Revolution Medicines, a clinical-stage oncology company dedicated to targeting RAS-addicted cancers, has announced the publication of a peer-reviewed research paper in Cancer Discovery. The paper showcases the efficacy of their RAS(ON) multi-selective inhibitor, RMC-7977 (representative of investigational drug RMC-6236), in preclinical models of KRAS-mutated non-small cell lung cancer (NSCLC). Specifically, RMC-7977 demonstrated potent and enduring anti-tumor effects, which were further enhanced when used in combination with RMC-4998, a RAS(ON) G12C-selective inhibitor (representative of RMC-6291), in models of KRAS G12C-mutated NSCLC. These findings resulted from collaborative research between Revolution Medicines and The University of Texas MD Anderson Cancer Center.
Oncogenic RAS proteins drive a significant portion of human cancers, including NSCLC, pancreatic ductal adenocarcinoma, and colorectal cancer. Current therapies targeting RAS focus mainly on KRAS G12C mutations, present in about 13% of NSCLC cases, leaving a substantial medical need for effective treatments for other RAS mutations and overcoming resistance.
The research highlighted that RMC-7977, both alone and in combination with RMC-4998, induced rapid, deep, and sustained tumor regression in preclinical models of refractory KRAS G12C-mutated NSCLC. The combination therapy showed superior anti-tumor activity compared to monotherapy, achieving cures (defined as recurrence-free survival post-treatment withdrawal) across all models, including those with associated genetic alterations like KEAP1 and SMARCA4. Notably, RMC-7977 also overcame acquired resistance to existing RAS inhibitors, emphasizing its robust efficacy.
Additionally, the paper identified a conserved mucinous regenerative program observed upon treatment cessation, suggesting potential strategies to prevent tumor recurrence by targeting these persistent cancer cell populations.
Dr. Jan Smith, Chief Scientific Officer of Revolution Medicines, commented on the significance of these findings and the ongoing clinical trials evaluating RMC-6236. This investigational drug, an oral RAS(ON) multi-selective inhibitor, is currently being tested in Phase 1/1b trials for advanced solid tumors with various RAS mutations. Encouraging early results have prompted plans for pivotal studies in pancreatic ductal adenocarcinoma (PDAC) and NSCLC, both as monotherapy and in combination therapies.
For more details, the publication titled “Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC” can be accessed online here.
Revolution Medicines, Inc., continues to advance its pipeline of RAS(ON) inhibitors, including RMC-6236 and RMC-6291, with ongoing trials exploring combination therapies to address the diverse landscape of RAS-driven cancers.
