Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company specializing in targeted therapies for RAS-driven cancers, has announced promising early data on RMC-9805, a selective inhibitor for the RAS(ON) G12D mutation. The preliminary safety and antitumor results for RMC-9805 were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona on October 25, 2024.
“We’re excited to share the initial clinical data for RMC-9805, our innovative, oral RAS(ON) G12D-specific covalent inhibitor, which has shown early signs of safety, tolerability, and antitumor activity, including tumor reductions,” said Mark A. Goldsmith, M.D., Ph.D., CEO and Chairman of Revolution Medicines. “These initial results strengthen our conviction in RMC-9805’s potential role in the evolving landscape of pancreatic cancer treatment, both as a standalone therapy and in combination. RMC-9805 is now the third tri-complex compound from our pipeline to demonstrate clinical proof-of-concept, underscoring our commitment to advancing new RAS(ON) inhibitors for patients with RAS-dependent cancers.”
The Phase 1/1b RMC-9805-001 study is an open-label, multicenter trial designed to assess RMC-9805 in patients with advanced solid tumors carrying a KRAS G12D mutation. By the cutoff date of September 2, 2024, 179 patients had been treated with varying doses of RMC-9805 (150-1200 mg once daily and 300-600 mg twice daily). Participants had previously undergone a median of two treatments (range: 0-9) as standard care.
The results showed that RMC-9805 had a favorable safety profile, being generally well tolerated at all dose levels. Among patients on the 1200 mg daily dose (n = 99), the most common treatment-related side effects (TRAEs) included mild gastrointestinal symptoms (nausea, diarrhea, vomiting) and skin rash, which were primarily Grade 1 and short-lived. Only one Grade 3 TRAE (elevated ALT) was reported, with no Grade 4 or 5 TRAEs. Four patients (4%) required dose reductions due to TRAEs, though none discontinued treatment, and no dose-limiting toxicities were encountered, suggesting the maximum tolerated dose was not reached.
In patients with pancreatic ductal adenocarcinoma (PDAC), the candidate Phase 2 dose of 1200 mg daily demonstrated early signs of efficacy. Among patients receiving RMC-9805 at 1200 mg once daily or 600 mg twice daily who had started treatment at least 14 weeks before the cutoff, 30% (n = 12) showed an objective response (confirmed or pending), and the disease control rate was 80% (n = 32).
“Pancreatic cancer, driven by RAS mutations—particularly the G12D variant—has limited treatment options, making this a high unmet need,” said David Hong, M.D., of MD Anderson Cancer Center and lead author of the study. “While pancreatic cancer remains challenging, we observed encouraging antitumor activity at tolerable doses in this Phase 1 trial.
