Ladies and gentlemen, thank you for standing by. Welcome to Revolution Medicines conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Ryan Acey, Senior Vice President of Corporate Affairs. Please go ahead.
Thank you and welcome everyone to this morning's webcast, where we'll provide updates on our clinical-stage RAS(ON) inhibitors. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, and Dr. Steve Kelsey, our President of Research and Development. Dr. Wei Lin, our Chief Medical Officer, 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, we've made tremendous progress at Revolution Medicines in advancing our three clinical-stage RAS(ON) inhibitors through important clinical milestones. Today, we'll summarize updated results and new clinical data across several of these programs, highlighting the progress we've made against the key 2024 development priorities we laid out at the beginning of the year. The first priority is to advance RMC-6236, our RAS(ON) multi-selective inhibitor, into phase III registrational studies. In October, we initiated our first phase III study called RASolute-302 in patients with second-line metastatic pancreatic ductal adenocarcinoma, often referred to as PDAC, and in the first quarter of 2025, we plan to initiate our second phase III study called RASolve-301 in patients with previously treated non-small cell lung cancer.
Our second priority is to begin to define the path to expanding the reach of RMC-6236 into earlier lines of therapy. The compelling second-line pancreatic cancer data we shared earlier this quarter substantiates our opportunity to move into the first-line setting, potentially even as a monotherapy treatment option. In addition, we believe data we'll describe today, highlighting the combinability of our RAS(ON) inhibitor portfolio with pembrolizumab, opens the door to the important first-line non-small cell lung cancer opportunity. Our third development priority this year is moving mutant selective inhibitors RMC-6291, a RAS(ON) G12C selective inhibitor, and RMC-9805, a RAS(ON) G12D selective inhibitor, toward late-stage clinical development. At the Triple Meeting in October, we shared encouraging initial results for RMC-9805 in patients with pancreatic cancer.
In addition, we will share today initial validation of the potential to combine our RAS(ON) multi-selective inhibitor with a RAS (ON) mutant selective inhibitor in the first-of-its-kind RAS (ON) inhibitor doublet consisting of RMC-6291 plus RMC-6236 in patients with advanced RAS G12C mutant solid tumors. While early, we believe these results begin to substantially expand the aperture for our opportunities to meaningfully impact patient lives with these pioneering investigational drugs. Slide four is a reminder that our RAS (ON) inhibitor pipeline is designed to target a significant number of human cancers driven by oncogenic RAS proteins, including common tumors such as pancreatic cancer, non-small cell lung cancer, and colorectal cancer. There continues to be a need to improve outcomes among these difficult-to-treat RAS tumors.
Central to our approach is 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) . Mutations in RAS proteins can drive uncontrolled RAS on signaling pathways that favor cell growth, survival, and tumor formation, and our approach focuses on targeting RAS(ON) signaling. Slide five reviews the differentiated mechanism of action of our innovative tri-complex inhibitors that bind directly to and inactivate the on form of oncogenic RAS proteins. Preclinically, these targeted compounds directly and rapidly inhibit the oncogenic RAS(ON) cancer drivers in tumor cells and induce deep and durable suppression of RAS cancer signaling. This approach to targeting RAS proteins aims to defy common mechanisms of drug resistance. Slide six shows the status of our rich development pipeline.
Having now studied over 1,000 patients with one or more of our first three RAS(ON) inhibitors, we've achieved initial clinical validation of these investigational drugs. Today, we will provide an update on monotherapy with RMC-6236 and share with you initial clinical evidence of the combinability of RAS(ON) inhibitors with immunotherapy and in RAS(ON) inhibitor doublets, a unique potential treatment paradigm enabled by our portfolio. I'll now turn the call over to Dr. Steve Kelsey, our President of R&D, to summarize what we believe to be promising new clinical results for RMC-6236 and RMC-6291 in several single-agent and combination treatment settings.
Thank you, Mark. I'll begin my remarks with an update on RMC-6236 in PDAC. As a reminder of the context, the table on slide eight summarizes the results of previously published clinical studies of various chemotherapy regimens in patients with previously treated metastatic PDAC. In the chemotherapy regimens evaluated, the median progression-free survival ranged between two and 3.5 months in the second-line setting, with median overall survival of six to seven months. The numbers in the third-line or later setting were even lower. The results consistently show a need to improve clinical outcomes for patients with PDAC whose tumors have progressed after first-line chemotherapy. It's also important to note that these chemotherapy regimens often have significant adverse events that result in approximately two-thirds of patients requiring a dose modification.
At the ENA Triple Meeting in October, we shared updated clinical results for a pooled population of patients with second-line PDAC treated with doses of RMC-6236 ranging from 160 mg to 300 mg daily. Beginning on slide nine, I'll summarize the results we've seen specifically at the 300 mg daily dose. As of the same July 23rd, 2024 data cutoff date that was presented at the ENA Triple Meeting, 76 PDAC patients have received RMC-6236 at 300 mg daily. Aside from being a more heavily pretreated patient population, we believe that the demographic and risk factors of patients reported in this analysis are generally representative of those we expect to see in our ongoing phase III study in second-line PDAC. Slide 10 shows that at a 300 mg daily dose, RMC-6236 was generally well tolerated.
The safety profile at 300 mg daily is generally consistent with that reported in October for the 100 mg to 160 mg to 300 mg pooled analysis. We and our investigators have previously described the common treatment-related adverse events of RAS-associated gastrointestinal toxicities such as stomatitis and diarrhea. 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 anti-cancer therapies, such as the low frequency and severity of liver toxicity. While there were some modest numerical changes in the adverse event rates, we believe that these do not meaningfully change the overall safety profile, and the data justify our decision to move forward with 300 mg daily as the phase III dose in PDAC.
On slide 11, we see how the treatment-related adverse events affected patients' ability to remain on RMC-6236 treatment. Just over 40% of patients required a dose modification of RMC-6236, and notably, none of these 76 patients discontinued RMC-6236 due to a treatment-related adverse event. These numbers translated to a mean dose intensity of almost 90%. We predict that the 90% dose intensity and modest dose modification rates may contribute to the clinical benefit profile of RMC-6236. We plan to prospectively evaluate in our phase III study whether the tolerability profile of RMC-6236 confers an improved quality of life versus standard of care chemotherapy for patients with metastatic PDAC. The best change in target lesions and the objective response rates for patients treated with 300 mg daily of RMC-6236 are presented in slide 12.
While the overall shape of the waterfall plot is consistent with the pooled analysis presented in October, the objective response rate, as shown in the table on the right, is higher at the 300 mg daily dose. In patients who received their first dose of RMC-6236 at least 14 weeks before the data cutoff date, which is a period that allows for two potential on-treatment CT tumor measurements, the objective response rate in second-line patients with a KRAS G12X mutation was 36%, and in patients with any RAS mutation was 27%. Progression-free survival analysis for second-line PDAC patients treated with RMC-6236 at the 300 mg daily dose is shown on slide 13. This patient population is consistent with those eligible for our ongoing phase III registration study.
The median progression-free survival in the KRAS G12X mutant population is estimated to be 8.8 months, compared with 8.5 months for the pooled analysis presented in October. The median progression-free survival in the broader RAS mutant population is estimated to be 8.5 months, as compared to the 7.6 month estimate for the pooled dose analysis. These results continue to reinforce our confidence in the ongoing phase III study. Moving to overall survival, which, of course, is the ultimate measure of efficacy. As of the July data cutoff date, the median overall survival duration for patients treated with 300 mg daily of RMC-6236 could not be estimated.
The shape of the Kaplan-Meier curve is striking, and the overall survival rate at six months, which is the proportion of patients who remain alive six months after starting treatment with RMC-6236, is 100% in the KRAS G12X population and 97% in the broader RAS mutant population. To summarize on slide 15, RMC-6236 monotherapy has shown compelling results in patients with second-line PDAC, a RAS-driven disease. As the first targeted investigational drug designed to directly inhibit all major forms of oncogenic RAS(ON), RMC-6236 at the phase III dose of 300 mg daily exhibited a manageable safety profile, favorable dose intensity, and compelling progression-free survival and overall survival. These data reinforce our ongoing confidence in the RASolute-302 study, our ongoing phase III study versus standard of care chemotherapy as a second-line treatment for patients with PDAC.
We aim to advance RMC-6236 into earlier lines of therapy for patients with PDAC as quickly as possible. I'll now move on to the RMC-6236 monotherapy results in RAS mutant non-small cell lung cancer, where there remains a continued need for better treatment options for the large and underserved patient population living with this disease. Slide 17 shows that approximately 30% of non-small cell lung cancer tumors have some form of RAS mutation. Approved KRAS( OFF) G12C inhibitors provide some benefit for the 12% of lung cancer patients whose tumors harbor a G12C mutation. The remaining 18% of patients with tumors harboring a RAS mutation still have no targeted therapy option. 13% of non-small cell lung cancer patients have tumors with a G12X mutation other than G12C, including G12D and G12V, and 5% have a RAS mutation other than G12X, including G13 and Q61 mutations.
As shown on Slide 18, docetaxel remains the most common standard of care for patients with non-small cell lung cancer harboring a KRAS mutation other than G12C. The median progression-free survival and median overall survival for patients with previously treated non-small cell lung cancer who received docetaxel ranges from three to 4.5 months and from 9.1 to 11.8 months, respectively, illustrating the ongoing unmet medical need in this disease. We have previously disclosed that RMC-6236 induces frequent responses and significant durable freedom from progression in preclinical models of RAS G12X non-small cell lung cancer. We have extended this data to non-small cell lung cancer models harboring G13X and Q61X mutations. This data, some of which is shown on Slide 19, provided the rationale for the clinical evaluation of RMC-6236 in RAS mutant non-small cell lung cancer.
Turning now to Slide 20, the first-in-human phase I study for RMC-6236 has now enrolled over 400 patients, including 132 patients with RAS mutant non-small cell lung cancer. Slide 21 shows the pharmacokinetics of RMC-6236 in patients with non-small cell lung cancer across the range of doses evaluated in the phase I study. Doses from 120 mg to 300 mg daily provided exposures that were consistent with tumor regressions in preclinical models of non-small cell lung cancer. In general, higher doses of RMC-6236 were associated with greater anti-tumor activity in our preclinical models. Moving to Slide 22, as of the September 30th, 2024 data cutoff date, 124 patients with RAS mutant non-small cell lung cancer were treated at doses ranging between 120 mg to 300 mg daily. These patients were generally heavily pretreated, with 56% of patients having had two or more prior lines of treatment.
81% had an ECOG score of one. Slide 23 details the safety profile for RMC-6236 in the 124 patients with non-small cell lung cancer treated with doses ranging from 120-300 mg daily. The table is broken out by dose range. Doses between 120 mg-220 mg are shown in the middle panel, and the 300 mg dose group is shown on the right. A starting dose of 120 mg-220 mg daily was generally well tolerated, with a profile similar to that previously described for PDAC. While the types of adverse events are similar across the dose ranges in patients with non-small cell lung cancer, the 300 mg dose shows a higher frequency and severity of tolerability-defining adverse events in these non-small cell lung cancer patients than in the patients treated with 120-220 mg daily.
The tolerability profile at 300 mg in non-small cell lung cancer patients looks less favorable than was reported to patients with PDAC treated at the 300 mg dose. The impact of this adverse event profile is shown on slide 24. The dose modification rate at 120 mg to 220 mg daily was 41%, with only 4% of patients discontinuing RMC-6236 due to a treatment-related adverse event. As a result, the mean dose intensity across this dose range was 88%. By contrast, the dose modification rate at 300 mg was 67%, resulting in a mean dose intensity of 72%, roughly equivalent to a continuous daily dose of 200 mg daily. For this reason, we have elected to recommend 200 mg daily as the right dose for further single-agent development of RMC-6236 in non-small cell lung cancer.
For the purposes of reporting the preliminary clinical activity and efficacy of RMC-6236 in RAS mutant non-small cell lung cancer, we have removed patients treated at the 300 mg daily dose and above and pulled the patients treated at 120 mg-200 mg daily to increase the number of patients and thus provide sufficient confidence in the outcome measures at our recommended dose. We have also restricted the analysis to patients who would be eligible to participate in our proposed phase III study, that is, patients with RAS mutant non-small cell lung cancer who have received either one or two prior treatments for locally advanced or metastatic disease and who have not received prior docetaxel . And because many patients with non-small cell lung cancer harboring G13 and Q61 mutations were treated at 300 mg daily in our study, this analysis is restricted to G12X mutations.
This reduces the number of patients evaluated for efficacy from 73 in the safety analysis down to 40. Looking at the objective response rate on slide 25, the waterfall plot includes 40 patients, all of whom received their first dose of RMC-6236 at least 14 weeks prior to the data cutoff date, thus permitting at least two treatment scans. The objective response rate amongst these 40 patients was 38%, including patients with a response that was either confirmed or is still pending confirmation. Approximately two-thirds of patients had their response occur within two months of starting RMC-6236 treatment. But as with our data in PDAC, a significant number of RAS responses took longer than two months to appear. On slide 26, we see that the median progression-free survival for these 40 efficacy-available patients is 9.8 months, with 95% confidence intervals ranging from six to 12.3 months.
The curve is relatively mature, as indicated by the median follow-up time of 10.8 months. Median overall survival, shown on slide 27, is estimated at 17.7 months, with the 95% confidence interval from 13.7 months to not yet estimable. Both progression-free survival and overall survival estimates from the interim data are encouraging and justify further development of RMC-6236 in RAS mutant non-small cell lung cancer. Based on these results, we plan to initiate a phase III study in patients with previously treated non-small cell lung cancer in the first quarter of 2025. While we're in the process of discussing our plans with the FDA, our proposed phase III study outline is shown on slide 28. We expect that the RASolve-301 study will randomize approximately 400 patients to either monotherapy RMC-6236 or docetaxel , with endpoints that include progression-free survival and overall survival.
We anticipate the study will involve patients who have received either one or two prior lines of therapy, which must include immunotherapy and platinum doublet chemotherapy administered either concurrently or sequentially. Prior treatment with the comparator docetaxel will not be permitted. Similar to our recently initiated phase III study in second-line PDAC, we expect our phase III study in non-small cell lung cancer to incorporate a nested design. In this nested design, the statistical testing of endpoints will be performed following a hierarchical sequence. The primary analysis will be performed in the core population of non-small cell lung cancer patients with all RAS G12X mutations except G12C. Because the proof of concept was established mainly in these patients, limiting the primary analysis to this population is designed to increase the probability of success.
The extended population will incorporate all patients with RAS mutant non-small cell lung cancer, including those with tumors harboring G12C, G13X, or Q61X mutations. In conclusion, we believe these data show compelling anti-tumor activity as measured by the important endpoints of progression-free survival and overall survival, as well as objective response rate at a clinically active dose range of 120 mg-220 mg daily. We believe the safety tolerability profile at these doses was acceptable and the dose intensity was favorable. We believe these results support the initiation of a global randomized phase III study of single-agent RMC-6236 in previously treated locally advanced or metastatic RAS mutant non-small cell lung cancer.
Consistent with the comments Mark made at the beginning of the call, accelerating RMC-6236 into earlier lines of therapy for RAS mutant non-small cell lung cancer is an important part of our strategy to attempt to maximize benefits for patients. In this context, demonstrating tolerability in combination with an immune checkpoint inhibitor such as pembrolizumab is critical to successfully moving RMC-6236 into studies of first-line non-small cell lung cancer. In preclinical models shown on slide 31, inhibition of RAS pathway signaling by RMC-6236 in RAS mutant tumors considerably increased susceptibility to PD-1 inhibition and resulted in durable complete responses. Unfortunately, the combination of KRAS(OFF) G12C inhibitors with immune checkpoint inhibitors has frequently resulted in liver toxicity, either preventing further development or requiring dose modification of the RAS inhibitor.
All grade hepatotoxicity has been reported in 20%-53% of patients treated with a G12C OFF inhibitor plus pembrolizumab, and grade 3 hepatotoxicity is in the range of 5%-47%. We have previously disclosed that we had not observed an increase in hepatotoxicity for patients treated with RMC-6236 within 90 days of a prior PD-1 or PD-L1 inhibitor, and longer-term follow-up for those patients has confirmed these initial observations. We will now show you the preliminary safety data for patients who received RMC-6236 concurrently with pembrolizumab. Slide 32 shows the baseline characteristics for the patients in our RMC-6236 plus pembrolizumab combination study. The analysis includes 20 patients, all of whom were at least second line. 85% had received prior therapy with an immune checkpoint inhibitor, which makes formal evaluation of additive efficacy from this cohort challenging.
I should note that, as expected, no pharmacokinetic interaction between RMC-6236 and pembrolizumab was detected. The safety table for patients treated with the combination of RMC-6236 plus pembrolizumab is on slide 33. As of the October 28th, 2024 data cutoff date, 20 patients were dosed with full-dose pembrolizumab plus RMC-6236 at 200 mg daily. As previously mentioned, this is our proposed phase III dose in non-small cell lung cancer. Follow-up is short, with a median duration of treatment of 2.3 months. However, 12 patients had been on treatment for at least 60 days at the time of the analysis, which is expected to be sufficient to detect the onset of liver toxicity were it to occur. Most treatment-related adverse events were low-grade and consistent with either agent as monotherapy alone. Importantly, only one grade 3 ALT elevation and no grade 3 or high AST elevations were observed.
The mean dose intensity of RMC-6236 was approximately 97%. Among the 20 patients, none discontinued treatment with RMC-6236 due to a treatment-related adverse event. Anti-tumor activity was observed, but since these patients had previously progressed on pembrolizumab treatment, we did not necessarily expect to see a higher overall response rate than previously observed with RMC-6236 alone. We're pleased with the initial safety results from the combination of RMC-6236 plus pembrolizumab in patients with non-small cell lung cancer. Concurrent dosing of the combination appears to be well tolerated, which is consistent with the findings from the RMC-6236 monotherapy experience, which showed low frequency and severity of liver enzyme elevations. We believe these encouraging data justify further investigation of the combination of RMC-6236 with pembrolizumab, including in the first-line setting. I'll now shift my remarks to the evaluation of RAS(ON) inhibitor combinations, which we refer to as doublets.
Specifically today, our mutant selective RAS(ON) G12C inhibitor, RMC-6291, and our RAS(ON) multi-selective inhibitor, RMC-6236. We have previously reported, including at AACR earlier this year, preclinical studies with RMC-6291 plus RMC-6236 across a range of KRAS G12C tumors, including non-small cell lung cancer and colorectal cancer. These models show that the depth of tumor regression and duration of freedom from tumor doubling can be significantly improved with the combination of a RAS(ON) G12C selective inhibitor such as RMC-6291 plus a RAS(ON) multi-inhibitor such as RMC-6236 compared with either agent alone. In some instances, this combination induced significant regressions in KRAS G12C tumors that were relatively resistant to either RMC-6291 alone or RMC-6236 alone. We recently presented similar encouraging preclinical data with the combination of our RAS(ON) G12D selective inhibitor, RMC-9805 plus RMC-6236 at the EORTC-NCI-AACR Triple Meeting in October.
Tumor pharmacodynamic data and modeling from these studies has showed that the occupancy of the driver RAS mutation was increased with the RAS(ON) RAS(ON) inhibitor combination. Downstream pathway inhibition was increased by the doublet, in part due to inhibition of wild-type RAS signaling, as well as deeper inhibition of the driver RAS mutation. In addition, tumor escape through wild-type RAS signaling was abrogated by the presence of RMC-6236 due to the well-described RAS wild-type inhibitory activity of the RAS(ON) multi-inhibitor. Several clinical data sets exemplified by Mark Awad's New England Journal of Medicine paper in 2021, reproduced on slide 38, have shown that tumor escape from KRAS(OFF) G12C inhibition frequently involves reactivation of the RAS signaling pathway. Some of these escape mechanisms, such as new mutations in KRAS G12C, remain sensitive to tri-complex RAS(ON) G12C inhibitors.
In addition, many of these escape mechanisms, including new RAS mutations in the wild-type RAS allele and upstream activation of RAS signaling via receptor tyrosine kinase activation, are amenable to inhibition by RMC-6236. Such escape mechanisms are especially common in colorectal cancer, which underlies the generally limited impact observed with RAS inhibitors as single agents in these tumors. Taken together, these results suggest that the combination of RMC-6291 and RMC-6236 warrants further investigation to determine whether the doublet could induce responses in tumors otherwise resistant to KRAS(OFF) G12C inhibitors, increase overall response rates in tumors that might be sensitive to KRAS G12C selective inhibitors, or significantly prolong the duration of response and/or progression-free survival over and above KRAS G12C inhibition alone through amelioration of putative escape mechanisms. Moving on to Slide 39.
In our RMC-6291-101 study, we initiated a series of clinical experiments with the combination of RMC-6291 and RMC-6236 to find a suitable dose or doses for the combination and to test the hypothesis just described. Slide 40 shows the baseline patient characteristics of the patients treated with RMC-6291 plus RMC-6236 as of the end of October. 74 patients across several tumor types were evaluated. All patients were previously treated with a median of three prior lines of therapy, and over half of the patients had progressed after prior treatment with a KRAS(OFF) G12C inhibitor. The RAS(ON) inhibitor doublet of RMC-6291 plus RMC-6236 was well tolerated. The safety and tolerability reported appear similar to RMC-6236 monotherapy at equivalent doses. There was one grade 4 hypokalemia, which was associated with grade 3 diarrhea and no grade 5 events.
Treatment-related adverse events led to dose reduction in 10% of patients and treatment discontinuation in 3% of patients. The mean dose intensity for both compounds was above 90%. The standard of care for patients with colorectal cancer whose tumors have progressed on combination chemotherapy followed by KRAS G12C inhibitor would be trifluridine and tipiracil, marketed as Lonsurf, either alone or in combination with Avastin. Slide 42 lists several recent studies of Lonsurf in relapsed refractory rectal cancer, showing response rates in the low to mid-single digits, median progression-free survival between 2 and 5.6 months, and median overall survival ranging from 6.4 to 10.8 months. Slide 43 highlights the limited clinical activity in relapsed refractory colorectal cancer that we've seen to date with monotherapy approaches with our RAS(ON) inhibitors.
RMC-6236 has shown a 9% objective response rate among 22 patients with RAS mutant colorectal cancer who had not previously received a RAS inhibitor. RMC-6291 has shown zero responses among six patients with KRAS G12C colorectal cancer whose disease had progressed on a KRAS(OFF) G12C inhibitor. These results illustrate how challenging the treatment of patients with later line colorectal cancer is, particularly those who have previously progressed on a KRAS inhibitor. The data suggest that meaningful clinical benefit from RAS inhibitors could likely be achieved in RAS mutant colorectal cancer with combination therapy. Because of the unimpressive monotherapy effects in this setting, I would like to highlight the anti-tumor activity of a RAS(ON) inhibitor doublet in the subset of patients with KRAS G12C colorectal cancer who had progressed on or after a KRAS(OFF) G12C inhibitor.
This is a subset of patients with a particularly poor prognosis, making it a good test of the mechanistic and clinical hypotheses underlying the RAS(ON) inhibitor doublet approach. Note on slide 44 that these patients had received a median of five prior lines of therapy for their cancer. Slide 45 describes the initial efficacy results for the 12 efficacy available patients with colorectal cancer who had progressed on a KRAS(OFF) G12C inhibitor and were subsequently treated with the RAS(ON) inhibitor doublet of RMC-6291 plus RMC-6236. The objective response rate was 3 out of 12 or 25%, and the disease control rate was 92%. The objective response rate includes patients with either confirmed or unconfirmed but pending responses, and due to the early nature of this data set, includes patients who received the first dose of combination therapy at least eight weeks prior to the data cutoff date.
It is an initial glimpse of anti-tumor activity, but not a mature data set. Durability of effect is not sufficiently mature to report at this stage. Recall that this is a patient population where no responses were observed in six patients treated with single agent RMC-6291 and where no data has yet been reported for KRAS(OFF) G12C inhibitor. More granularity on the anti-tumor activity of RMC-6291 plus RMC-6236 and the underlying scientific basis for it is provided by a case report, including analysis of circulating tumor DNA. The patient described on slide 46 had a KRAS G12C colorectal cancer that progressed on adagrasib.
At the start of RAS(ON) inhibitor doublet treatment, the tumor was found to harbor the original KRAS G12C mutation and an additional Y96 mutation in KRAS G12C that has previously been shown to confer resistance to adagrasib but retain sensitivity to tri-complex KRAS(ON) G12C inhibitors. In addition, the tumor harbored two receptor tyrosine kinase fusion genes, one involving ALK and one involving MET. Both ALK and MET mutations drive flux through both mutant and wild-type RAS. The patient went on to have a complete response on the combination of RMC-6291 plus RMC-6236, and after one cycle of RAS doublet therapy, circulating tumor DNA was cleared to below the limit of detection.
A second patient, not shown here, achieved a significant reduction in circulating tumor DNA and radiologic stable disease on the RAS(ON) RAS(ON) inhibitor combination, despite the presence of multiple additional RAS mutations, including the well-described driver mutations KRAS G13C and KRAS G13D. Taken together, the preclinical data, along with the preliminary clinical results, are consistent with the RAS(ON) inhibitor doublet suppressing a wide variety of emergent mechanisms of RAS pathway activation in KRAS(OFF) G12C resistant colorectal cancer cases, something that we believe is unlikely to be achieved by standard care therapy or single agent RAS inhibition. We are currently enrolling additional patients at 200 mg b.i.d.
of RMC-6291 plus at 200 mg daily of RMC-6236, including those with colorectal cancer, non-small cell lung cancer, and PDAC, and including patients who have received the prior KRAS(OFF) G12C inhibitor, as well as those who have not been previously treated with a RAS inhibitor. With these encouraging findings with the RAS(ON) inhibitor doublet, I'll now briefly touch on the RMC-6291 plus pembrolizumab combination. Our desire remains to be able to replace first-line chemotherapy for patients with advanced KRAS G12C non-small cell lung cancer with a triplet combination of RMC-6291, RMC-6236, and pembrolizumab. We have previously shown, as seen on slide 49, that this triplet combination is effective in an immune-competent pre-clinical model that responds poorly to single agent RAS(ON) inhibitor with checkpoint inhibitor. Central to this clinical strategy is determining whether, like RMC-6236 shown earlier, RMC-6291 can be safely combined with pembrolizumab.
Slide 50 shows the baseline characteristics for 15 patients with KRAS G12C tumors who have been treated with the combination of RMC-6291 at 200 mg b.i.d. plus pembrolizumab. All patients had received prior therapy for non-small cell lung cancer. 73% had received prior therapy with an immune checkpoint inhibitor, and a third had received a prior KRAS G12C(OFF) inhibitor. The majority had non-small cell lung cancer, although two patients enrolled early in the study to expedite the safety evaluation had colorectal cancer. As with the RMC-6236 plus pembrolizumab study, this study was designed as a safety evaluation, and because of prior treatment with immunotherapy and limited sample size, the results we are sharing are safety-focused. As shown on slide 51, median duration of treatment for these 15 patients is short, but seven patients have been on treatment for at least 60 days. The combination appears to be well tolerated.
All treatment-related adverse events were grade 2 or lower. Importantly, only one case of grade 1 ALT/AST elevation has been reported. There were no treatment-related adverse events leading to treatment discontinuation, dose reductions, or dose interruptions at this dose level, and the mean dose intensity of RMC-6291 was 98%. As noted on slide 52, while preliminary, the combination of RMC-6291 plus pembrolizumab in patients with non-small cell lung cancer appears to be well tolerated. The encouraging initial safety data from this combination enables the potential for a triplet combining RMC-6236 and 6291 with pembrolizumab, which opens the door to evaluation of a potential chemotherapy-sparing option for patients with first-line non-small cell lung cancer.
Having provided an update on RMC-6236 in pancreatic cancer, encouraging new data on RMC-6236 in non-small cell lung cancer, initial evidence of combinability of RMC-6236 or RMC-6291 with pembrolizumab, and initial evidence that a RAS(ON) inhibitor doublet can outperform monotherapy in patients with refractory RAS mutant tumors, I'll pass the mic back to Mark.
Thank you, Steve. Our objective at RevMed is to revolutionize treatment for patients with RAS-addicted cancers. Expansion of our late-stage development efforts is supported by the growing list of clinical milestones we are achieving in patients with a range of tumor types, stages of disease, and lines of therapy. We've now obtained initial clinical validation of three clinical stage RAS(ON) inhibitors: RMC-6236, RMC-6291, and RMC-9805, each investigational drug designed with a differentiated RAS-targeted profile.
We've provided evidence of promising initial clinical activity and tolerability profiles in treating patients with three common difficult-to-treat RAS-addicted tumors: pancreatic cancer, non-small cell lung cancer, and colorectal cancer, and we've shared growing clinical evidence of clinical activity through three potential treatment paradigms: as single agents, in combination with pembrolizumab, and as RAS(ON) inhibitor doublets, consisting of combinations within our own pipeline. As we close out this productive year, the results we've summarized today highlight the continuing clinical momentum of these programs and the significant opportunity we believe we have to meaningfully impact the lives of patients with RAS-addicted cancers. I'd like to take a moment to recognize and thank the patients, caregivers, and clinical investigators who participate in this important work and the extraordinary efforts by RevMed employees on behalf of patients. Without this shared commitment, our progress wouldn't be possible.
I'll now turn the call over to the operator for the Q&A session.
Thank you. And as a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. And to withdraw the question, please press star 11 again. Please limit to one question and one follow-up. Please stand by for our first question. And the first question will come from Ami Fadia with Needham. Your line is now open.
Hi, good morning. Thanks for taking my question. Well, this is a lot of great progress and great data. As we think about sort of furthering kind of the pipeline, how are you thinking about your next steps in first line as opposed to the studies that you have ongoing in second line and prioritizing how you're going to develop this portfolio?
And then secondly, outside of your own internal pipeline, are you thinking about exploring new combinations with other mechanisms that are sort of being developed by other companies in the industry? Thank you.
Hi, Ami. Thanks very much for your questions. The first question related to our strategy in first line, I think it's important for us to emphasize that that realm is a very high priority for us, for sure. We've already indicated in pancreatic cancer that we're committed to a first-line study in pancreatic cancer. It's likely that that study would include at least an RMC-6236 monotherapy arm based on the compelling second-line data that we've presented from the single-arm work so far. The question for us at hand is whether or not to include a third arm, which is a combination of RMC-6236 with chemotherapy.
We're evaluating the safety of combining those kinds of agents now, and we'll make a decision before we finalize the phase III trial design. But we're very committed to that study, and we'll move it forward as quickly as we can. First line, lung cancer, as Steve described today, we now have a number of different opportunities for moving into first line. Our highest ambition is to move into the triplet combination with a doublet of RAS on inhibitors combined with pembo. We think the data now substantiate that concept, and that could create an exciting chemo-free strategy for patients with KRAS G12C-driven lung cancer, which is 12% of non-small cell lung cancer.
That wouldn't address the remaining 18% who have RAS mutations that are not G12C, and that could be addressed by a combination of 6236 with pembrolizumab, which we believe is safe based on the data we have so far, and that could include chemotherapy or without chemotherapy that needs to be evaluated, so we're very committed, again, to both pancreatic cancer and lung cancer in the first line and even earlier line contexts, and you can see that we have a lot going on pointing in that direction, and we'll lay out those plans as they become more definitive. Your second question related to combination with other innovative compounds, well, of course, combination with pembrolizumab, you've just seen a fair amount of data on, that's very important, but then we are well aware of other things going on in the field.
We recently disclosed, for example, that we are in collaboration with Tango Therapeutics to provide RMC-6236 and RMC-9805 for a combination study with a PRMT5 inhibitor in patients who have tumors that have both a RAS mutation and deletion of MTAP. So we're very open to this general concept. We're constantly being asked by various other parties whether or not we would do such combination studies, and we explore each of these on a case-by-case basis. And where there are strong preclinical data and good mechanistic rationale, we are very open to that kind of thing.
And our next question comes from Eric Joseph, and your line is now open.
Oh, thanks for taking the question. Good morning. Just a couple of questions on the monotherapy 6236 update.
Just within the focal population of 40 patients, can you talk a little bit about sort of the representation of different G12X mutant types? Are you seeing any difference in either the ability to enter response, at least a partial response by mutation status, or the duration of either response or PFS? Thank you.
Thanks, Eric. Steve, do you want to comment on that?
Yeah. Eric, we'd have to give you the same answer that we gave when we were asked about the pancreatic cancer data, which is with 40 patients and the diversity of different G12X mutations that we have, it's just impossible to draw any conclusions about any differences in outcome for any particular RAS G12 mutation.
With regards to the actual spread of mutations that appear in the study, it's pretty consistent with the epidemiology of the mutations that occur in non-small cell lung cancer, with the exception of G12C, which, of course, we deliberately avoided enrolling patients with G12C mutations in our RMC-6236 monotherapy study for a couple of reasons. The main one being that we wanted to prioritize them for our G12C inhibitor trials, and secondly, because there's a lot of other options for those patients as well.
Yeah. If I could add to Steve's comment, it's clear that RMC-6236 binds to all these different forms of RAS. We've shown that previously in various biochemical and biophysical assays. And it's quite clear that it can also induce objective responses across a wide range of mutations.
I think Steve emphasized, though, that to get a quantitative answer in either response rates or durability would require a much larger study. If you think about the fact that we're studying a couple hundred patients in each arm, just comparing to standard of care across the aggregate, it's hard to understand how we could answer that question in a much smaller subset across different genotypes. So we just don't know. We may know a little bit more at the end of the phase III trial. Even that won't have a very large number of any particular mutants. So we'll just have to live with the aggregate for now.
Thank you. Maybe one follow-up, if I could, regarding the safety combination of pembrolizumab.
What's your level of confidence that really the really low rates, really the good tolerability that you're seeing here, mostly in a second-line, PD-1 experienced population should replicate in a PD-1 naive first-line population? Thank you.
Well, I could give you my opinion on that, but I think it might be more useful to hear Dr. Lin, our Chief Medical Officer. The question is whether or not we expect the results that we've seen so far in 6236 plus pembro, the safety results. How would we expect that to play out in pembro naive first-line patients?
We hope even better.
That's a simple answer.
Yeah. Did you hear that, Eric?
I did. Thanks for taking the questions.
And our next question will come from Jonathan Chang with Leerink Partners. Your line is open.
Good morning, and thanks for taking the questions.
First question, can you talk about how we should be thinking about the potential difference in the RMC-6236 monotherapy dose between pancreatic cancer and lung cancer? And as a follow-up to that, can you discuss the 6236 monotherapy efficacy profile in lung cancer at the other doses beyond the 120-220 mg bucket, and how that impacts your thinking on an RMC dose? Thank you.
I don't fully understand the second question, but maybe Steve does. Anyway, maybe you want to address both of the questions. So difference in doses between pancreatic cancer and lung cancer, and then something about the efficacy of different doses.
Yes. I think so. Yeah. No, that's fine. Firstly, let's focus on the principles of dose optimization.
It's not without precedent for anti-cancer drugs to be used at different doses in different patient populations, certainly across different genotypes, but even within different genotypes, so I think the point of dose optimization is to make sure that we have the right dose for the right patient population, and in this instance, mainly due to the number of dose modifications and the average dose, we think that the right dose for patients with lung cancer is 200 mg daily compared with 300 mg daily in pancreatic cancer. I mean, it is obviously 200 mg daily. Even that range and even the 200 mg daily dose is a very active dose in non-small cell lung cancer. The tolerability profile is perfectly acceptable, and why it is different from pancreatic cancer, we don't know.
We can tell you with some confidence it's probably not due to difference in pharmacokinetic exposures, and it's probably due to the expectations of the patient populations themselves, with lung cancer patients maybe being slightly less tolerant of the toxicity profile that we see. But the reality is that we're confident that a 200 mg daily dose is a good dose for patients with lung cancer, and we have every confidence in going forward at that dose level. With regards to reporting efficacy outside of that range, we just haven't done it. I just don't think there's any point. There were very few patients with lung cancer treated at doses below 120 mg daily. So we can't really report anything with confidence for those patients.
We don't report efficacy for doses that we have deemed to have unacceptable toxicity because the efficacy profile is ultimately confounded by the tolerability profile. So we just haven't reported it. It would be misleading and, I think, erroneous for us to do that.
I can add two small points of just color on top of Steve's comments. One is that the tolerability profile is essentially the same between PDAC and lung cancer on a qualitative basis. And what we're talking about is some differences in the frequency with which those events and/or severity occur. So biologically, they look quite similar. And it's really important that we get the dose as close to correct as we can get. That will maximize impact for patients. And so it's the right thing to do.
Secondly, with regard to Steve's comment about doses below 120, it's true that we don't really have quantitative information because we don't have large numbers. We certainly have seen activity below 120 mg. We've seen activity down to the very first dose level that we ever tested. So it is active across a very wide range. But we feel very comfortable that the range that Steve has talked about here, 120 mg-200 mg, which within that range is a pretty similar pharmacokinetic profile, that that's a very good dose range for lung cancer patients.
Understood. Thanks for taking the questions.
Our next question will come from Michael Schmidt with Guggenheim. Your line is now open.
Hey, good morning. Thanks for taking our questions. The RAS inhibitor doublet data in colorectal looks very impressive, especially the complete response that was seen in that cohort.
Do you have any early insights from lung cancer patients treated so far with the doublet in the study? And then similarly, for the 6236 monotherapy lung cancer data, any visibility on response rate in non-G12X mutant patients? Thanks so much.
Okay. Thanks, Michael. Yeah. As Steve pointed out, we have data across several different tumor types. We don't have as large a dataset in lung cancer. It certainly is very active as a doublet. But to sort of give a quantitative answer, we just don't today have enough confidence around the numbers to convey it. We thought that the colorectal context was most powerful, as you've sort of alluded to, because the monotherapy has historically been, and in our hands, not very active.
And so it's much easier to see the difference, which is what I've, over the last six to 12 months, referred to as looking for a qualitative answer to the question. And that's the sort of qualitative answer. But of course, we'll continue studying other populations and other tumors. Because 6236 is so active as monotherapy and 6291 is so active as monotherapy in lung cancer in particular, looking for that combinatorial effect will just take more time to develop some level of confidence around it. Second question, I'm not sure I completely understood it. 6236 lung cancer in the non-G12X.
Yeah. That's the patient population I referred to. Most of those patients we enrolled in an expansion cohort at the 300 mg dose level, which we subsequently determined based on dose modifications was likely to be too toxic.
So we haven't reported, as I said, we don't report aggregate response rates or PFS for any cohort that was treated at a dose that was considered to be unacceptable toxicity. But what we can tell you is that there was clearly clinical activity in the G13X and Q61X mutant lung cancers treated at 300 mg daily. So on an anecdotal basis, we're pretty confident that we have activity against those mutations. A fairly broad range of different, there are probably eight or nine different separate mutations within that bucket. And we've seen a pretty wide range of activity against those mutations. But we're unlikely to report that as a sort of aggregate response rate. Again, it just isn't meaningful because it's so confounded by the tolerability.
And Michael, you might remember that Wei Lin reported several cases in various tumor types back at the AACR meeting, again, across different mutational hotspots.
So, reinforcing Steve's comment, we're quite sure that it's active across a wide range of mutations. And we just won't develop a specific answer at 200 mg until we run the phase III trial. We'll get the answer there.
Thank you.
And the next question will come from Alec Stranahan with Bank of America. Your line is open.
Hey, guys. Thanks for taking our questions. Two from us. First, in the most recent PDAC data cut, the mean dose intensity at 89% looks to have dropped a couple percent from the last update. Maybe help us understand what could be causing this decrease. And is there a mean dose intensity level that was factored into powering and design of the phase III ?
And then thinking about combos in lung cancer, given the majority of responses with monotherapy occurred within the first two months, curious how you're thinking about staggering timing of 6236 with either chemo or pembro to strike the best therapeutic window in your future combo studies? Thanks.
Thanks, Alec. So your questions about the 89% dose intensity in pancreatic cancer and that that's a 1 or 2% below what we reported before is 91 or 92%. I think that was the question. Wei, do you want to comment on that? Is that a meaningful difference?
It's not a meaningful difference. It may be just a little bit longer follow-up for patients who have a dose reduction. To be honest, that would easily account for the 1% reduction in the mean dose intensity.
The same patients with the same result just simply measure over a longer period of time.
Okay. And then the second question was whether or not we would stagger treatment with 6236 in a combination in first line with pembrolizumab.
I'm not sure we see any reason to do that at this point, given the profile that was just shown. I mean, we could do that, but I'm not sure, Wei or Steve, is there any—yeah. Nobody's rising to the occasion to endorse the strategy. So I think at the moment, we don't see any reason to do it.
Got it. Thank you.
And our next question comes from Marc Frahm with TD Cowen. Your line is now open.
Hi. Thanks for taking my questions. You first with the 6236 pembo combo. Can you talk to the patient population that's been enrolling there?
Should we view this as kind of analogous to what you're showing the efficacy data from for 6236 monotherapy, or is this really becoming much more of a G12C trial just given the epidemiology there? And therefore, is it the monotherapy response rate number that kind of the expectation people should be benchmarking versus, or is there kind of another unknown number that we're going to ultimately need to benchmark against? And then, back on the dose, can you explain kind of the difference between 300 mg, kind of the tolerability in PDAC versus lung cancer, and kind of how patient expectations may be impacting things? Because my impression is diarrhea rating is kind of very quantitative unlike some other AEs that are much more subjective.
Thanks, Marc. The first question, the pembrolizumab plus 6236 study, well, that was non-G12C.
That would have been G12X patients because we haven't really studied 6236 in any G12C patients except in the combo with 6291. So all of those patients should be the same genotypically, the same as the patients who are in the monotherapy second line, third line dataset that we just put forward. And I see heads nodding here, so whatever I'm saying is supported. So I'm not sure that that would drive a different genotype selection in the study. Of course, there will be G12C patients in that study too. They're part of that outer ring that would be included in the second hierarchical statistical test. But in terms of the response rate or, most importantly, PFS and OS in the G12X without C population and core population, we believe that should be consistent with the data that we've just shown. Does that address that question sufficiently?
Yeah, I think so. I was just under the impression the pembro combo was allowing G12C patients in now.
Only in the combination with the RAS doublet where 6291 was in place.
Okay. And then the second question about. Just on that issue, yeah. Before you get to the second one, just on that, can you just speak to. I understand it's hard to say there's additive efficacy because you need large numbers since there's a real expectation for monotherapy efficacy for 6236. But are you at least seeing response rate kind of in line with the monotherapy, or is that still too early to tell also?
You know, Mark, we're just disciplined about not getting out of our skis and making statements that based on small n. So there's nothing to hide here.
It's just to make a statement about a number when you have a small n just as a setup for regretting it here. So as Steve said, we definitely see activity. We don't see anything concerning. We don't see anything that makes us worry. But to be able to put out a number there, we would just need a larger sample size to feel confident that what we're saying is supported. So no concerns, but nothing more to add to that right now. On the second question, which was 6236 dose, you said diarrhea seems higher or more severe.
Yeah. The diarrhea rate, the rate of grade 3 diarrhea for patients with lung cancer treated at 300 mg is clearly higher than the rate of grade 3 diarrhea for pancreatic cancer patients treated at 300 mg. Yeah. We don't have a very good biological explanation for that.
I think you're right. It is numerically higher. And as the CTC grading of diarrhea is based on the frequency with which you have to go to the bathroom, you're right that there is some objectivity. But the rationale, whether there's a clinical or underlying biological reason for that, we really can't tell. All we can tell is the impact that that has on the patients and investigators' decisions to either temporarily stop the drug or reduce the dose of the drug. And it clearly, in the lung cancer patient population, results in a few temporary cessations and in dose reductions resulting in a mean dose intensity that's closer to 200 mg. So taking a pragmatic approach, we feel we'd be much better off, and actually, they would be much better off starting at 200 mg daily than at 300 mg daily.
To define Steve's comment about 300 mg at dose intensity of 72% is the same as 200 mg. What he means is 70% times 300 mg is a little over 200 mg, which is in the range of that dose. So we're not too concerned about it. These are both very active doses. Probably use either dose in either patient. But we'd like to keep patients on drug as long as possible, as continuously as possible, because they'll benefit from it. And so that's the whole point of the dose optimization. It's why Project Optimus encourages dose optimization. So it's just the optimal thing to do for patients. And again, we feel very good even at lower doses. It's a very active drug.
Okay. Thank you.
And our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.
Great. Thank you very much.
Two questions, if I may. You made a comment about expectations for not seeing incremental efficacy when you do the combination on top of checkpoint inhibitors. And I was looking to see if you could frame this in terms of what we should be thinking about going forward across different lines of treatment. And secondly, with your ongoing first-line study in PDAC, it would appear that there's fairly limited competition. Anything you can help us with in terms of commentary about timeline expectations, pace of enrollment, and when we might be able to see some data from that would be appreciated. Congratulations on all the updates. Thanks, Mark.
Yeah. Thanks, Chris. The first question was on incremental efficacy.
Just to be clear, I don't think we were making the statement that we wouldn't see combination combinatorial efficacy in first-line patients, which would be measured by both ORR and durability, which is really the most important ultimate measure. I think what Steve was alluding to was the fact that all of these patients have already seen pembro or almost all of them. And so the possibility that they then get an additive benefit of combining a new round of pembro with RMC-6236, there's just no logic to that. So again, we see activity. We see plenty of activity. But looking for that incremental ORR, which is really the thing you can measure in the near term, it's just not the right patient population to ask that question. And we've indicated this for the last year since we first introduced the concept of this study.
Ultimately, it will be a combination effect on durability. That's really the whole point behind combining an immune modulator with a RAS(ON) inhibitor or a combination of RAS(ON) inhibitors. Second question was our ongoing study in PDAC. That's a second-line study. I think I heard you say first-line study. Just want to correct that. That is the second-line study in PDAC with monotherapy. And I think you were asking, can we give any guidance about enrollment pace or timing?
Correct.
Yeah. No. We're not providing any of that. I mean, there certainly is a lot of enthusiasm for the study. And at this point, there's not much that we can say we'll enroll it as quickly as we can. Once it's fully enrolled, the first readout will be triggered by the event rate. So we'll just see how that all plays out.
Thank you.
And by the way, that study is not rate limiting to initiating a first-line study. Those are really separate things. And we'll determine the first-line study based as I refer you back to the comments I made to Ami Fadia's question, we're developing the plans for the first-line study, and that will be initiated when we feel ready to and have alignment with the FDA on that first-line study independent of the timing with regard to the second-line study.
Appreciate the additional color.
And our next question will come from Ellie Merle with UBS, and your line is open.
Hi. Sam for Ellie. Can you just provide any color on the QT prolongations that you saw in the 6236, 6291 doublet, and the 6291 pembro combo? And then can you provide any details on the TRAEs that led to dose reductions in the 6236, 6291 doublet?
And then I guess thinking forward, what are your next steps for the combo as the data continue to mature? Thanks.
Yeah. Thank you, Ellie. QTc, maybe Wei can comment on that. We did see some QTc prolongation with 6291 alone. That clearly is a feature of 6291.
Yeah. Happy to. It is so far the only safety signal we've seen in this platform is with 6291, our RAS(ON) G12C inhibitor. It has not been seen with either the 6236 or with the 9805, our RAS(ON) G12D, at least not to any significant extent. So when we combine with either pembrolizumab or with 6236, we do not see a material difference in what we have seen before. And just be clear that we've seen that signal in a dose-dependent manner. And so we intentionally halved the dose at 200 mg b.i.d. to really optimize the safety as well as the efficacy of 6291.
And it appears that, at least given the data today, we've successfully done so. And so as you can see, the QTc has not been an issue in combination with either 6236 or with pembrolizumab. And we think at this dose, the 200 mg b.i.d. for 6291 has been optimized. And that's going to be our recommended dose moving forward.
And then with regards to TRAEs, so she's asking in the doublet, the RAS(ON) inhibitor doublet, there were dose reductions in some patients with the doublet. Do we have any color on what those dose reductions were driven by?
Dose reductions were mainly predominantly 6236 related, and they're predominantly related to RAS. Yeah. So 6291 is a pretty clean compound from a safety perspective. We're not really seeing anything additive to 6236. It's basically the 6236 profile remains the 6236 profile.
Okay. That's really helpful. Thank you so much.
Yeah, and the next question will come from Laura Prendergast with Raymond James. Your line is open.
Hey, guys. Congrats on the update today. I was curious if you're seeing the same deepening of responses with time on therapy for lung cancer mono and the colorectal cancer combination as you reported with PDAC, and then generally, are you guys seeing any evidence of CNS activity in lung cancer?
Thanks, Laura, so two questions. One is that we see a deepening responses in pancreatic cancer over time. We saw something like 40-some% of the responses at first scan, but then the remainder at a subsequent scan. What about in lung cancer?
More than half do respond at the first scan, but still significant portions do not respond until subsequent scans.
Yeah. Make sure everybody caught that, so there's sort of an inversion.
More than half now in lung cancer occur earlier, but still something approaching half occur at some point later, so it's a shift, but the overall profile is pretty similar. I don't know if we know the answer in CRC.
In CRC, no.
We just don't really have any information on that. Although it was interesting, the case report that Steve showed did show a response early with that patient on cycle three, day one. It was confirmed on cycle five, day one, and then by cycle ten, day one, it had converted to essentially a complete response, so that does, again, suggest that more time on drug, even in the context of CRC, even in a difficult CRC with heavily pretreated, that longer time on drug is better for the patient.
Back to our dose optimization question earlier, that's part of why one dose optimizes so patients can stay on drug as long as possible. And then the second question was CNS activity. We haven't really reported on that yet. I think it's probably too early for us to do that in this context. We did report preclinically that 6236 was active in a preclinical model, the same model that Mirati had used to show activity for adagrasib, and in fact, looked quite similar to adagrasib's activity in the same model system. But we've not reported anything in humans yet to date.
Got it. Thanks for taking the questions. Thank you.
I would now like to turn the call back over to Mark Goldsmith for closing remarks.
Thank you, operator. Thank you, everyone, for joining us and sustaining through this lengthy discussion.
We appreciate it very much, and we appreciate your ongoing support of Revolution Medicines.
This concludes today's conference call. Thank you for participating. You may now disconnect.