same time, obviously, we'll make data-driven decisions, and we have lots of internal checks and balances to make sure that we do so and that we do so in close alignment with a compelling strategy.
Alec Stranahan (VP)
Thank you.
Operator (participant)
I would now like to turn the conference back to Dr. Mark Goldsmith for closing remarks.
Mark Goldsmith (Chairman and CEO)
Thank you, operator. Thanks to everyone for participating today. We appreciate your continued support of Revolution Medicines.
Operator (participant)
This concludes today's conference. Thank you for participating. You may now disconnect.