Okay, thank you. Good morning, everyone. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. Our next presenting company is Revolution Medicines, and to talk us through the story today is CEO Mark Goldsmith. There's a Q&A after the presentation, so if you have a question, just raise your hand, and we'll bring a mic over to you. And for folks tuning in via the webcast, feel free to submit a question via the portal, so with that, Mark, thank you.
Good morning, everyone, and thank you, Eric and J.P. Morgan, for the invitation to speak today. Please review our notice on slide two regarding legal disclaimers. At Revolution Medicines, our mission is to revolutionize treatment for patients with RAS-induced cancers through the discovery, development, and delivery of innovative targeted medicines. We're proud to be pioneers in this space. We are the first to develop oral drug candidates that target the active oncogenic ON state of RAS, the common driver of life-threatening cancers.
Scientific innovation by our organization has given rise to the first three RAS(ON) inhibitors with highly differentiated and promising clinical profiles, including RMC-6236, our groundbreaking multi-selective RAS(ON) inhibitor to be known by its generic or international non-proprietary name, daraxonrasib. RMC-6291, our distinguished G12C selective inhibitor to be known as elironrasib. And RMC-9805, our highly innovative G12D selective covalent inhibitor to be known as zoldonrasib. In 2024, we continue to build a track record of effective execution by advancing this exciting pipeline, and we begin 2025 with the talent, the capabilities, and the financial wherewithal to continue solidifying our position as leaders in the treatment of patients with RAS-induced cancers. Today, let's begin with a strategic roadmap for our ambitious vision and then focus on our key 2025 priorities.
There are several strategic components to maximizing the impact of our RAS(ON) inhibitors for patients with RAS-induced cancers. Our near-term aim is to commercialize daraxonrasib initially in late-stage disease, supported by the ongoing RASolute- 302 study in previously treated metastatic pancreatic cancer and the pending RASolute-301 study in previously treated non-small cell lung cancer. In parallel, we are moving aggressively to develop RAS(ON) inhibitors in earlier lines of therapy, including first-line metastatic, locally advanced, unresectable, and adjuvant treatment settings. A key element of the earlier disease strategy is developing optimal, biologically rational drug combinations, and as an organization learning valuable lessons every day from our uniquely broad clinical program, we also work to sustain our strategy by continuously producing innovative and differentiated drug candidates for patients.
RevMed's vision is to create the industry-leading targeted medicines franchise for patients with RAS-induced cancers, and our priorities in 2025 are based on three pillars. First, our pioneering clinical-stage RAS(ON) inhibitors have shown our discovery capabilities to be among the most innovative and productive in the industry. Aiming to sustain this position, we intend to progress a fourth program to clinic readiness, RMC-5127, selectively targeting RAS G12V, and also to advance next-generation RAS-focused programs that we expect will continue to raise the bar for what's possible in treating patients with RAS-driven cancers. Second, our first-class development capabilities have been demonstrated by efficiently advancing multiple assets through first-in-human studies and advancing into late-stage development. We're now focused on executing registrational trials for daraxonrasib in previously treated pancreatic and lung cancer and on advancing this compound into a first pivotal trial in first-line pancreatic cancer.
Committing to a first pivotal trial with elironrasib or zoldonrasib is also a strategic priority. Third, as we build our platform for delivering products to patients, that includes U.S. commercial and medical affairs infrastructure, we will continue to partner with translational and clinical experts and leading patient advocacy organizations. We're also now manufacturing daraxonrasib at commercial scale. A key priority in 2025 is to continue building out these operational capabilities in support of a successful U.S. launch, of course, subject to FDA approval for daraxonrasib . We also continue exploring potential commercial partnership opportunities to help us serve patients outside the U.S. Revolution Medicines has focused during most of its 10 years primarily on unmet needs in RAS-dependent cancers.
RAS is a cellular switch normally cycling between off and on states in a controlled fashion to regulate normal cell growth, and a wide range of RAS mutations can cause abnormally high levels of activated RAS(ON) , thereby driving excessive cell growth that underlies nearly all pancreatic cancers and a significant share of non-small cell lung and colorectal cancers. Therefore, inhibiting RAS(ON) signaling is a central objective in serving patients with these difficult-to-treat tumors. Our sophisticated drug discovery platform delivers compounds that bind to and inhibit diverse RAS(ON) proteins, leveraging both chemistry and a unique mechanism of action that are differentiated from those of first-generation RAS(OFF) inhibitors. To date, we've reported extensive preclinical and clinical validation of this approach through 128 scientific presentations and six published peer-reviewed scientific papers. We've had substantial clinical experience with investigational drugs derived from this scientific work.
More than 1,000 patients have participated in a clinical trial with one or more of these. We're proud to note that the generic names for these drugs, these drug candidates, are all centered on the phrase onrasib that alludes to this innovative mechanism of action for the new class of compounds. Our development vision for these assets is to maximize the clinical impact across tumor types and lines of therapy through both single-agent approaches and combination strategies. I'd like to take a few minutes now to review the profile and strategic focus for each of these three drug candidates. The crown jewel in our portfolio, daraxonrasib, commonly known as RMC-6236, is a first-of-its-kind RAS(ON) multi-selective inhibitor that is active against a wide spectrum of RAS driver mutations.
Daraxonrasib has the potential to inhibit most or all primary RAS cancer drivers and to counter many secondary RAS mutations and wild-type RAS that often underlie resistance to first-generation RAS(OFF) inhibitors. This bold compound is clinically active against many tumor types, including pancreatic, non-small cell lung, and colorectal cancers. Based on the strength of the first-in-human study, we have launched our first registrational study for daraxonrasib as an oral, once-daily monotherapy in patients with previously treated metastatic pancreatic cancer. An expanding number of U.S. clinical study sites are actively enrolling patients, and we have received regulatory clearance to open sites in the EU and Japan. We also expect to reach regulatory alignment and initiate a registrational study for patients with previously treated non-small cell lung cancer this quarter.
In addition, we are exploring daraxonrasib as a first-line treatment in pancreatic cancer as monotherapy and/or in combination with standard of care, and initiating a pivotal trial in 2025 is a priority. In addition to the standout performance of daraxonrasib monotherapy, we have our sights on multiple combination approaches. Encouragingly, in combination with pembrolizumab, it has shown little evidence of synergistic toxicity, opening the path to further evaluation in patients with first-line lung cancer. We are also evaluating combination approaches in colorectal cancer and other RAS-driven tumors. Let me briefly highlight the compelling clinical data that we shared in 2024 for monotherapy daraxonrasib. The major form of pancreatic cancer, pancreatic ductal adenocarcinoma, or PDAC, is a grave RAS-driven disease, largely treated by chemotherapy rather than targeted drugs today, and with significant room for improvement in treatment outcomes.
Daraxonrasib exhibited a manageable safety profile with favorable dose intensity in patients treated with 300 milligrams daily, the phase 3 dose for pancreatic cancer. Previous phase 3 studies with common chemotherapy regimens for previously treated patients with metastatic disease have reported progression-free survival of approximately three months and overall survival of approximately six months. As the Kaplan-Meier graphs from the 6236-001 study shown on slide here indicate, the median progression-free survival and overall survival estimates for the second-line patients treated with daraxonrasib at 300 milligrams in the single-arm study are compelling. As of the data cutoff, the progression-free survival was estimated to be 8.8 months for patients receiving daraxonrasib for tumors harboring a KRAS G12X mutation and a very similar 8.5 months for patients with tumors carrying a broad range of RAS mutations.
While the median overall survival duration for patients in this study had not yet been reached, it is striking that 100% of patients treated for tumors carrying a KRAS G12X mutation were alive at the six-month mark, and 97% of patients with broader RAS mutations also at the six-month mark. These data reinforce our confidence in the ongoing RASolute- 302 phase three randomized controlled trial. Lung cancer is also a major cause of cancer deaths, and there remains a significant need for new targeted agents designed to treat the roughly 30% of non-small cell lung cancer patients with tumors harboring RAS mutations. Daraxonrasib targets a wide spectrum of RAS mutations that can cause lung cancer, including, again, diverse RAS G12 mutations.
Published reports of phase 3 studies of common chemotherapy regimens for previously treated lung cancer have reported progression-free survival of approximately four months and overall survival of approximately 10 months. As these Kaplan-Meier graphs on slide 10 indicate, as of the data cutoff date, the estimate for progression-free survival was 9.8 months, and for median overall survival was 17.7 months for patients with a KRAS G12X mutation treated with daraxonrasib in the active dose range of 120 to 220 milligrams. I'll now provide a short overview of elironrasib, also known as RMC-6291. Elironrasib targets the RAS G12C variant and has demonstrated encouraging safety, tolerability, and anti-tumor activity in lung cancer patients, including those naive to and those previously treated with first-generation G12C OFF inhibitors. The G12C mutation is found most commonly in non-small cell lung cancer and is represented less frequently in other cancer types.
Given the increasingly competitive G12C inhibitor space, we have prioritized various combination strategies to best demonstrate differentiated clinical impact for elironrasib. First, central to achieving success in first-line treatment of non-small cell lung cancer is safely combining with the dominant standard of care, pembrolizumab. We have reported that previously treated lung cancer patients treated with elironrasib with pembrolizumab showed no signs of synergistic toxicity, including hepatotoxicity. These preliminary findings strongly support further evaluation in first-line patients. Second, the RAS(ON) inhibitor doublet of elironrasib with the multi-selective inhibitor daraxonrasib is an innovative and potentially exciting combination. Since monotherapy treatments with RAS inhibitors in colorectal cancer to date have not proven to be sufficient, more active combination approaches, such as a RAS(ON) inhibitor doublet, could be important options.
Indeed, last month, we reported initial proof of concept safety and anti-tumor activity for this drug combination in patients with late-line KRAS G12C colorectal cancers. While follow-up has been relatively short since our December presentation, based on ongoing assessment, we are encouraged that the majority of these patients remain free from progression and continue on treatment, regardless of prior treatment with a G12C inhibitor plus EGFR antibody. Finally, the favorable initial observations from the doublet of elironrasib plus daraxonrasib , as well as initial evidence that both of these compounds are well tolerated in combination with pembro, encourage us to pursue a potential chemotherapy-free drug triplet, combining pembrolizumab plus elironrasib plus daraxonrasib for first-line patients with advanced KRAS G12C lung cancer. This interesting case study illustrates the anti-tumor activity of elironrasib plus daraxonrasib in a patient with advanced KRAS G12C colorectal cancer.
This patient began receiving RAS(ON) inhibitor doublet therapy after progressing on adagrasib, at which time circulating tumor DNA revealed several recognized RAS inhibitor resistance mutations, the KRAS Y96 mutation and two receptor kinase variants that drive signaling through mutant and wild-type RAS(ON) proteins. After one cycle of RAS(ON) inhibitor doublet therapy, circulating tumor DNA was cleared to below the limit of detection, and the patient developed a partial response, converted to a complete response, and continued on treatment. These observations support the hypothesis that in the doublet, daraxonrasib may suppress the emergence of RAS variants contributing to drug resistance and thereby enhance clinical impact. G12D is the most common RAS mutation in solid tumors and thus deserves a particular focus. Zoldonrasib, also known as RMC-9805, is a groundbreaking oral RAS(ON) G12D selective covalent inhibitor.
We've presented the first clinical data for zoldonrasib monotherapy, demonstrating a highly favorable initial tolerability profile, along with promising initial anti-tumor activity in patients with pancreatic tumors harboring the G12D mutation and treated at the candidate-recommended phase two dose of 1,200 milligrams daily. I'm also pleased to report that zoldonrasib appears to be highly active in patients with previously treated lung cancer harboring a G12D mutation. Moreover, the profile to date is very encouraging for potential combination strategies. Dose escalation for the doublet of zoldonrasib with daraxonrasib has been completed, and the doublet appears to be well tolerated at the single-agent recommended phase two dose for each, with expansion work underway. Finally, we are also evaluating zoldonrasib in combination with chemotherapy and other targeted agents.
Slide 14 provides an example of a response in a patient with non-small cell lung cancer who was treated with zoldonrasib. This patient, who had progressed through multiple rounds of chemotherapy, radiotherapy, and surgical resections, showed a partial response in the first on-treatment scan, including resolution of extensive lung and lymphangitic carcinomatosis. This patient also experienced a substantial improvement in quality of life, including coming off supplemental oxygen within the first week of starting treatment, and she returned to exercising daily. As highlighted moments ago, drug combinations are likely to play a significant role in advancing these assets into earlier lines of therapy. Our portfolio provides a uniquely wide range of options for combinations across various tumors and lines of therapy. A combination highlighted earlier is our innovative RAS(ON) inhibitor doublets, built on the foundation of daraxonrasib paired with each of our mutant selective inhibitors.
Exciting initial data activity of the doublet containing elironrasib against G12C tumors encourages us with regard to doublet combinations containing zoldonrasib in G12D tumors, and we anticipate pursuing a doublet with RMC-5127 in G12V tumors after monotherapy dose finding. A second combination discussed earlier is with pembrolizumab. We observed encouraging initial tolerability profiles for pembro in combinations with daraxonrasib and elironrasib, and an analogous combination with zoldonrasib is on the horizon. Further combination approaches under evaluation include both established targeted agents such as EGFR antibodies and novel agents with compelling preclinical validation such as PRMT5 inhibitors. Finally, while our ambition is to provide patients with chemotherapy-sparing regimens, we are also evaluating RAS(ON) inhibitors in first-line settings in combination with widely used chemotherapy regimens.
All in all, Revolution Medicines has established a strong record of innovation and execution with an industry-leading portfolio of targeted RAS-focused investigational drugs. We pioneered the RAS(ON) inhibitor class of compounds, delivered compelling clinical data from monotherapy with each of our first wave of inhibitors, and reported evidence of promising initial combination strategies, including proof of concept for the first RAS(ON) inhibitor doublet. We continue to deepen our late-stage clinical development presence with registrational studies and paths toward first-line approaches, and we have strengthened our organization and enhanced our core capabilities to prepare for a first regulatory approval. We have developed a range of select partnerships, including with distinguished patient advocacy groups such as the Pancreatic Cancer Action Network, or PanCAN, and industry academia translational research partners such as Break Through Cancer organization.
We ended 2024 in an exceptionally strong financial position, which allows us to continue executing on our ambitious patient-centric mission. This morning, I've walked through an overview of exciting RAS targeted programs. While the quantitative study parameters we report are essential, they certainly don't tell the entire story of how a patient experiences cancer or cancer treatment. To meet patients' needs, it's crucial to understand and address this experience, often including significant pain, nausea, anxiety, and extreme disruptions to life, such as infusion center visits. I'm honored to share with you this painting by Myra Eastman, a friend of ours from Santa Cruz, California, who was diagnosed with pancreatic cancer last year. As an artist, Myra decided to paint her way through the journey to share her experience through these very moving pieces of art that depict different facets of her treatment.
These paintings speak for themselves, and they tell us more about living with cancer than does an objective response rate, a CT scan, or a Kaplan-Meier curve. In addition to extending progression-free and overall survival, it is imperative that new treatments also provide a better quality of life for people living with cancer. Thank you, Myra, from all of us at RevMed for your inspiration. Building on critical achievements in 2024, we enter this year with the conviction to fulfill our responsibility to patients, investors, and employees as we seek to develop the industry-leading targeted medicines franchise for patients with RAS-addicted cancers. This year, as we move closer to fulfilling this vision, a top priority is to successfully execute daraxonrasib registrational trials in previously treated pancreatic and lung cancers. We aim to advance daraxonrasib into a first-line pancreatic cancer pivotal trial.
Another priority is committing to a first pivotal trial for at least one of our mutant selective inhibitors. We also intend to begin making data-driven prioritization decisions regarding combination options for early lines of therapy. In parallel, we are putting the necessary operational capabilities in place to help us deliver a successful first commercial launch. We also expect RMC-5127, our mutant selective G12V compound, will be our fourth RAS(ON) inhibitor to reach clinic readiness. And we never lose sight of the essential role early discovery plays in RevMed's mission, and we will continue to invest in scientific innovation to maintain our leadership position in developing new targeted therapies on behalf of patients with RAS-addicted cancers. We hope 2025 will be another exciting year.
I'd like to recognize the patients, caregivers, and clinical investigators who participate with us in this important work, and to thank RevMed employees for their tireless commitment to patients. Thank you very much.
Well, thanks. We have some time for questions.
Welcome, Steve? / Steve Kelsey.
He's going to join us for the Q&A portion. Thanks, Steve. I can start out. And by the way, if you just have questions, raise your hand. We'll get a mic over to you. With Mark and Steve, with the RASolute, both second-line trials, both in pancreatic cancer and lung cancer getting underway, I know a lot of attention is focused on the front-line opportunities where there are several moving parts, I guess, and seemingly still being evaluated to ultimately inform the path forward there. In pancreatic cancer front line, maybe can you just talk us through what regimen you're sort of evaluating currently with 6236? Forgive me for not using the new name just yet, right? Sort of how far you are in evaluating combinations with chemo to date and the extent to which the signaling you're seeing there is going to inform combination selection in the front line.
Daraxonrasib .
I'm getting there. I've been trying to get there. I'll get there.
Clearly, daraxonrasib is a very active compound in pancreatic cancer based on the second-line and even third-line patients. The study parameters so far, the outcome measures so far, suggest that it would be superior or could be superior to first-line chemotherapy in first-line disease. For sure, we're interested in a monotherapy approach as part of that first-line study. I think the question for chemotherapy combination really has a couple of components. One is that pancreatic cancer doctors are very committed to using chemotherapy because for their entire careers, that's all that's been available, and switching over to something new without having demonstration in first-line patients might be challenging for some of them. That's one reason. A more biologically sound reason is that there could be additivity. They have different chemotherapy, and targeted agents have different mechanisms of action, so there may be additivity between those.
So we're interested in evaluating them. Maybe Steve can just comment on our current status for evaluating with chemotherapy.
Sure. Is this on?
Can you make sure this mic is on?
Is this my comm?
Here.
Okay. Thank you.
Okay. Thank you. That's better. Yeah. So most of you who follow the pancreatic cancer space will know there are basically two types of chemotherapy for patients with advanced disease. One of them is based on 5-FU oxaliplatin-based regimen. It's usually called FOLFIRINOX. There's a variant of that, which is a recently approved liposomal form of irinotecan. The second class of chemotherapy is a gemcitabine-based regimen, which usually includes nab-paclitaxel or Abraxane. So both of those are currently being evaluated in combination with daraxonrasib or RMC-6236. As many of you who follow our literature will know, there is a potential for overlapping toxicity, and so we are evaluating different doses of both daraxonrasib in combination with chemotherapy and different doses of chemotherapy in combination with daraxonrasib.
At the end of the day, we are firmly of the belief that with the data that we have in second-line metastatic pancreatic cancer, the outcomes that Mark reported to you today are actually numerically superior to the outcomes achieved with chemotherapy in first-line metastatic pancreatic cancer, and therefore, we're very much committed to daraxonrasib being a significant component of the first-line regimen, and our philosophy has been that any chemotherapy with daraxonrasib is probably better than chemotherapy. Nevertheless, the studies are ongoing, and as soon as we have them completed, then we can plan our phase three trials, and no doubt at that point, with all of the logistics that we have to go through, we'll be able to report the results of the phase one and phase studies.
And then we'll make a decision about whether to run a two-arm or a three-arm trial just based on that. Okay.
Yeah. Just thinking, I mean, just when it comes to thinking about chemotherapy in front line currently, I mean, these are finite courses of treatment, really, or really, correct me if I'm wrong, but really sort of after a few cycles, there really isn't a maintenance course of treatment. I'm just wondering about the fact that ostensibly benefit with daraxonrasib in sort of like a post-chemo window is kind of an easy unmet need opportunity where it could be used.
Okay. Good job on that.
Okay. Yeah. Great.
Yeah. I mean, Steve probably has a nuanced answer.
I mean, again, let's be clear. There's an opportunity here for combining with chemotherapy, and hopefully, the chemo will make the daraxonrasib better or the daraxonrasib will make the chemo better. A lot of patients don't even get to the end of their chemotherapy. I mean, this is such an aggressive disease that a lot of patients are progressing before they've even finished their last cycle of chemotherapy. The other challenge, of course, is that the chemotherapy itself is extremely toxic and is often dose-limiting. Patients are compromised by recurrent bouts of hematologic toxicity, GI toxicity, and neuropathy, which is cumulative. And so, but for the patients that do manage to get to the end of their chemotherapy, yeah, once it finishes, there's a very finite amount of chemotherapy that the human body can tolerate. Those regimens were designed based on a maximum tolerated dose principle.
So patients are taken right up to the edge of what is actually tolerable. And there's a huge opportunity, obviously, to try to prevent the inevitable progression that occurs after you've finished chemotherapy. And this is where we really do believe, Eric, that daraxonrasib has a huge potential because a lot of those progressions are due to reactivation of RAS signaling. And as we've already said, daraxonrasib has a very broad anti-RAS activity, not just against the primary driving mutations, but against potential emergent new mutations that cause resistance and against wild-type RAS signaling that also is a very common cause of progression, both in clinical trials and in preclinical models.
Question over here.
How are you thinking of the IO combo?
Wait one moment.
Question over here.
Thank you.
How are you thinking of the IO combos in the GI space? So the CRC and the.
Yes. Well, we're certainly interested in them. The primary focus so far has been to get through the established IO combination in lung cancer since that obviously is a high priority. And I think we feel very confident we'll be able to do that with daraxonrasib or 629, elironrasib, or the two of them together. But we do have belief that there is justification for evaluating it in the GI tract. I don't know if you want to put any framework around how we.
Let's firstly, the GI space isn't really a single space. First, we have to draw a very broad distinction here between colorectal cancer and pancreatic cancer, which I think are two very different diseases. Let's just stick with this generally. We are very interested in the role of the immune system in all of the RAS-driven cancers and particularly in the role of our RAS(ON) inhibitors to modulate the immune microenvironment. I don't think that the interest in the immune system as a way of augmenting RAS inhibitors is restricted just to checkpoints. There are a number of other immunological interventions that we have been exploring preclinically and would be very interested to take those further into clinical evaluation.
We just haven't done that yet for a number of logistical reasons, mainly due to the fact that we have a lot of other higher priority things to be getting on with right now, but also due to the fact that there are other companies with these really interesting immune modulators, and negotiating those sort of types of clinical collaborations is also time-consuming as well, so definitely on the cards. Very interested. We've published a lot of data, as have other people, on how RAS inhibition favorably modulates the immune microenvironment, so it is a priority for us generally.
Yeah. The last point that Steve just made, just to emphasize it for folks who aren't as familiar, that we talk about inhibiting RAS as a way of killing the tumor, but it also very much has implications for very, very profound changes in the tumor immune microenvironment that reverse some of the adverse effects that the RAS-driven cancer promotes, and that's really important for potential additivity or synergy, as Steve alluded to.
Thank you.
Within the activity and durability data that you've presented so far with daraxonrasib, I guess, how should we think about any potential variation in likelihood of response or durability of response by a particular G12 mutation? And I guess this is something where you might present data foreseeably.
Right. So the question is, how different are the different genotypes in the biology that they drive sensitivity to a particular RAS inhibitor? You started with daraxonrasib . We don't really know the answer to that, to be honest. There's a whole scientific field, a whole sort of subfield of studying this. But the fact is, if you go back to just the chemotherapy literature, of which there is a large amount, and ask whether or not these tumors with different RAS genotypes respond differently to or have different durability in their response to chemotherapy, the answer is hard to tell from the literature. You can find papers that are completely contradictory to each other, which means neither of them knows the answer to that. So if that's not established after 20 years of doing this, the bar is a quite difficult question to answer.
We sometimes see some differences, but they're with relatively small numbers, even in our largest studies. The phase three studies will be larger. They still won't be as large as the chemotherapy retrospective studies that have been done by any stretch of the imagination. So we do get asked this question a lot. I would just encourage people to recognize it's a difficult question to answer. And so I would not set the expectation that we'll be able to speak at the next conference and tell you the answer to that question.
Are regulators kind of seeking an answer to that question in terms of the feedback they've given you on trial design?
We've done this grouping, particularly G12X, which was based on good scientific empirical evidence in preclinical models that the G12X tumors tended to behave better with RMC- 6236, not because the compound binds differentially to those different genotypes. This has to do with cellular wiring among these different tumor types and different mutations. So we've prioritized that grouping, and that's what we've presented to the FDA. And I think that they understand that grouping and haven't really shown any resistance to it. That doesn't mean that there won't be subset analyses done as part of ultimately evaluating for approvals. But I think the main drivers will be the endpoints that we're agreeing on with the FDA as the endpoints. And those endpoints are more around groups and not individual genotypes.
And just kind of picking up on the groupings that you're.
By the way, there are only two groups. There's G12X and there's non-G12X.
Right.
Right.
Yes. And with those two groups, you're doing sort of a nested analysis for your primary endpoints of PFS and OS. I guess to enable as broad a label as possible, what do you need to satisfy for the non-G12X component? Do you need to see, I don't know, in terms of numbers there, you'd be able to see a significant difference there? Is it more of a trend? What needs to be satisfied in order to allow for?
Yeah.
Yeah, as broad a label as possible.
so the core methodology of nesting involves first, in isolation, evaluating the core of the study, which is the G12X population, quite independently of anybody else who happens to be enrolled. If we satisfy the endpoints, then a broader analysis is done of the core plus the non-G12X, so the G12X plus. And then that is studied statistically to see if, again, those outcome measures meet statistical significance. That's the formal established part of the testing. It really doesn't involve separately looking at the non-G12X. As I alluded to, though, for sure, the FDA will, and I'm sure we will, provide data that allows them to cut it by non-G12X. Not sure that there will be enough patients to be able to say Q61L versus Q61H versus Q61R, but certainly, there'll be some effort to look at those.
That's done more as a sort of a sensitivity testing than it is. It's not really asking the independent question of whether you robustly demonstrate the differences. So it's more, is there anything underlying this larger group that we're missing here? That's what it's looking for. So I still don't think you'll come back with an answer that you're asking for. As I said, we get asked this a lot for what the non-core group looks like on its own, that we won't really have a definitive answer to it, but we'll have a sense of it from the sensitivity analysis.
Yeah. And maybe a last quick question on lung, particularly frontline, where it seems, well, there are a couple of places where you might go with RAS/RAS combinations, but also individual RAS plus pembrolizumab combinations to pursue the frontline opportunity. I guess in the latter scenario, one could envision sort of a multi-arm approach, right, using a common comparator arm. Is that something that is workable, something that you're considering here, or ultimately, should we think more of a sequential staggered pivotal program when looking at pembrolizumab combinations with daraxonrasib, elironrasib, and so forth?
Yeah. I think we don't have an answer to that today. We really want to establish the clinical foundations for each of those arms before we commit to how those studies would be run. We're certainly very excited. I talked several times in this presentation about that RAS(ON) inhibitor doublet. We're not there yet to declare that that is going to be in the phase 3 trial. So the first question is, what are the arms that we just want to study based on the clinical evidence? And we don't have enough yet to finalize that. And then the second is, what's the most efficient clinical trial way to get there? And while I know it's very appealing to think that a six-arm study that uses one control group will be less costly and more efficient than two or three two-arm trials, not necessarily.
It creates a lot of complexity for sites. So site management, helping them through it, can be very complex. And so it may or may not be worth it. That's sort of an operational question that we defer right now. Our operations team, we're very good. We'll figure that out when they're advised as to what they need to figure out. But right now, we're just holding off and let's first figure out what are the trial arms?
Okay. Great. We'll have to leave it there for time. So thanks, everybody. Thanks for your questions. Thanks, Mark and Steve for the Q&A.
All right. Thanks a lot. All right.