Revolution Medicines Reports Strong Anti-Tumor Effects of RAS(ON) Inhibitors in KRAS-Mutated NSCLC Models

A new peer-reviewed study published in Cancer Discovery reveals that a RAS(ON) multi-selective inhibitor showed strong anti-tumor effects alone and in combination with a RAS(ON) G12C-selective inhibitor in preclinical trials targeting difficult-to-treat KRAS-mutated non-small cell lung cancer (NSCLC). The research, conducted by Revolution Medicines, Inc. and The University of Texas MD Anderson Cancer Center, highlights the effectiveness of the investigational compound RMC-7977, which represents the drug candidate RMC-6236. This compound demonstrated significant anti-tumor activity in preclinical models of KRAS-mutated NSCLC. The activity was further improved when combined with the RAS(ON) G12C-selective inhibitor RMC-4998, a model for the investigational drug RMC-6291.

RAS proteins are implicated in around 30% of human cancers, including NSCLC, pancreatic ductal adenocarcinoma, and colorectal cancer. Among these, RAS G12 mutations like G12D, G12V, and G12C are most common. Current approved therapies focus only on the KRAS G12C mutation, which is found in about 13% of NSCLC cases, leaving a significant need for improved treatment options for patients with other KRAS mutations.

The study emphasizes that direct RAS inhibition using a RAS(ON) multi-selective inhibitor, either alone or combined with a RAS(ON) G12C-selective inhibitor, resulted in rapid and sustained tumor regression and extended the time to tumor doubling in preclinical KRAS G12C-mutated NSCLC models. The combination therapy showed dramatically enhanced anti-tumor effects compared to the RAS(ON) multi-selective inhibitor alone, achieving cures in models with alterations in genes associated with KRAS G12C-mutated NSCLC, such as KEAP1 and SMARCA4. The RAS(ON) multi-selective inhibitor also overcame resistance acquired from RAS(OFF) and RAS(ON) G12C-selective inhibitors, highlighting its robust activity.

The paper also identifies a conserved mucinous regenerative program that emerges upon cessation of treatment, possibly supporting the persistence of tumor cells under sustained RAS pathway inhibition. Understanding the characteristics of this group of persister cells, which are slow-cycling and may survive despite ongoing inhibitor treatment, provides insights into potential strategies to prevent recurrent tumor growth.

"RAS-addicted cancers are notoriously difficult to treat with current therapies," said Jan Smith, Ph.D., Chief Scientific Officer at Revolution Medicines. "Our study evaluated the anti-tumor activity of a broad-spectrum RAS(ON) multi-selective inhibitor, both alone and in combination with a RAS(ON) G12C-selective inhibitor, in challenging subsets of KRAS G12C-mutated NSCLC. Given the novel mechanism of these inhibitors, we were keen to explore whether resistance would emerge following treatment. These promising preclinical results support our ongoing combination study of RMC-6236 with RMC-6291 in advanced KRAS G12C-mutated cancers."

Revolution Medicines is advancing its investigational drug RMC-6236, a RAS(ON) multi-selective inhibitor, in clinical trials for patients with cancers driven by various common RAS mutations. RMC-6236 is currently being tested as a monotherapy in a Phase 1/1b trial for advanced solid tumors with G12X, G13X, and Q61X mutations. Following promising early data, the company plans to start pivotal studies of RMC-6236 as a monotherapy in pancreatic ductal adenocarcinoma and NSCLC. Additionally, RMC-6236 is being evaluated in combination with pembrolizumab and chemotherapy for advanced RAS-mutated solid tumors, and in combination with RMC-6291 for advanced KRAS G12C-mutated solid tumors.

Revolution Medicines specializes in developing targeted therapies for RAS-addicted cancers. Their research and development pipeline includes RAS(ON) inhibitors aimed at a wide range of oncogenic RAS variants and companion inhibitors for combination therapies. Their leading candidates include RMC-6236, RMC-6291, and RMC-9805, targeting various RAS mutations in current clinical development programs.