Revolution Medicines Announces Publication Demonstrating Robust Anti-Tumor Activity of RAS(ON) Inhibitors in Preclinical Models of Refractory KRAS-Mutated Non-Small Cell Lung Cancer

Original research published in Cancer Discovery reveals a RAS(ON) multi-selective inhibitor exhibited robust anti-tumor activity alone or in combination with a RAS(ON) G12C-selective inhibitor in preclinical models of difficult-to-treat KRAS-mutated non-small cell lung cancer (NSCLC)

Results also highlight that, in contrast to mutant-selective RAS inhibition, broad-spectrum, reversible RAS-GTP inhibition with a RAS(ON) multi-selective inhibitor alone drove durable anti-tumor activity in these models with infrequent resistance occurrence and the potential for emergence of rare persister, slow cycling cells

Excerpt from the Press Release:

REDWOOD CITY, Calif., July 11, 2024 (GLOBE NEWSWIRE) — Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the publication of a peer-reviewed research paper in Cancer Discovery. The scientific paper demonstrates that the RAS(ON) multi-selective inhibitor RMC-7977 (a preclinical tool compound representative of the investigational drug candidate RMC-6236) exhibited robust and durable anti-tumor activity in multiple preclinical models of KRAS-mutated NSCLC. The data show this activity was further enhanced in the doublet combination with a RAS(ON) G12C-selective inhibitor RMC-4998 (a preclinical tool compound representative of the investigational drug RMC-6291), in preclinical models of KRAS G12C-mutated NSCLC. These findings are the result of original, collaborative research between scientists at Revolution Medicines and The University of Texas MD Anderson Cancer Center.

Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably NSCLC, pancreatic ductal adenocarcinoma and colorectal cancer. RAS G12 mutations, such as G12D, G12V and G12C, predominate in these RAS-addicted cancers. Approved RAS-targeted cancer therapies target only one RAS mutation, KRAS G12C, which is present in approximately 13 percent of NSCLC. There remains a large unmet medical need for improved clinical outcomes with KRAS G12C-selective inhibitors and for extending therapy options to patients harboring KRAS non-G12C-driven tumors.

The paper highlights that direct RAS inhibition with a RAS(ON) multi-selective inhibitor monotherapy, alone or in combination with a RAS(ON) G12C-selective inhibitor, elicited rapid, deep and sustained tumor regressions and significantly prolonged time to tumor doubling in preclinical models of refractory KRAS G12C-mutated NSCLC. The combination dramatically improved anti-tumor activity as compared to RAS(ON) multi-selective inhibitor monotherapy and elicited cures (defined as recurrence free survival following treatment withdrawal) in all of the preclinical models bearing alterations in genes associated with the subsets of KRAS G12C-mutated NSCLC (e.g. KEAP1 and SMARCA4).

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