Revolution Medicines provides updates from RAS(ON) inhibitor combo studies

RAS(ON) Inhibitor Combination Studies: RMC-6236 with Pembrolizumab: RMC-LUNG-101B is an arm of the Phase 1b study of RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS mutant NSCLC. A total of 20 patients treated with RMC-6236 at 200 mg QD and pembrolizumab at the standard dose of 200 mg once every three weeks were evaluated as of an October 28, 2024 data cutoff date. The median duration of treatment for these patients was 2.3 months. The combination of RMC-6236 with pembrolizumab was generally well tolerated and the safety profile was consistent with previously reported results for the individual agents. TRAEs of Grade 1 aspartate aminotransferase elevation were reported in two patients and a TRAE of Grade 2 AST elevation was reported in one patient. A TRAE of Grade 1 alanine transaminase elevation was reported in one patient and a TRAE of Grade 3 ALT elevation was reported in one patient. The mean dose intensity for RMC-6236 was 97%. Next steps: The company believes the data from this study support continued evaluation of the combination of RMC-6236 with pembrolizumab in 1L NSCLC patients. RMC-6291 and RMC-6236 RAS(ON) Inhibitor Doublet: RMC-6291-101 is a Phase 1b study of RMC-6291 in combination RMC-6236 in patients with RAS G12C mutant solid tumors. The study has evaluated RMC-6291 at doses of 100 mg or 200 mg BID and RMC-6236 at a dose range of 100 mg to 300 mg QD. As of an October 28, 2024 data cutoff date, 74 patients were evaluated for safety with a median duration of treatment of 2.3 months. The combination of RMC-6291 with RMC-6236 was generally well tolerated across all dose levels evaluated. The most common TRAEs were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were observed in greater than 5% of patients. One Grade 4 TRAE of hypokalemia was associated with Grade 3 diarrhea. TRAEs leading to dose interruption or reduction occurred in 30% and 10% of patients, respectively. The mean dose intensities for RMC-6291 and RMC-6236 were 95% and 92%, respectively. A subset of efficacy-evaluable patients with colorectal cancer who were previously treated with a KRAS(OFF) G12C inhibitor was evaluated for antitumor activity on treatment with RMC-6291 with RMC-6236. As reference values, the company also reported that the ORR for patients with CRC treated with RMC-6236 monotherapy at a dose of 300 mg daily in the RMC-6236-001 study as of a data cutoff date of September 30, 2024 was 9%, and the ORR for patients with CRC previously treated with a KRAS(OFF) G12C inhibitor who were subsequently treated with RMC-6291 monotherapy at a dose of 200 mg twice daily in the RMC-6291-001 study as of a data cutoff date of October 28, 2024 was 0%. In the combination study, patients with CRC who were previously treated with a KRAS(OFF) G12C inhibitor and who received their first doses of the two study drugs at least 8 weeks prior to data cutoff were included in the analyses. The ORR was 25%, including one patient with an unconfirmed complete response, and the DCR was 92%. The median treatment duration was 2.3 months. Next steps: The company believes the data from this combination study support continued development of RAS(ON) doublets in a broad range of tumor types and earlier lines of therapy. RMC-6291 with Pembrolizumab: RMC-LUNG-101A is an arm of the Phase 1b study of RMC-6291, a RAS(ON) G12C-selective inhibitor, in combination with pembrolizumab, with or without chemotherapy, in patients with RAS G12C mutant NSCLC. A total of 15 patients treated with RMC-6291 at 200 mg twice daily and pembrolizumab at the standard dose of 200 mg Q3W were evaluated as of an October 28, 2024 data cutoff date. As of this date, 47% of these patients had been on treatment for 60 days or more. The combination of RMC-6291 with pembrolizumab was generally well tolerated and the safety profile was consistent with previously reported results for the individual agents. A TRAE of Grade 1 AST elevation was reported in one patient and a TRAE of Grade 1 ALT elevation was reported in one patient. There were no TRAEs of Grade 2 or higher AST or ALT elevations reported. The mean dose intensity for RMC-6291 was 98%. Next steps: The company believes the three pairwise combinations of RMC-6291 with RMC-6236, RMC-6236 with pembrolizumab and RMC-6291 with pembrolizumab justify investigation of the triplet combination of RMC-6291 and RMC-6236 with pembrolizumab as a potential chemotherapy-sparing option for patients with 1L NSCLC.