Co-mutations effects on KRAS G12C inhibitor efficacy in advanced non-small cell lung cancer

A study recently published in Cancer Discovery shows that co-mutations in three tumor suppressor genes are independent determinants of poor clinical outcomes with KRAS G12C inhibitors in advanced non-small cell lung cancer.

Clinical outcomes with KRAS G12C inhibitors vary widely from long-term durable responses and prolonged survival to early disease progression seen in ~5-16% of treated patients; molecular or clinical determinants of distinct clinical outcomes with KRAS G12C inhibitors are hitherto poorly defined and validated markers for patient stratification prior to treatment initiation are lacking. Since co-mutations can impact responses to standard of care systemic therapies, authors systematically dissected the impact of genomic and clinical features on outcomes with KRAS G12C inhibitors in a large cohort of 424 non-small cell lung cancer patients from 21 centers in the U.S. and Europe treated with sotorasib or adagrasib. Results demonstrate that prevalent co-alterations in KEAP1, SMARCA4 and CDKN2A are associated with inferior clinical outcomes with KRAS G12C inhibitors therapy and collectively define a subgroup of patients with poor prognosis, capturing ~50% of those with early disease progression (progression free survival less than 3 months). Data also revealed a possible association between defective DNA damage response/repair and improved KRAS G12C inhibitor efficacy. «We propose a framework for patient stratification with implications for treatment selection and clinical trial development for KRASG12C-mutant NSCLC, with a treatment personalization based on the co-mutational status of individual tumors», authors conclude.