Revolution Medicines provides updates from RAS(ON) inhibitor portfolio

Revolution Medicines (RVMD) announced key clinical updates from its RAS(ON) inhibitor portfolio. The data to be presented during an investor webcast today at 8:00 a.m. Eastern Time will focus on updated clinical data from the Phase 1 RMC-6236 monotherapy study in pancreatic ductal adenocarcinoma and non-small cell lung cancer. In addition, new clinical data will be provided from several combination studies, including those evaluating RMC-6236 with pembrolizumab, RMC-6291 with pembrolizumab, and the first-of-its-kind RAS(ON) inhibitor doublet combination of RMC-6291 and RMC-6236. RMC-6236 Monotherapy Study: RMC-6236-001 is a multicenter, Phase 1/1b study designed to evaluate RMC-6236, a RAS(ON) multi-selective inhibitor, as monotherapy, in patients with advanced solid tumors. As of September 30, 2024, a total of 436 patients were treated across NSCLC and PDAC and other solid tumors cohorts. Patients were treated across a range of doses, from 10 mg to 400 mg once daily. PDAC Cohort: As an update to data reported at the EORTC-NCI-AACR conference in October 2024, the company shared a new analysis of safety and activity data from the July 23, 2024 data cutoff date in patients with previously treated PDAC treated with a 300 mg QD dose, the same dose used in the ongoing RASolute 302 Phase 3 PDAC trial. Key findings: In 76 patients with RAS mutant PDAC, RMC-6236 at 300 mg QD was generally well tolerated and showed an overall safety profile consistent with the results reported at ENA. No differentiated safety signals were observed. The most common treatment-related adverse events were rash and gastrointestinal-related toxicities that were primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were observed in greater than 10% of patients. There were no treatment discontinuations due to TRAEs and the mean dose intensity was 89%. In 37 patients with 2L RAS mutant PDAC, RMC-6236 at 300 mg QD demonstrated compelling antitumor activity. Patients with PDAC harboring a KRAS G12X mutation achieved a median PFS of 8.8 months, while the median OS was not estimable. Patients with PDAC harboring any RAS mutation achieved a median PFS of 8.5 months, while the median OS was not estimable. The proportion of patients who remained alive six months after starting treatment with RMC-6236 was 100% and 97% in patients with PDAC harboring a KRAS G12X mutation and patients with PDAC harboring any RAS mutation, respectively. The objective response rate was 36% and 27% in patients with PDAC harboring a KRAS G12X mutation and patients with PDAC harboring any RAS mutation, respectively. RASolute 302, the company’s randomized Phase 3 study of RMC-6236 versus standard of care chemotherapy in 2L patients with previously treated metastatic PDAC, is currently ongoing. Next steps: Based on the encouraging monotherapy data update, the company aims to advance RMC-6236 into earlier lines of therapy for patients with metastatic PDAC. NSCLC Cohort: As an update from a smaller initial cohort reported at ESMO 2023, data from a September 30, 2024 data cutoff date were reported for 124 patients with previously treated RAS mutant NSCLC who received RMC-6236 at clinically active doses in the range of 120 mg to 300 mg QD. Key findings: In patients with previously treated NSCLC, RMC-6236 was generally well tolerated at doses of 120 mg to 220 mg QD, while the 300 mg QD dose demonstrated a higher frequency and severity of TRAEs. In the 120 mg to 220 mg dose range, 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 10% of these patients. In the 120 mg to 220 mg dose range, TRAEs leading to dose modification occurred in 41% of patients with 4% of patients discontinuing treatment due to TRAEs and the mean dose intensity was 88%. RMC-6236 at 120 mg to 220 mg QD demonstrated encouraging antitumor activity in the population of 40 efficacy-evaluable 2L or third-line patients with NSCLC who had received immunotherapy and platinum chemotherapy but had not received docetaxel. These patients achieved a median PFS of 9.8 months, a median OS of 17.7 months and an ORR of 38%. Next steps: The company expects to initiate RASolve 301, a randomized Phase 3 study of RMC-6236 versus docetaxel in patients with previously treated, locally advanced or metastatic RAS mutant NSCLC, in the first quarter of 2025.