Revolution Medicines a clinical-stage oncology company developing targeted therapies for RAS-driven cancers, announced significant clinical updates from its RAS(ON) inhibitor portfolio. The data, presented during an investor webcast, focused on the Phase 1 RMC-6236 monotherapy study in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), along with results from combination studies involving RMC-6236 and RMC-6291.
Advancing RAS-Driven Cancer Treatments
“Our mission is to transform the treatment landscape for patients with RAS-addicted cancers,” stated Mark A. Goldsmith, M.D., Ph.D., CEO of Revolution Medicines. “With initial clinical validation of three distinct RAS(ON) inhibitors, we’ve shown promising efficacy and tolerability across various RAS-driven tumor types and treatment paradigms—monotherapy, combinations with pembrolizumab, and doublet RAS(ON) inhibitors. These advancements position us to pursue pivotal trials and broader late-stage opportunities.”
RMC-6236 Monotherapy Updates
Phase 1 Study Overview:
The Phase 1/1b study evaluated RMC-6236 as a monotherapy in advanced solid tumors, enrolling 436 patients across NSCLC and PDAC cohorts, with doses ranging from 10 mg to 400 mg daily.
Key Findings in PDAC:
- Safety: RMC-6236 at 300 mg daily was well tolerated. Common treatment-related adverse events (TRAEs) included mild rash and gastrointestinal issues, with no severe adverse events leading to discontinuation.
- Efficacy: Among 76 patients with RAS-mutant PDAC, the objective response rate (ORR) was 36% in those with KRAS G12X mutations and 27% in all RAS mutations. Median progression-free survival (PFS) for the KRAS G12X subgroup was 8.8 months.
Next Steps: The ongoing RASolute 302 Phase 3 trial will compare RMC-6236 with standard chemotherapy for metastatic PDAC. Revolution Medicines aims to explore earlier lines of treatment for metastatic PDAC based on these results.
Key Findings in NSCLC:
- Safety: Doses of 120–220 mg daily were well tolerated, while the 300 mg dose saw higher toxicity rates.
- Efficacy: Among 40 evaluable patients who had received prior immunotherapy and chemotherapy, median PFS was 9.8 months, and ORR was 38%.
Next Steps: The RASolve 301 Phase 3 trial, comparing RMC-6236 with docetaxel in previously treated NSCLC, is planned for early 2025.
RAS(ON) Combination Studies
RMC-6236 and Pembrolizumab:
In NSCLC, the combination of RMC-6236 with pembrolizumab was well tolerated, with a mean dose intensity of 97%. Results support continued evaluation in first-line NSCLC patients.
Doublet Combination: RMC-6291 and RMC-6236:
In a Phase 1b study, this first-of-its-kind RAS(ON) inhibitor doublet demonstrated a 25% ORR among colorectal cancer patients previously treated with KRAS(OFF) G12C inhibitors.
RMC-6291 and Pembrolizumab:
Early results suggest this combination is safe and warrants further investigation, particularly as part of a potential triplet combination with RMC-6236 and pembrolizumab for first-line NSCLC treatment.
