Okay, good morning. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. Our next Presenting Company is Revolution Medicines, and presenting on behalf of the company is CEO Mark Goldsmith. There'll be a Q&A session after the presentation. Just raise your hand, wait for the microphone before asking your question, and for folks joining via Webcast, you can submit questions also via the portal. So with that, thanks, Mark.
Good morning, and thank you, Eric and J.P. Morgan, for the opportunity, to provide an update on Revolution Medicines. Please review our notice regarding legal disclaimers. Our ambitious goal is to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. Our pipeline of pioneering RAS(ON) inhibitors targets the active, oncogenic or ON state of RAS cancer drivers of common life-threatening cancers. In 2023, we achieved high-impact clinical milestones with this pipeline, demonstrating that the unprecedented RAS(ON) multi-selective inhibitor, RMC-6236, and RAS(ON) G12C selective inhibitor, RMC-6291, both show promising and highly differentiated Initial Clinical Profiles.
We believe we are well on track toward late-stage development of RMC-6236, further clinical development of RMC-6291, and progress on our clinical-stage RAS(ON) G12D selective inhibitor, RMC-9805. Today, I'll review our progress, provide additional color about each of these three assets, and outline a roadmap for key 2024 activities building on the momentum. Numerous RAS mutations are known to cause high levels of activated RAS or RAS(ON), leading to excessive cell growth and cancer. Large unmet needs remain among cancers, among patients with tumors harboring common RAS mutations, including major cancers in the lung, pancreas, and colon. Our pioneering pipeline of targeted therapeutics is designed to extinguish RAS(ON) signaling that drives many of these cancers. Today, we have three RAS(ON) inhibitors undergoing clinical evaluation.
RMC-6236 is a bold investigational drug that targets a broad range of RAS variants, and we have reported initial clinical evidence of encouraging safety and antitumor activity in patients with tumors carrying substitutions at amino acid position 12 or G12X. RMC-6291 is an innovative investigational drug that selectively and covalently targets the G12C variant, most commonly seen in lung cancers, and we have reported initial clinical evidence of differentiated antitumor activity in patients with tumors carrying a cysteine substitution at position 12. RMC-9805 is a novel investigational drug that selectively targets the G12D variant of RAS, most commonly seen in GI tumors, with a groundbreaking covalent binding mechanism, and we began dosing patients in the second half of the year.
We enter 2024 with an especially strong financial position and an expansive set of compelling development opportunities for our RAS-ON inhibitor pipeline, backed by a large and growing body of supportive evidence. While the overarching goal is to maximize clinical impact and shareholder value, we intend to be data-driven and disciplined in capital allocation to ensure that we are using our financial and human resources to achieve the highest strategic priorities while maintaining our financial health. The top priority this year is to propel RMC-6236 into the company's first pivotal trials in one or more major second-line indications, which will command the largest share of our resources.
Our second priority is to define the path for expanding the reach of RMC-6236 into first-line treatment for major indications, determining the full range of tumor types for which this investigational drug would be appropriate, and establishing the breadth of RAS genotypes that display clinical sensitivity. Meeting these goals through targeted clinical experiments should open critical gates for future stages of development. Third, we will work toward qualifying RMC-6291 and RMC-9805 in turn for subsequent stages of development. Having reported compelling clinical experience that we believe validates the RAS(ON) inhibitor platform broadly, we will continue leveraging our extraordinary know-how, aiming to maintain our lead position in the RAS(ON) inhibitor field for many years to come. Through these investments, we aspire to establish the industry-leading targeted medicines franchise for RAS cancers.
I'd now like to cover the lead assets in some detail. At the Triple Meeting and ESMO in October, Dr. Spira and Arbour presented the safety profile for RMC-6236 monotherapy from the phase I Dose Escalation Study, focused initially on patients with advanced solid cancers harboring KRAS mutations at position 12, but excluding G12C. As recapitulated here, RMC-6236 was well tolerated across the 80-400 mg daily dose range that provides exposures consistent with inhibition of mutant and wild-type forms of RAS and in which we've observed significant antitumor activity. With ongoing follow-up since ESMO, this safety profile has remained relatively consistent, with few Grade three adverse events overall and no new Grade four or five events. Skin rash continues to be the most frequent treatment-related adverse event and the most common dose-limiting toxicity.
At higher doses, some GI toxicity is observed, although Grade three events remain uncommon. This emerging profile compares favorably with those previously reported for some of the G12C OFF inhibitors and with standard of care cytotoxic chemotherapy... With additional follow-up and more patients, we now observe that dose intensity has been in the range of 90%, including at the 300 mg dose level, reflecting relatively few interruptions or discontinuations. The majority of patients in the October reports had either pancreatic or lung cancers exhibiting the spectrum and frequency of G12 mutations consistent with the epidemiology and had received a median of two prior treatment regimens. We have focused so far primarily on these two major indications, and as I'll discuss later, we are now actively exploring others.
At ESMO, Dr. Arbour showed evidence of promising antitumor activity in patients previously treated for non-small cell lung cancer, as we recapitulated here, reporting an aggregate objective response rate of 38% across the 80-400 mg daily dose range and a disease control rate of 85%. With two months of additional follow-up since the ESMO reports, particularly in the higher dose cohorts, we're seeing favorable trends for aggregate objective response rate from the reported 38% figure into the low-to-mid 40s range. Of note, in the 300 mg cohort specifically, the rate is trending even higher. The Aggregate Disease Control Rate remains strong in the high 80s, and these interim observations are encouraging, particularly with reference to the historical benchmarks for chemotherapy standard of care in second-line non-small cell lung cancer.
RMC-6236 is the first targeted RAS inhibitor described with clinical activity against lung cancer harboring either of the two most common RAS mutations in human cancers, KRAS G12D or G12V. We also expect tumors harboring other mutations to be sensitive, including but not limited to G12C, and overall, RMC-6236 could prove to be applicable for 25%-30% of non-small cell lung cancer patients. We await a more mature dataset for determining progression-free survival in non-small cell lung cancer patients, particularly at the higher dose levels, as a key part of our regulatory package supporting final dose selection and expected pivotal trial launch information, which we anticipate sharing later in the year.
For patients with previously treated pancreatic ductal adenocarcinoma, we reported an aggregate objective response rate of 20% across the 80-400 mg daily dose range for single agent 6236 and a disease control rate of 87%. With additional follow-up, we're observing favorable trends for aggregate objective response rate into the mid-20s. Further, in the 300 mg cohort in particular, this figure is trending even higher, and the disease control rate likewise remains strong in the high 80s. These interim observations are encouraging, particularly in reference to the historical benchmarks for treatment in second-line pancreatic cancer with chemotherapy or even lower benchmarks for third-line patients who are representative of many patients in our study. This rate of response is more consistent with established benchmarks for first-line treatment.
These results suggest an increase in antitumor activity with higher doses and longer follow-up, as we had anticipated. We await a more mature dataset for determining progression-free survival in these patients as well, particularly at higher doses, as a key part of our regulatory package for dose selection and expected pivotal trial launch, information which again, we anticipate sharing later in the year. In sum, so far, 300 milligrams daily appears attractive for safety and antitumor activity in both of these major tumor types. Plasma exposure data for 6236, presented by Dr. Spira at the Triple Meeting, are reproduced here, on the right side on a linear rather than a logarithmic scale for clarity.
Mean AUCs increased with increasing dose, including at doses above 160, although the 200 milligram cohort appears to be a bit of an outlier. The mean AUC at 400 milligrams, representing only a one-third increase in dose above 300 milligrams, is modestly incremental, which may not be pharmacologically significant in view of typical interpatient variability. Considering the favorable safety and antitumor trends mentioned earlier at 300 milligrams for both pancreatic and lung cancer, we are now focused on cohort expansions at 300 milligrams and below for both indications and are no longer escalating in either. Results from continuing follow-up in the ongoing study will serve as the basis for exposure response analyses that will inform discussion of go-forward dose with regulators. This progress is central to propelling RMC-6236 into pivotal trials.
We're pleased to observe these favorable trends and further clarity around dose and expect to report a more fulsome update sometime later this year, likely in the second half. Based on the strong performance of 6236 so far, we are moving forward with several dedicated monotherapy cohorts at 300 milligrams to support both the primary pivotal trial goals and the second priority I described, that is, expanding the reach of RMC-6236. This table lists ongoing studies, including expansions in the core, lung, and pancreatic G12X populations to support dose optimization with other RAS mutations and in colorectal cancer. Patients are already enrolled in all of these cohorts. Let's return briefly to our top priority, which is propelling RMC-6236 into one or more pivotal trials.
First, non-small cell lung cancer remains the most lethal of all cancers, and significant unmet needs remain in second-line patients who have progressed following first-line treatment. Oncogenic RAS variants are the most common genetic drivers of non-small cell lung cancer, and the activity of 6236 observed so far is promising, and as I mentioned, potentially applicable for up to 30% of previously treated non-small cell lung cancer patients. We are planning a global randomized phase III trial comparing 6236 against docetaxel in patients with RAS-mutated lung cancer who have been previously, previously treated with immunotherapy and with platinum-containing chemotherapy.
In this initial design, shown last quarter, we addressed the potential complexity and opportunities associated with patients with RAS mutations spanning positions G12, G13, and Q61 by incorporating a nested design with hierarchical testing as an analysis strategy that ensures statistical power for the core study group while potentially capturing a broader patient population. The design presented here is preliminary and may change. We have begun preparing to discuss plans with regulators and hope to be able to launch this trial in the second half of the year. We also anticipate disclosing key clinical data supporting this plan publicly around the time of the study launch. Second, pancreatic cancer is notorious for having the worst prognosis among all major cancers. More than 90% of pancreatic cancers harbor a RAS mutation, making it the dominant oncogenic driver in this devastating disease.
Clinical results so far for RMC-6236 strongly support its continued evaluation in RAS mutated pancreatic cancers. We anticipate conducting a global randomized phase III trial comparing RMC-6236 against a physician's choice of chemotherapy regimens in second-line patients with RAS mutated pancreatic cancer, an initial outline of which is reproduced here. And as for lung cancer, we have incorporated nesting with hierarchical testing. This design is likewise preliminary and may change. We have begun preparing to discuss plans with regulatory authorities and hope to be able to launch the trial also in the second half of the year. We also anticipate disclosing key clinical data supporting this plan publicly around the time of study launch.
Beyond its broad utility as a single agent for treating patients with diverse RAS-addicted cancers, RMC-6236 will be evaluated in several combination configurations, including as the backbone for doublet combinations with mutant-selective inhibitors from our pipeline and as the targeted component of combinations with standard of care treatments, including immunotherapies. We will return to those concepts in a few minutes. RAS(ON) mutant-selective inhibitors from our pipeline may also play important roles in future treatment for RAS-addicted cancers. They may provide alternative monotherapy options, they may be complementary to RMC-6236 in RAS(ON) inhibitor doublet regimens, and/or they may exhibit differentiated, targeted drug profiles and standard of care combinations, including immunotherapies.
Allow me to provide a brief update on our most advanced mutant-selective inhibitor, RMC-6291, our RAS(ON) G12C, the first RAS(ON) G12C selective inhibitor in the clinic. At the Triple Meeting, Dr. Janne provided an initial report on patients treated with 6291 in the dose escalation study outlined here, most with colorectal cancer or lung cancer, with a median of three prior therapies. 6291 was generally well tolerated, and Grade one or two gastrointestinal toxicities, predominantly nausea or diarrhea, were the most frequent treatment-related adverse events. QTc prolongation was observed, although only one case showed an increase in QTc to greater than 500 milliseconds, and there have been no cardiac toxicities associated with this electrocardiographic abnormality.
Only one treatment-related AE, a Grade three QTc prolongation in a patient who was otherwise tolerating RMC-6291 well, required discontinuation of RMC-6291 per protocol. Increases in liver enzymes were of low grade and low frequency, which is notable since one-third of the lung cancer patients reported had received an immune checkpoint inhibitor within 12 weeks of starting RMC-6291, supporting the potential for combination with immune checkpoint inhibitors. As reproduced here, among patients with lung cancer treated across all doses, 3 of 7 or 43%, who had not previously received a G12C OFF inhibitor, responded to 6291. Further, 5 of 10 or 50% of patients who had previously received a G12C OFF inhibitor responded to 6291.
The disease control rate for both sets of patients was 100% with no early progression. For patients with colorectal cancer who had not previously received a G12C off inhibitor, 8 of 20 or 40% had a partial response, and the disease control rate was 80%. Together, these results provide encouraging initial evidence of a clinically meaningful differentiated profile compared to other G12C inhibitors described. Today, I can report that these initial trends have remained relatively stable in observation since the October presentation, and we are currently conducting expansions of the 200 and 300mg BID cohorts in order to determine a recommended phase II dose.
We've also modeled target engagement based on preclinical measurements and human plasma PK from this study and project that both of these dose levels should drive irreversible binding to 90% or more of the G12C proteins in tumor cells, which compares favorably against comparable projections reported for adagrasib. While we continue collecting data from the single-agent dose escalation cohorts, we're also initiating key combination studies that will help inform strategic planning for late-stage development of 6291 to maximize its clinical impact and to drive business value. I'll summarize those studies momentarily.... Our third RAS(ON) inhibitor in clinical development is RMC-9805, a RAS(ON) G12D selective compound. Preclinically, this compound is quite distinctive. It is orally bioavailable across multiple species.
It breaks new ground by covalently and selectively binding the RAS aspartic acid twelve, and it is highly active in xenograft models of cancers where G12D mutations are frequent. Dose escalation continues in a phase I trial that was begun in Q3. Early results have confirmed that RMC-9805 is orally bioavailable in patients, exhibiting pharmacokinetics consistent with expectations from preclinical data, including dose-dependent increases in plasma exposure on once-daily dosing, and the option of twice-daily dosing is also enabled. Further, we've cleared several dose levels and observed good tolerability, with no DLTs reported so far, but we have not yet reached a recommended phase II dose and schedule. We expect to be able, to be able to provide additional information from the ongoing study in the second half of the year. Let's return to the topic of combination treatment strategies with RAS-on inhibitors.
Evaluating combination options is an essential component of our 2024 work to inform late-stage strategy beyond this year. As summarized here, we have activated or soon will activate multiple combination cohorts for this purpose. Based on preclinical findings, our first combination to evaluate in patients is a doublet of two RAS(ON) inhibitors, that is, combining the multi-selective inhibitor 6236 with a mutant-selective inhibitor, such as the G12C-selective compound 6291. Patients are being treated now in the dose escalation portion of a study dedicated to this doublet. Another drug combination for testing within our second priority for 2024 is combining either 6236 or 6291 with a checkpoint inhibitor, a paradigm that is especially relevant for first-line treatment in lung cancer. We are currently recruiting patients for a dedicated study of these combinations.
Overall, 2023 was a very productive year for Revolution Medicines. For our RAS(ON) multi-selective inhibitor, RMC-6236, we reported encouraging initial monotherapy safety and antitumor activity profiles in patients with lung or pancreatic cancers. Today, I indicated that favorable trends continue to build, including in the 300-mg daily cohort, and favorable dose intensity has been observed, also including 300 mg. The clinical profile to date supports prioritizing 300 mg daily and below for ongoing dose optimization in both major indications, and we continue to do so. Regarding our RAS(ON) mutant-selective inhibitors, we reported encouraging initial RMC-6291 monotherapy safety and antitumor activity profiles in patients with lung and colorectal cancers, and currently, dose optimization is underway at 200-300 mg BID. RMC-9805 began dosing, and so far is exhibiting good oral bioavailability, including dose-dependent exposure increases.
On the business front, we completed the acquisition of EQRx in the fourth quarter, and we ended the year with a very strong estimated cash and marketable securities balance of $1.85 billion, with which the company projects it can fund planned operations into 2027 under our current plan. In summary, having achieved broad clinical validation of our lead assets across RAS genotypes and tumor types in 2023 and reinforced our financial wherewithal through a major transaction, we are now poised to begin late-stage product development in 2024. The highest imperative for us is to propel RMC-6236 into its first pivotal trial or trials later this year, and key near-term activities are underway in support of this primary goal.
Our second priority is to expand the reach of RMC-6236 across tumor types and mutations and to inform our path to first-line treatment, and key enabling activities are underway. And finally, we aim to qualify mutant-selective inhibitors for late-stage development, and important activities are underway to help prioritize paths with the greatest potential clinical impact and value creation for our shareholders. 2024 will be a packed year for Revolution Medicines. We are deeply grateful for the willingness of patients and their families to participate in our clinical trials, for the first-rate investigators who guide and conduct these trials, and for the tireless commitment to patients, by the superb employees of Revolution Medicines as we move even closer to our goal to outsmart cancer. Thank you, and we'll be happy to take questions.
Just as a reminder, for those who have questions, just raise your hand, and we'll get a mic over to you. But, Mark, maybe I'll start with the first question. Just picking up on an incremental factoid from the RMC-6236 study in pancreatic cancer. You noted response rates trending in the above the 20% range with the 300-milligram dose. Can you just sort of put a little more color around that update, sort of the incremental patient numbers that comment reflects?
The question was, can I provide more information than I just provided? And the answer is unfortunately, no. So what we're trying to provide here is sort of directional information, rather than sort of detailed report today. We will, of course, provide all of that, you know, as the year progresses.
Okay. You want to go ahead?
So this may be an unanswerable question as well. It's also on pancreatic cancer. But you mentioned that most of your patients were second line or third line. Can you expand on the survival rates of the patients in those second line and third line groups, and maybe even in particular, in relation to your 300 milligram data?
Your opening statement was right. I can't, I can't provide really any, any information on that just now. We're still collecting information, just from longer follow-up and, of course, larger ends and so on, to, to be sure that we have a rigorous outcome from it. So we'll report on that later in the year, but I don't have any progression-free survival data to share today.
But specifically, can you talk... Thank you. Is there any way you can talk to the benchmarks that patients without your treatment in that 2L and 3L setting-
Oh, sure.
Would experience as a comparison against those 20% or 25% rates that you're looking at?
Yeah. So, I had a slide on that, and maybe I'll be able to pull that up quickly here. But that does show us something here. So here's pancreatic cancer in our study that we reported in October, and you can see on the bottom right, it provides the standard care benchmarks for response rates. Now, these are essentially second-line data, and that is 11% versus for ORR and 56% for disease control rate. We don't really have third-line data. It's hard to obtain. There are small studies from which you can extract numbers, but we didn't put it on a slide. So clearly, we're well a bunch above both of these benchmarks. But in terms of the outcome that we have with progression-free survival, that will have to just wait until later in the year.
Discouraging questions by not answering the question.
This one won't touch on, I think, data specifically in the trial, but just thinking about, your phase III plans, both in for 6236, both in lung cancer and in pancreatic cancer. You know, there's some hedging, I guess, in terms of when you expect to start trials for the respective indications. Can you just talk a little bit about sort of what the gating factors, I think, would be to sort of, you know, you know, pin down and... What, Sorry, what other... Yeah, what gating factors, I guess, you need to sort of see resolved in order to kind of firm up guidance for when you might start a phase III trial in,
Yeah
in lung cancer and in pancreatic cancer? I wonder whether it's whether the gating factor, gating factors revolve more around sort of trial design or the patient population that you look to conduct the study in, or is it more of a data-dependent decision?
Yeah, well, the simple answer to that is largely coming to agreement with the FDA around trial design, enrollment criteria, endpoints, et cetera. And we can't come to agreement with them until we present them with a package of information, and that package of information requires extensive exposure response analyses across, comparator groups, different, you know, different dose levels. So we're just doing all that work now. I'm not trying to quite say that we're hedging here. We're just making the point that we would anticipate starting, these pivotal trials, likely both of them, in the second half of the year. But we're not the sole deciders, in that, and we need to work things out with the FDA.
Can you just talk a little bit about just general physician feedback in the wake of the presentation of these slides, of these data at ESMO and just that impact-
Yeah
the impact there that may have... Sorry, and how that's translated perhaps into sort of recruiting the studies in the expansion cohorts or in the backfilling of the lower dose cohorts?
Investigator interest is extremely high, and we find that when any slots are opened up, they're reserved very quickly. By the time they're opened, they're filled. So really, recruiting patients is not rate-limiting to any of this. It's really just deciding, observing them long enough and then deciding what we're doing with that information, doing the analyses and deciding it. But Wei, do you have— Our Chief Medical Officer, Wei Lin, is here. Do you have any comments, since you're a little bit closer to those interactions?
Yeah, no, I totally agree with you, Mark. Hello?
Oh, you might just have to speak loudly.
Okay. Yeah, I fully agree with you. I think the overall enthusiasm is just tremendous, as you pointed out, not right now, not only in the pancreatic and lung cancer, but colorectal, just by the halo effect, we're getting tremendous amount of interest in other solid tumors, so enrollment is really robust.
You noted that you're no longer exploring 400 milligrams and higher-
Correct.
focusing on 300 down.
Yeah.
I guess within that window, I guess, are there certain dose levels that you are, you know, seeing, that you're prioritizing, within the 80-300 milligram range? You know, if we are thinking about the doses that you advance into pivotal studies, would it be a common dose for both pancreatic and lung cancer, or would you just kind of, kind of bifurcate them?
Okay, I'll comment sort of on that last point here. I mean, clearly we're seeing some convergence here, which we didn't know. I think, last time we were asked that question, we were still dosing at 400 and trying to decide whether we would stay with that dose, go to a higher dose. And as I mentioned, based on the overall profile, safety, tolerability, antitumor activity, and PK, there just isn't a really compelling justification for continuing at 400 or higher. So 300 milligrams, now the top dose for both, which really does begin to narrow it down. And so whether or not we land on the same exact dose will depend on those exposure response analyses. I know everybody wants us to sort of jump ahead of those, but we can't.
You know, the data will tell us what the answer is, but they're looking more and more alike than we would have known, let's say, three, six months ago. Wei or Steve want to add to that? Steve Kelsey, our President of R&D.
Hello. Well, I mean, just to be straight, Eric, the priority dose is 300.
Okay.
I mean, we've been pretty convinced ever since we started preclinical evaluation of RMC-6236, that there's a dose response, or, or at least an exposure response. As the exposures, as Mark said, as the exposures start to get very noisy above 300, we think 300 is the dose that we're gonna be persuaded to go forwards with. And we think that if we can persuade ourselves that that's the right dose to go forwards with, we'll certainly be able to persuade the FDA that that's the right dose to go forwards with. There are other doses below 300 that are being backfilled just to make that case as strongly as possible. But I think we would all internally be surprised if we end up electing to go forwards with a dose other than 300, to be quite frank.
A supportive fact to go with that is that we've opened all these other monotherapy cohorts at 300 milligrams. So that clearly indicates what we think, and we can't get ahead of the FDA, but they'll hear what we think and hopefully be supported by the data that we provide them.
The AE profile that you're seeing with monotherapy at 300, is that conducive to combinations with checkpoint or other RAS inhibitors at that level, or would you kind of anticipate needing to?
We do think so, because it's basically been pretty well tolerated, and I think I mentioned that the dose intensity, which is in some ways maybe the most objective way to just assess that, is, you know, in the range of 90%, even in the 300 milligram group. So there's really not a rationale from a toxicity point of view to go to a lower dose. And in terms of checkpoint inhibitor, I think, again, that preliminarily, we don't see a reason to have a particularly high concern other than that there have been problems throughout the field. So, of course, we have to have a high, you know, eyes wide open on that. But we're gonna, we're evaluating that very soon, and that will come through.
In terms of combining with other agents, like our own RAS inhibitor, we again, don't see overlapping monotherapy toxicity profiles that are of particular concern, and therefore, would not expect something. But until we evaluate that in patients, we just can't take a definitive position on it.
Okay. On the G12D,
Mm-hmm.
You know, you're teasing us a little bit here again, in terms of, you know, seeing a PK profile as anticipated, well-tolerated. Where you are in the dose escalation scheme, are you now at levels that are predicted to be in sort of the efficacious range? And then, along those lines, I guess, when should we be thinking about sort of a, you know, a presentation of the dose escalation results so far?
Yeah, I, you know, I think where we are with 9805 is sort of where we were with 6236 a year ago, sitting in a different room with you, talking about 6236 at that time. And there, we also gave the sort of validation of oral bioavailability and, and PK, but, and, and tolerability, but nothing more than that. So I think we're in a pretty similar position. I think as this year rolls out, we'll see more and more evidence around its, you know, its, its behavior as a clinical, antitumor agent. You know, in terms of exposures, the exposures are behaving or consistent with what we expected preclinically at the levels we've tested so far.
And because this was a well-tolerated compound, preclinically, there was no reason to start at the exceedingly low doses that we, you know, we started with, with 6236. 10 milligrams was, you know, barely much of a dose, although it actually, you know, had some pharmacologic activity. But we clearly were very cautious with 6236. We were, you know, more aggressive with 9805. I, I think later this year, we'll be able to say something more about, nine eight oh five, but predicting what that is, seems like it can only get me in trouble, so we'll, we'll find out.
How can I not follow up on that? I'm gonna try anyway. Look, I've asked this question several times before, really. Just given the coverage that you have against G12D mutations with 6236-
Yeah.
You know, it seems like you might have to sort of prioritize, or it begs the prioritization question of, you know, between these two compounds. Nevertheless, perhaps, 9805 might have a different activity profile in some histologies. To that end, I guess, can you talk a bit about sort of the mix of patients that are coming into the phase I trial, and to the extent that they might differ at all from the experience with 6236, to be able to perhaps,
Mm.
You know... speak to that potential differentiation or different, different activity profile?
So we'll come to your question in a second, and maybe Wei can comment on that. We just don't know yet how it may be different or similar. 6236 is pretty compelling, as we've talked about, and so it does set a pretty high bar for what 9805 has to do to either complement it or to displace it. But ultimately, we're probably gonna combine it with 6236, and so as long as there's not overlapping toxicity, we may be able to get away with taking the benefits of both of those. But 6236 is a remarkably good KRAS G12D oral G12D inhibitor, is now proven across, you know, many patients in multiple tumor types. So it's the lead horse.
One other comment, and then Wei can answer your specific question. You know, from a priority point of view, 6236 is our highest priority. You know, I said that several times in the talk, and I wanna make that clear. It would be foolish for us not to double and triple down on it, so we're very committed to 6236. We just have now a very substantial body of experience, you know, and evidence with it. But 9805 will have its day, and when we see what it does, we'll have a much more meaningful, more mature answer to the question of how it's different or not.
Yeah, I agree with you, all that Mark has said. I think, I think one of our firm beliefs is, something Mark had stated very early on. It's we're focused on RAS-addicted cancers, and I think that addiction highlights that, if hitting it hard produce efficacy, hitting it harder would produce even better efficacy. I think having the within our armamentarium, the combination of the RAS multi plus the mutant-selective G12D allow us to, through combination, hit it harder than anyone else could potentially do, and I think that's a hundred scientific hypothesis we'll be pursuing as we explore combination, and that's gonna be one of our priorities.
Okay. All right, great. I think we'll leave it there for time, so everybody can get to lunch. So thanks again, Mark, for your time.
Sure.
Thanks, team, for your answers. Thanks, everybody, for joining. Have a great conference!