Dr Skoulidis on Determinants of KRAS G12C Inhibitor Efficacy in NSCLC

Ferdinandos Skoulidis, MD, PhD, MRCP, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses molecular determinants of KRAS G12C inhibitor efficacy in advanced non–small cell lung cancer (NSCLC).

The development of KRAS G12C inhibitors has represented a key milestone in targeted therapy for the treatment of cancer, Skoulidis begins. Although agents such as sotorasib (Lumakras) or adagrasib (Krazati) have been approved by the FDA and have displayed efficacy in the treatment of patients with KRAS G12C-mutated NSCLC, there are currently no methods to identify which patients are likely to derive long-term benefit from single-agent treatment with a KRAS G12C inhibitor. By being able to more accurately identify patients who are less likely to benefit from single-agent treatment with a KRAS G12C, it could allow for an intensified approach to therapy, or a different course of treatment entirely, Skoulidis says.

To address the molecular determinants of the efficacy of KRAS G12C inhibitors, Skoulidis and colleagues collected and analyzed retrospective data of patients with advanced KRAS G12C–mutated NSCLC treated with either sotorasib or adagrasib to assess the effect of co-mutations on clinical outcomes.

Findings presented at the 2023 AACR Annual Meeting showed that co-alterations in the tumor suppressor genes KEAP1, SMARCA4, and CDKN2A/2B were individually and independently associated with worse clinical outcomes, Skoulidis expands. Approximately one-third of patients in the study harbored a KEAP1, SMARCA4, or CDKN2A/2B co-mutation, and more than half of patients who experienced disease progression within 3 months had one of those co-mutations, Skoulidis says.

Findings from the study demonstrated which co-mutations could lead to early disease progression following treatment with KRAS G12C inhibitors, and these results could help inform strategies and potential drug combinations to individualize treatment.