Mirati Therapeutics and Sanofi Announce Clinical Collaboration to Evaluate Adagrasib and SHP2 Inhibitor SAR442720 Combination in KRAS G12C-Mutated Non-Small Cell Lung Cancer

On October 7, 2021, Mirati Therapeutics announced a clinical collaboration agreement with Sanofi. The two companies will conduct a Phase 1/2 dose-escalation and expansion trial to evaluate the efficacy of combining Mirati’s investigational KRAS G12C inhibitor adagrasib with Sanofi’s investigational SHP2 inhibitor SAR442720 (RMC-4630) in patients with previously treated non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations.

Adagrasib is a highly selective and potent oral KRAS G12C inhibitor optimized for durable target inhibition. It features a half-life of up to 24 hours and extensive tissue distribution, and is capable of penetrating the blood-brain barrier, which helps maximize therapeutic efficacy. In June 2021, the U.S. FDA granted it Breakthrough Therapy Designation for the treatment of previously treated patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations. In a Phase 2 trial reported this September, the drug achieved an objective response rate (ORR) of 43% in patients with NSCLC.

SAR442720 is a potent oral SHP2 inhibitor. SHP2 is an upstream cellular protein that mediates cell signaling through the RAS/MAPK pathway. SHP2 is a well-validated oncogene and serves as a convergence node for multiple signaling pathways that activate RAS. Given that RAS activation plays a central role in regulating cancer cell survival and growth, SHP2 has emerged as a cancer target of significant current interest.

▲SHP2 regulates the RAS signaling pathway (Image source: Revolution Medicines official website)

KRAS G12C inhibition and SHP2 inhibition possess complementary mechanisms of action and have demonstrated additive anti-tumor activity in preclinical models. Therefore, the combination of these two drugs is expected to achieve a "synergistic" therapeutic effect.

References:

[1] Mirati Therapeutics to Collaborate with Sanofi on Phase 1/2 Study Evaluating Combination of adagrasib with a SHP2 Inhibitor in KRAS G12C-mutated Lung Cancer. Retrieved October 8, 2021, from https://ir.mirati.com/press-releases/press-release-details/2021/Mirati-Therapeutics-to-Collaborate-with-Sanofi-on-Phase-12-Study-Evaluating-Combination-of-adagrasib-with-a-SHP2-Inhibitor-in-KRAS-G12C-mutated-Lung-Cancer/default.aspx

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