Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Ryan Aase, Senior Vice President, Corporate Affairs. Please go ahead.
Thank you, and welcome everyone to our webcast, where we'll summarize data that were presented at the EORTC NCI AACR, or Triple Meeting, this week, and provide additional context. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' Chairman and Chief Executive Officer, and Dr. Wei Lin, our Chief Medical Officer. Dr. Steve Kelsey, our President of R&D, will join us for the Q&A portion of today's call. As we begin our presentation, I would ask that you review our legal disclaimer on slide two. With that, I'll turn the call over to Dr. Mark Goldsmith, our Chairman and Chief Executive Officer. Mark?
Thanks, Ryan, and thank you to everyone who has joined us today. As outlined on slide three, at Revolution Medicines, our mission is to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development, and delivery of innovative targeted medicines. Today, we'll summarize the data presented at the Triple Meeting this week that highlights the progress we are
making toward that goal. As a reminder, we have a deep portfolio of targeted RAS-ON inhibitors, including three programs that have demonstrated compelling clinical proof of concept. Our remarks today will focus on two of these clinical stage programs, RMC-6236, our RAS-ON multi-selective inhibitor, and RMC-9805, our RAS-ON G-12 D selective inhibitor in previously treated pancreatic ductal adenocarcinoma, or PDAC.
In slide four is a reminder that RAS acts as an intracellular switch, transitioning between an inactive GDP-bound state we refer to as RAS-OFF, and an active GTP-bound state we call RAS-ON. Tightly regulated RAS-ON proteins are needed to control normal cell growth. Mutations in RAS proteins can drive uncontrolled RAS-ON signaling pathways that favor cell growth, survival, and oncogenesis.
Pancreatic cancer is a devastating disease. It is the third leading cause of cancer mortality in the US, with approximately sixty thousand people expected to be diagnosed and fifty thousand people expected to die this year alone. PDAC is known to be a RAS-driven cancer. Over 90% of PDAC tumors harbor an oncogenic RAS mutation, and RAS proteins are also likely to play a role in many of the remaining 10%. G12D is the single most common RAS mutation.
There's clearly a need to improve outcomes in patients with metastatic PDAC, currently treated in a second-line setting with standard of care chemotherapy-based regimens. I'll briefly highlight on slide five the unique approach we have taken to targeting RAS. Our innovative compounds bind to and inhibit the active RAS-ON form of RAS. We call these compounds tricomplex inhibitors because they are designed to bind selectively and with high affinity to a relatively flat surface on the RAS target by forming
a tricomplex structure that contains RAS, a highly abundant cellular chaperone protein, and the tricomplex inhibitor bound in a pocket between them. Preclinically, these compounds directly and rapidly inhibit the intended oncogenic RAS-ON cancer drivers in tumor cells, inducing deep and durable suppression of RAS cancer signaling by a mechanism of action that is unique and differentiated from first generation RAS-OFF inhibitors.
We have now demonstrated clinical proof of concept with our first three programs, and today we will review new clinical data from two of these investigational drugs that provide further validation of this approach. RMC-6236, our oral RAS-ON multi-selective inhibitor, has been clinically validated across diverse oncogenic RAS variants, including G12D. RMC-9805, our oral RAS-ON G12D selective covalent inhibitor, has been clinically validated against oncogenic RAS G12D. As context for these new results,
please review the table on slide six that summarizes the results of previously published phase 3 clinical studies of various chemotherapy regimens in patients with metastatic PDAC. The results across treatment regimens consistently show a need to improve clinical outcomes for previously treated patients.
These reported findings from clinical trial settings show that regardless of the chemotherapy regimen evaluated, the median progression-free survival ranges between two and three and a half months in the second-line setting, with median overall survival of six to seven months. The numbers in the third-line plus setting are even lower. It's also important to note that these are aggressive chemotherapy regimens,
with approximately two-thirds of patients typically requiring a dose modification. Patients with metastatic pancreatic cancer deserve better outcomes, meaningfully longer survival, with a better quality of life, and these are the aims of our development programs. I'll now turn the call over to Dr. Wei Lin, our Chief Medical Officer, to summarize RevMed data presented at the medical conference this week regarding patients with metastatic pancreatic cancer treated with RMC-6236 or RMC-9805. Wei?
Thank you, Mark. We're pleased today to update the data we first shared with you at our July fifteenth investor event. We believe that these more mature data strengthen the efficacy proof of concept we presented in July, and if reproduced in the ongoing phase three study, will change the standard of care for patients with previously treated metastatic pancreatic cancer. In addition, the safety profile of RMC-
6236 has remained stable with longer follow-up, suggesting that it may be given for a longer term as a monotherapy with the aim of providing prolonged clinical benefit. On slide 8, as of the July twenty-third data cut-off date, which represents two and a half months longer follow-up than the analysis we shared on July fifteenth, 127 patients with pancreatic cancer have been treated with RMC-6236 at doses between 160-300 milligrams daily.
Pulling the results from the 160 to 300 milligram dose levels provides a more robust assessment. Among them, 57 patients received RMC-6236 as second-line therapy. The distribution of RAS mutations in tumors of these patients is approximately representative of what we expect to see in our ongoing phase 3 trial, with the majority of patients having tumors harboring a KRAS G12X mutation and a minority
harboring KRAS, NRAS, or HRAS mutations at other amino acid positions. The proportion of patients with poor prognostic factors, such as ECOG performance status 1 or liver metastases, is similar to or higher than the proportion in other trials in previously treated metastatic pancreatic cancer, such as the NAPOLI-1 study that supported approval of the Onivyde chemotherapy regimen.
In addition to RAS mutation status, we also believe that other demographic and risk factors of patients reported in this analysis are representative of those we expect to see in our ongoing phase 3 trial in second-line pancreatic cancer. Moving to slide nine. Here, we see a more mature progression-free
survival analysis of pancreatic cancer patients treated with RMC-6236 at doses between 160-300 milligrams daily. This second-line pancreatic cancer patient population is more relevant to our ongoing phase 3 registration trial. The Kaplan-Meier curves are represented by the solid green and yellow lines on the left, and the median PFS estimates are listed in the top table on the right.
In patients who received RMC-6236 as a second-line therapy, the median follow-up is six months for patients with KRAS G12X pancreatic cancer and six point two months for the broader RAS mutant population, and the minimum follow-up is approximately three months. The median PFS in the KRAS G12X mutant population is estimated to be eight point five months, compared to eight point one months
in our July presentation. The median PFS in the broader RAS mutant population is estimated to be seven point six months, which is the same as in the July presentation. The PFS rate of the three-month mark or the proportion of patients who are progression free at three months, is approximately 90%. These stable or even improved results after longer follow-up increase our confidence in the estimates and potential translatability to our pivotal trial.
On slide ten, we show overall survival, which of course, is the ultimate measure of efficacy. We've just seen that the median PFS for RMC-6236 in second-line metastatic pancreatic cancer has been substantiated in a more mature data set. Now we're pleased to report that with a longer follow-up, we have our first estimate of median OS in second-line metastatic pancreatic cancer, and it is fourteen point
five months. The estimate is the same in KRAS G12X and the broader RAS mutant populations. The lower bound of the 95% confidence interval is eight point eight months in both populations. The OS rate at six months, which is the proportion of patients who remain alive six months after starting treatment with RMC-6236, is approximately 90% in both the KRAS G12 and the broader RAS mutant populations.
We're encouraged by the consistency between PFS and OS outcomes and within the two mutant-defined populations, as well as their consistency over time. The best change in target lesions and the objective response rates are presented in slide 11. While the overall shape of the waterfall plot has remained the same compared to our July presentation, some patients have experienced deepening of
response, which is consistent with the observation that only half of all responders achieved their initial RECIST response within the first two months of treatment with RMC-6236. Similar to the July presentation, the pooled OR analysis of 160-300 milligrams daily, presented in the table on the right, includes all KRAS G12X patients who received their first dose of RMC-6236 at least 14 weeks before the data cut-off date, which is a period that allows for two potential on-treatment CT tumor assessments....
Unlike the July presentation, here we have analyzed separately the ORR for the second-line population and the third-line population. Due to the longer follow-up, the overall efficacy evaluable population, inclusive of all second-line and third-line plus patients, has increased from 97 to 105. The ORR in second-line patients was 29%, and in third-line plus patients was 22%. The DCR for both populations
was approximately 90%. These numbers are consistent with the ORRs we reported in July, consistent with the general trend to greater efficacy when a therapy is used in an earlier line of treatment and supportive of the early observation that the responses increase with longer time on drug. As shown in slide 12, these findings were obtained at well-tolerated doses of RMC-6236.
The treatment-related adverse events, or TRAEs, in pancreatic cancer patients treated at doses between 160 and 300 milligrams daily of RMC-6236 are presented in this table. The overall safety profiles remain consistent with what we presented in July. While there were some modest numerical changes in the adverse event rates, we believe these do not meaningfully change the overall safety
profile. Both any grade and grade three or higher TRAEs are listed here for the 127 patients treated at these dose levels. Again, we present here a pooled safety analysis because the adverse event rates were similar across these dose levels, and the larger database provides a more robust assessment of the safety profile. The TRAEs that occurred in 10% or more patients are listed in the top half of the table.
They mainly fall into three categories: dermatologic, which include rash and paronychia, GI, which include nausea, vomiting, and diarrhea, and mucosal, which include stomatitis and mucosal inflammation. Most adverse events were low grade, with 29% of patients experiencing grade three or higher adverse events. These adverse events have generally been manageable and reversible. Rash, a
bundle term that included acneiform and maculopapular, as well as other skin reactions, occurred in 91% of patients. These were mainly low grade, with around 8% of patients experiencing grade three rash. These rash events were predominantly acneiform, early in onset, and responsive to the same management used for EGFR inhibitors. Therefore, we have recommended rash prophylaxis with oral antibiotics in the ongoing randomized phase 3 second-line pancreatic cancer trial.
Based on the experience of rash prophylaxis for EGFR inhibitors, we believe we may see a reduction in both the frequency and severity of rash and improvement in the tolerability of RMC-6236 with the introduction of prophylaxis. Stomatitis and mucosal inflammation occurred in 31% and 13% of patients, respectively. These adverse events are similar to those associated with mTOR inhibitors, where a simple
steroid mouthwash has been effective as prophylaxis. We have recommended this prophylaxis as well in our phase 3 trial, aiming to further improve overall tolerability. The lower half of the table lists several notable adverse events that are uncommon in patients treated with RMC-6236, but are worth highlighting because of the implications on the combinability of RMC-6236 with other anticancer therapies used in first-line PDAC, colorectal cancer, and non-small cell lung cancer.
The low rates of cytopenias and liver enzyme elevations suggest improved chance for combinability with chemotherapy and immunotherapy, respectively. On slide 13, we see how the TRAEs affected patients' ability to remain on RMC-6236 treatment. As of the data cutoff, the median time these patients have been on treatment with RMC-6236 has been extended to 5.3 months with this analysis. Even
without adjusting for treatment duration, the dose modification rate remains favorable. Around one third of patients required any dose modification of RMC-6236. The majority of these were dose interruptions, with only around one-fifth requiring dose reductions. Remarkably, none of these 127 patients discontinued RMC-6236 due to TRAEs. These numbers translated to a mean dose intensity of 92%.
We project that the high dose intensity and modest dose modification rates may contribute to clinical benefit, and we hope the tolerability profile confers an improved quality of life for patients on RMC-6236. Slide 14 shows the design for our registration trial to enable the first approval of RMC-6236 in second-line pancreatic cancer, which is called RESOLUTE-302. In this randomized phase III trial, all patients with metastatic pancreatic canc
er previously treated with one line of systemic therapy will be eligible, including patients with tumors harboring RAS G12X mutations, other RAS mutations, and without an identified RAS mutation. The exceptions are patients with tumors harboring an actionable mutation for which an approved targeted therapy is available. For example, a BRAF mutation.
We plan to randomize approximately 460 patients to either monotherapy RMC-6236, or an investigator's choice of standard therapy. The dual primary endpoints will be PFS and OS in patients with pancreatic cancer harboring a RAS G12X mutation. Should efficacy be demonstrated in this core population, PFS and OS will be evaluated in all enrolled patients. Additional secondary endpoints include ORR, DOR, and
quality of life measures. We're pleased that we have begun dosing patients on this trial. Moving to slide 15. To summarize, with two and a half months of additional follow-up since our July presentation, the PFS estimates in second-line metastatic pancreatic cancer have remained consistent or improved, with a median PFS of 8.5 months in patients with PDAC harboring a G12 mutation.
Our first estimate of median OS is 14.5 months, consistent with the observation that 90% of patients who started treatment with RMC-6236 were still alive after six months. The RESOLUTE-302 phase 3 trial in second-line pancreatic cancer is ongoing. Enthusiasm from pancreatic cancer investigators and patients worldwide has been high. The primary analysis for PFS and OS will be event-driven. Now, I want
to provide some additional context shown on slide 16. Earlier in the presentation, we showed a slide indicating the median overall survival in second-line pancreatic cancer is between 6.1 months and 6.9 months for patients receiving standard care chemotherapy. This slide lists the three approved therapies for patients being treated in the first line, metastatic pancreatic cancer.
The median survival from the registrational studies for these three first-line patient populations range from 8.5 months to 11.1 months. The unmet need for patients with metastatic pancreatic cancer across all lines of therapy remains very high. The encouraging data just described for RMC-6236 in the second-line pancreatic cancer treatment setting also support the evaluation of RMC-6236 as monotherapy in
first-line and early disease settings, and we are currently designing a first-line registrational trial. Transitioning to RMC-9805, I'll briefly discuss preliminary safety and anti-tumor activity from the ongoing phase I study of our oral RAS-ON G12D selective tricomplex inhibitor in patients with KRAS G12D pancreatic cancer.
Moving to slide 18, RMC-9805-001 is a first-in-human study of RMC-9805, evaluating the safety, tolerability, and preliminary anti-tumor activity of RMC-9805 in patients with advanced solid tumors. The study evaluated RMC-9805 as monotherapy, which consisted of dose escalation in part one, followed by dose optimization and expansion in part two. Slide 19 shows that RMC-9805 exhibited a dose-
dependent increase in exposure from 150 mg to 1200 mg once daily dose. Shown on the left is the mean steady-state concentrations from cycle 1, day 15, following once daily administration. Shown on the right is the individual steady-state blood AUC data for both daily and BID schedules. Comparable exposure was observed between daily and BID schedules at equivalent daily dose levels.
The dashed line represents the mouse 100 milligram per kilogram human equivalent AUC, and is the dose that induced robust tumor regression in the majority of PDAC preclinical models. Oral dosing in humans achieved comparable dose exposure levels, and objective responses were achieved in the clinic at doses greater than or equal to 600 milligram daily dose, as predicted by preclinical models. The PK
data support a 1200 milligram once daily dose as a candidate recommended phase II dose in patients with pancreatic cancer. Slide 20 shows the waterfall plot of best percentage change in tumor size for all pancreatic cancer patients who received their first dose of RMC-9805 at least 14 weeks before the data cut-off date, which allows for two potential scans.
The green bars represent patients treated with RMC-9805 at 1,200 milligrams daily, and the yellow bar represent patients treated with less than 1,200 milligrams daily. Among pancreatic cancer patients treated with 1,200 milligrams daily dose, the objective response rate was 30%, which includes patients with a confirmed response or a response that is pending confirmation. The disease control rate was
80%. The arrows under the waterfall denote the patients who remain on study treatment. As the numbers of post-baseline scans listed below the waterfall suggest, the duration of follow-up so far is short. Therefore, other efficacy endpoints, such as PFS and OS, will need to wait for longer follow-up. RMC-9805 was well tolerated across all dose levels, as reported at the ENA meeting.
For this summary, as shown on slide 21, I'll focus my remarks on the candidate RP2D of 1200 milligrams, which included 60 patients at 1200 milligrams daily and 39 patients at 600 milligrams BID. Primarily, AEs occurring in 10% or more of the 99 patients are shown here. GI toxicities and nausea, diarrhea, and vomiting were the most common GRAEs, all of which were grade one or two in severity, were
manageable and reversible. In fact, over 80% of nausea were grade one, and around half of these events occurred and resolved in the first 4 days of starting treatment. 10% of patients at the 1200 milligrams dose also experienced grade one rash, which is likely due to some activity against wild-type RAS protein at the highest dose evaluated.
No treatment-related grade four or five adverse events or serious adverse events have been reported. ALT and AST elevations were uncommon and mostly grade one, and only one patient experienced a grade three event, which predicts a low risk for hepatotoxicity when combined with immunotherapy. This exceptional safety profile translated to a high degree of tolerability, with only 4% of patients requiring a dose reduction due to TRAEs, and no patients had a dose discontinuation due to TRAEs. In fact, as was
highlighted by the case report by Dr. David Hong, shared at his oral presentation at ENA, more than one patient being treated with RMC-9805 has asked their investigator whether they were on placebo. These questions captured the patient experience with RMC-9805 better than any safety table we can show. In summary, on slide 22, RMC-9805 is a potent, mutant-selective, covalent inhibitor of RAS-ON G12D.
RMC-9805 has shown encouraging antitumor activity in patients with KRAS G12D pancreatic cancer. However, assessment of durability will require longer follow-up. RMC-9805 is well tolerated at all dose levels evaluated, including the candidate RP2D of 1,200 milligrams daily. The preliminary safety and
efficacy data support the ongoing development of RMC-9805 as a single agent and in combination with other therapies, including our RAS-ON multi-selective inhibitor, RMC-6236, in pancreatic cancer as well as in other solid tumors such as non-small cell lung cancer and colorectal cancer. With that, I'll pass the mic back to Mark.
Thank you, Wei. I'll conclude our prepared remarks on slide 24 with a reminder about why this work is so important and why these results have the potential to be so impactful. Metastatic pancreatic cancer is a devastating disease, and there is an urgent need to provide new and better treatment options to patients with both improved efficacy and greater tolerability. PDAC is a RAS-driven cancer, with the vast majority
of tumors having a KRAS G12X mutation. Of these, G12D is the single most common RAS mutation, representing approximately 40% of all pancreatic cancer cases. RMC-6236 and RMC-9805 are the first two oral investigational targeted therapies to demonstrate encouraging clinical activity in KRAS G12D cancers, and they have done so at doses with acceptable tolerability profiles.
RMC-6236 has shown acceptable tolerability and a promising efficacy profile, which has driven us to initiate the ongoing phase three trial in second-line PDAC. RMC-9805 has shown acceptable tolerability and encouraging initial antitumor activity with mature ORR data and durability assessments such as PFS and OS, pending longer follow-up. While RMC-6236 and RMC-9805 are likely to serve partially overlapping patient populations, these RAS-targeted therapies have distinct mechanisms of action and complementary profiles that could enable multiple treatment options.
... consistent with our aim to deliver the best possible clinical outcomes to the broadest number of patients. To support our commitment to serve the widest range of patients with the best possible treatment regimens, in addition to exploring the potential of these investigational drugs as monotherapies, we are investigating multiple rational combination strategies, including as RAS inhibitor doublets and with non-RAS-directed therapies. These approaches serve our objective to develop
meaningful new treatment options for patients with RAS-addicted cancers across a range of tumor types, stages of disease, and lines of therapy. The data updates we've outlined today highlight the significant opportunity we believe we have to deliver on this objective, and the initiation of our first phase III clinical study in second-line PDAC is an exciting step on our path to doing so. With that, I'll turn the call over to the operator for the Q&A session.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster, and we ask that you limit yourself to one question, one follow-up. Again, that's one question and one follow-up. One moment for our first question. Our first question comes from Michael Schmidt from Guggenheim. Your line is now open.
Hey, good morning, and thanks for taking my questions. Congrats on the data presentations this week. I just had a clarification on the RMC-9805 response rate data, Mark. So when I look at the waterfall chart, I see actually 14 responses at 1,200, 8 ongoing unconfirmed PRs and 6 confirmed PRs, which would result in a 35% response rate. Can you just clarify how you end up at that 30% response rate? And then I had a follow-up.
Yeah. Hi, Michael. Thanks for your question. I'm going to ask, Wei Lin, our Chief Medical Officer, to comment on that.
Yeah. So the what you're referring to, I believe, is the difference between how you count the waterfall versus the table. The waterfall include all the patients who are evaluable, versus the table included only patient who had fourteen weeks of a minimum follow-up of fourteen weeks, meaning that they were
dosed fourteen weeks before the sort of the inclusion on the table. So they at least dosed for fourteen weeks before, so which includes the potential for two scans. So that's the difference. So in some ways that's why the calculation of the OR is different between what you can count from the waterfall and the table.
Oh, okay. Thank you so much for clarifying. That makes sense. And then, you know, obviously, the data for 9805 looks very encouraging, and I was just wondering how you expect the data to improve with further follow-up. When we look at the 6236 data, obviously, the data matured nicely over time, and I was wondering if you were to expect, you know, similar longer duration, you know, responses with the 9805 program.
Yeah. Thanks, Michael. Of course, it's hard to predict the future, so I think we want to avoid making predictions about it. But our experience with RMC-6236 is, as you well know, and just described, was that we were initially reporting a response rate of around 20%, and we did not have any durability data. And over time, that response rate stabilized at a significantly higher number. So that may happen here.
It's difficult in an ongoing dose escalation study to sort of hone in on what the real response rate is until that study is no longer enrolling patients and every patient has been followed for a number of cycles, simply because the denominator and the numerator might move at different rates, and so the numbers could go up or down, you know, at various points. So it is certainly possible that we'll see some change over time. But we can't make any predictions about that right now.
Great. Thanks again for clarifying. Really appreciate it.
You bet.
Thank you. One moment for our next question. Our next question comes from Marc Frahm from TD Cowen. Your line is now open.
Hi. Thanks for taking my questions, and congrats on both data sets here at the triple. Maybe first on it's slide nineteen, where you show the PK curves for 9805 can you just kind of explain why the efficacy analysis is cut at twelve hundred milligrams, since the kind of exposures look pretty similar once you're up above nine hundred, and as you've mentioned in the prepared remarks, you know, you're seeing responses at six hundred and above. Just why is twelve hundred the right cut point?
Maybe Dr. Kelsey wants to comment on that.
Twelve hundred is our candidate recommended Phase II dose, which is why we focused our attention on that. I think to include any other dose level in the analysis at this stage may be confusing in the long run. The exposures, by the way, are not completely identical between the twelve hundred milligram dose
levels and the nine hundred milligram dose levels. I think the plots that you see on the right were mainly put there to illustrate the comparison with the mouse data, 100 mgs per kg. But if you look at the plot on the left, you'll see that the brownie gold line is clearly higher than the red line. And that, admittedly, that data is only for patients that were dosed once a day versus twice a day.
But we are seeing slightly higher exposures and slightly higher Cmax with the 1200 milligram dose level. So this is not, strictly speaking, like the RMC-6236 analysis, where we pulled 160 to 300. I think with the safety profile we have, we're fairly confident that we're gonna make a very strong case for moving forward to 1200 milligrams daily as our dose. So that's the focus on that dose for all the efficacy data.
I'd like to add just one point to Steve's comment, which is, keep in mind that RMC-6236 is a non-covalent compound, and so the area under the curve analysis that we've historically shown for that, is probably the most relevant parameter for, projecting target coverage. RMC-9805 is a covalent compound, and the
AUC is probably not the most informative parameter to look at. So I think, as Steve said, with the good tolerability up to and including 1200 milligrams, the fairly remarkable safety profile, it makes sense for us to drive that number up to 1200. There's really no disadvantage to doing so that we can see, and so we'll proceed with that.
Okay. That's just really helpful. Then just also, can you characterize the level of inhibition you think you're driving here with RMC-9805, you know, it versus, say, with a G12D patient might be experiencing at the, you know, the go-forward dose with RMC-6236? Like, you know, is this an order of magnitude more inhibition, something more subtle? Just how would you kind of characterize the relative inhibition between the two assets?
Something more subtle would be the answer to that question. Maybe Steve can-
Well, I think it depends on how you measure it. We obviously are not measuring it in patients. The only surrogate of clinical activity that we measure in patients is ctDNA data, which we will collate and disclose in due course. But if we look in the mouse models, the combination of the covalent binding of RMC-9805 to G12D with the non-covalent inhibition of G12D, that's due to the tricomplex, is basically means
that we have to measure downstream markers of pathway activation. And when we measure downstream markers of pathway activation in preclinical models treated with RMC-9805 at 100 milligrams per kilogram, we see 100% inhibition of pathway activation. So it's very hard to compare against RMC-6236, which also induces 100%
Yeah
... inhibition of downstream pathway activation when you dose at the equivalent of 300 milligrams daily. So by definition, I mean, clearly, if one of them is inducing 99% pathway inhibition, the other one is inducing 99.9% pathway inhibition, then yes, we have an order of magnitude increase, but we can't detect that, unfortunately.
Yeah.
Okay. Thank you.
And thank you. And one moment for our next question. And our next question comes from Eric Joseph, from JP Morgan. Your line is now open.
Oh, thank you. Thanks for taking the questions. And, yeah, let me add my congrats on this great data set at the conference. Just on the... A couple questions on the 6236 update. Just looking at the maturing safety profile, you know, you still have very low rates of grade three elevated transaminase levels. But can you elaborate a little bit on sort of the onset of grade three and higher events that the few that you're
seeing here, and whether there were any sort of other clinical factors contributing to that signal? And then just on dose intensity, it's come down a little bit since the July presentation. Can you say where mean dose levels are shaking out and whether any patients are managed at doses less than 160 milligrams?
Thanks, Eric. Thanks for your questions. I think Wei can take these on one at a time. The first question had to do with are there, is there any, are any of these events occurring later in time? And is there anything else you can say with regards to the liver enzyme increases?
Yeah, I mean, they do occur over a spectrum of period of time. I think majority of the AST/ALT do occur early in the first three cycles, and then it becomes less and less common with longer follow-up if they don't emerge early. I think the numerically even though there are slight numerical changes with these, I think just given the patient population, that's to be expected. There's, in general, there's some variability. When we look at this liver enzyme elevations. In fact, just looking at shift tables, there's as many patients who have increases, they have declining.
So I think given this is a predominantly, this is a pancreatic cancer patient with, typically, majority of them have, liver metastases, you do expect some variability, in liver enzyme, just over time as you follow up. We don't think the numerical changes, between this data cut and the July data cut is materially different.
And so from a clinical perspective, I don't think, we're seeing any new signal, regarding, the liver enzyme. And so we're still, I think, feel optimistic about this level as a early indicator of potential combinability with immunotherapy. Obviously, we're generating the, that data with, with IO, and then when, when that data is available, we'll be sharing that.
And then the second question, I think, has to do with the dose intensity slide and whether there's a difference between 92% and-
Yeah. Again, I don't think this is materially different. I think achieving over 90% dose intensity is just remarkable in itself. I think with longer follow-up, obviously, you're gonna have some variability in that regard, and then there's more opportunity for a dosing interruption and reduction. But regardless, I think getting a dose over 90% over this longer duration, this number of patients, I think just makes us feel pretty confident we have the right dose.
Okay, great. Thanks for taking the questions. I'll hop back. Thank you.
Thank you. One moment for our next question. Our next question comes from Jonathan Chang from Leerink Partners. Your line is now open.
Hey, guys. Congrats on the data, and thanks for taking my questions. First question, can you discuss how you're thinking about a frontline pancreatic cancer strategy across your pipeline?
Yeah, that's not a short question, or at least it's not a short answer, but we're certainly very committed to advancing into frontline. I think we've already publicly disclosed that we are working to develop a strategy around RMC-6236. Now, it appears we may have that opportunity with RMC-9805, and in fact, one of the most common questions we were asked here at this meeting was: How quickly can we move 9805 into first line? Those may not be mutually exclusive ideas, because certainly the possibility combining 9805 with 6236 is something that we're currently exploring.
It may be possible to combine with chemotherapy, and so we do need to generate some additional data that will help us define, at a minimum, which of those combinations are safe, and whether or not we study them in a single, frontline study or in more than one frontline study. So there are a lot of options being created here, and we certainly can't test all of them in a phase III context, so we'll try to prioritize. But, it is certainly possible that we'll pursue more than one, first-line strategy, in parallel because patients need it.
Understood. The follow-up is, with the data presented at the triple meeting, what is your latest thinking on the combinability of RMC-6236 with mutant selective inhibitors in your pipeline and with anti-PD-1? Thank you.
Yeah, thanks. I don't think we can give any specific update on that because we haven't shared any public information yet. Of course, the RMC-6236, RMC-6291 study is underway. It had a head start compared to the RMC-9805, RMC-6236 study, and we have publicly committed to providing an initial peek under the hood at that combination by the end of the year. The RMC-9805 study, I don't think is gonna be ready to disclose that information.
But the RMC-6236 plus RMC-6291 experiment is sort of the point of the spear for establishing that strategy of a mutant selective with a multi-selective is valid and would certainly be encouraging around the possibility of other combinations like RMC-9805 and other mutant selective inhibitors as well. But that's pending, and we'll provide that update later this quarter.
Understood. Thanks for taking the questions.
Thank you. One moment for our next question. Our next question comes from Ellie Merle from UBS. Your line is now open.
Hey, it's Sam on for Ellie. I guess just from, like, a scientific perspective, how are you thinking about how Nine eight oh five could build on the efficacy of 6236 in a combination setting? And like, how might Nine eight oh five drive deeper efficacy from G-twelve D targeting versus the multi-approach, and any learnings from the current data that you have that kind of inform your thinking about this?
Sure. Thank you very much for the question. I think, Dr. Kelsey looks enthusiastic about it.
I'll just say two things about the combination of RMC-6236 and RMC-9805. The first is that as we said, they have different and complementary mechanisms of action. The way that RMC-9805 inhibits KRAS G12D is mainly through its covalent binding to G12D. But if you add RMC-6236, you do increase the non-covalent inhibition of G12D over and above what you see with RMC-9805 alone. So the combination may be a better inhibitor of G12D. I cannot prove that. I can just it's speculation.
But more importantly, if you look at the mechanisms by which tumors escape from mutant selective RAS inhibitors, a large proportion of those mechanisms are amenable to inhibition of RMC-6236, and that's the main reason for conducting the combination experiments that we're doing, not just with 9805, but
also with 6236. We don't have any information yet about how tumors, particularly pancreatic tumors, might escape from RMC-9805, but if they're adopting the same mechanisms as the other tumors have to the KRAS G12C inhibitors, then we have a fairly good shot at being able to prolong the time to disease progression by adding RMC-6236. So that's the predominant thesis that we're testing with that combo.
Awesome. Thank you so much. And just a quick follow-up. Do you have any color on whether any of the, like, unconfirmed, partial or complete responders in either of the studies have been confirmed since the data cutoff? And I guess if you could give any color on what your expectations are for how many you might expect to be confirmed at subsequent cuts? Thanks.
I can't comment on anything since the data cut, so we'll have to wait till the next data cut before I can comment on anything since the last data cut. But we-- I will say that the, our experience to date has been, with both RMC-6236 and RMC-9805, is that the majority of responses do confirm. And not only do they confirm, but as you-- I think if you had had the opportunity to hear the presentation, you will have seen the case report where the tumor continued to shrink with each subsequent scan. And we see that fairly often, is the tumors shrink and then they keep shrinking.
How many scans elapse before they cross the magic 30% is variable from patient to patient, but it is very unusual for a patient with a response to not confirm. It's not unheard of, but it's extremely unusual for patients with a response to not confirm. Unlike, I must say, chemotherapy, where about half of the responders don't confirm. If you look at the Napoli-1 study, the response rate was 17%, and the confirmed response rate was 8%.
Okay, thank you so much. Really appreciate it, and congrats again on the data.
Thank you.
Thank you. One moment for our next question. Our next question comes from Kelly Shi from Jefferies. Your line is now open.
Congrats on the progress, and thanks for taking my questions. I'm wondering if your view of the previously communicated regulatory path for six two three nine in PDAC could change given this updated overall survival benefit? It is a single-arm study, but it's a reasonable delay, a large sample size, and OS benefit more than doubled anything in the standard of care. Also, I have follow-up. Thank you.
Yeah. Hi, Kelly. Thanks for your question. Yeah, we do get asked that a lot. It's hard to read the minds of folks who make those decisions. They're, you know, generally, the FDA's public view is stated as event-driven studies really require a comparator arm to be interpretable, and I think formally, that's true. Of
course, we all see data like this, and we have a strong feeling that it might predict, you know, success in a randomized trial with a control arm, but that's generally the FDA's view. Could that change when they evaluate data? We'll just have to see. In any event, we're going ahead with a randomized control trial with RMC-6236, where that study is already underway.
We're dosing patients now, and we think ultimately we'd like to, just with data, with real rigorous analysis, demonstrate that sort of OS benefit, which I think would very much solidify RMC-6236 as a, you know, as a potential treatment of choice. So we're just going to play it that way, and you know, we'll see whether the FDA take a different view.
Thank you very much. And just quick follow-up. Does the dose reduction of 9805 also caused by rash in case I missed? I think this was mentioned for 6236. Thank you.
Yeah, thanks. I think that the rash that was seen in a small fraction of patients with RMC-9805 was pretty mild. But maybe Dr. Lin can comment on what caused the dose reductions in-
... Sure. Yeah, just follow up on Mark's comment. I can confirm that the rashes observed to date have all been grade one, and so they don't lead to dose modifications. And so the dose modification as Dr. Hong had during his presentation mentioned one of the events. First of all, there were very few, and one of the events was actually due to the grade three ALT elevation. And the others were predominantly GI toxicities that led to the dose modification. So yeah, nothing to do with the rash. So the rash has not been a strong safety signal.
Okay, thank you. Congrats again.
Thank you.
Thank you. One moment for our next question. Our next question comes from Peter Lawson from Barclays. Your line is now open.
Great. Thank you. Thanks for taking the questions, thanks for the update as well. On to the comparison between your G12D and your multi RAS inhibitor. On the safety side of things, is that molecule-related? It seems that the G12D is safer than the multi, both being safe, but incrementally safer for G12D. But is it molecule-related, mechanisms of action, or hitting more mutations, or is it patient differences we should be thinking about?
Yeah, thank you, Peter. I think it stands out pretty strongly that RMC-6236 would be expected to have effects that go beyond simply inhibiting the mutant that's driving the cancer, because RMC-6236 is designed to inhibit all forms of mutant K-, N-, and H -RAS mutant forms and wild-type forms, and it will do
so in normal tissues as well as in the tumor. So I think it's always been expected that RMC-6236 would have some degree of side effect profile, which is essentially an on-target side effect profile. In fact, it was predicted to be so strong that it was expected that this compound would be dead on arrival a couple of years ago by you know, some leading RAS scientists.
But just the opposite has proven to be the case, which is, while there are side effects, clearly it's not like taking drinking water, but it's a particularly well-tolerated for most patients, and that is at achieving drug levels that are driving quite significant tumor responses in quite difficult to treat diseases. That's a
paradigm shift from where people were several years ago when they really questioned it. RMC-9805 is a very different molecule. It is ultimately, its activity is driven by the covalent binding, as Steve described, even though there is some non-covalent binding that might be causing some low level of rashes in a small fraction of patients. So it's clearly not hitting the wild-type at the same level that RMC-6236 is.
And in fact, it's designed not to hit the wild type at the same level of RMC -6236 . So I think from our point of view, this difference between these is entirely driven by the mechanism of action that was designed into the molecules. And we're just really pleased, though, that we have two molecules that are generally well-tolerated and two molecules that can deliver such antitumor effects in these patients.
Thank you, and then just picking up on the question you said you were posed about how quickly 9805 can move into the front line. With the additional combination data, is that the kind of gating factor, and when could we see that additional combo data, whether it's for chemo or other agents?
Yeah. I'm just a little bit amazed that we've spent most of our day today talking about first-line pancreatic cancer treatment with RMC-9805, and today is the first time we've ever shown any data on RMC-9805. So I think it does speak to the profile, and that it immediately takes everybody to that place, and it takes
us there as well. Yeah, I think the main thing we have to characterize now, as Wei described earlier, is the combination opportunities. We have to evaluate those for safety. One would now project that RMC-9805 would combine quite well with other agents that might have side effects, because it has such a minimal side effect profile. So that's very exciting, but we need to establish that.
And of course, as Wei emphasized and Steve talked about further, we are very excited about and feel compelled by the preclinical data that support a combination of a mutant selective inhibitor like RMC-9805 with RMC-6236, the RAS multi inhibitor. So I think before we just rush into launching a, you know, expensive, very large first-line trial, we wanna make sure that we're bringing to patients the options in that trial that have been prioritized based on clinical data and primarily safety, so that we don't run into unexpected problems.
Perfect. Thank you so much.
Thank you. We have one last question. Our question comes from Laura Prendergast, from Raymond James. Your line is now open.
... Hey, guys, congrats on the data this week. Two questions for me. You know, first, you know, when you look at the left side of the waterfall plot and the disease control rate, you know, very early for 9805, do you think this is all, at all reflective of, you know, the importance of hitting wild-type RAS in PDAC with the pan- RAS inhibitor? And then, you know, generally, did you guys see any difference, I know, small numbers, but in overall response trends in second-line patients and later-line patients in the 9805 data set?
Okay, thanks for your questions, Laura. Let me touch on the first one, and then, maybe, Wei or Steve can comment on the second one. And that is, the question was whether or not the left hand of the waterfall plot, which basically is non-responders or patients who, or who had tumors that grew on treatment, whether that reflects the lower anti-wild- type activity of RMC-9805. That's what I understood the question to be. We don't know that. Did I misunderstand the question?
More so, when you're comparing, you know, the waterfall plots of six two three six and
Yeah
... RMC-9805, you know, do you think that, you know, having more stable disease or disease control could be reflective of the importance of hitting wild-type RAS in PDAC?
Yeah, yeah. No. Okay, I think I think I'm understanding the question. It could be. We just don't know the answer to that. We've generally thought of the wild-type form of RAS as being more of a downstream resistance mechanism, a later resistance mechanism, something that reduces the duration of the antitumor response rather than one that affects the initial response rate. But in fact, I don't know that we
really know that. That's really inferred by sort of historical data and so on. I don't think we have an experimental basis for answering the mechanistic question that you're asking. It certainly could be a part of the contributor. Ultimately, I think we need to see over time what happens and get sort of more stable data sets out of it.
Really what we need to get is durability parameters, which, as Wei mentioned, will just take some time before we have enough information to share. I don't think we're particularly focused on whether the response rate is, you know, twenty-nine or thirty-four or thirty-six, because that's really not going to drive much in the way of decision-making, and it certainly doesn't drive for patients much in the way of how they will assess the benefit.
Thank you. And then the second question was if you're seeing any trends for RMC-9805 responses in second-line versus later-line patients.
Yeah. So in this study, in this report, we didn't separate second line from third line plus. And, do you wanna just comment on that?
I think at this stage, I mean, this is a preliminary report, and you know, the more ways you cut the data, the more you get into such ridiculously low numbers that they become essentially meaningless because they're very wide confidence intervals around them. So we will almost certainly report on any differences between second line and third line plus, as we did for 6236, when we have a sufficiently large database. But at the moment, I don't think that we can do that with any real confidence.
Got it. Thank you very much.
Thanks for your question.
Thank you. Now I would like to turn the call over to Mark Goldsmith for closing remarks.
Oh, well, thank you, operator, and thanks to everybody for joining us today. We look forward to providing additional updates as they become available.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.