Dr Skoulidis on the Methods of Analyzing 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 the methods utilized in a retrospective study that investigated molecular determinants of KRAS G12C inhibitor efficacy in patients with advanced non–small cell lung cancer (NSCLC).

At the 2023 AACR Annual Meeting, Skoulidis and colleagues presented retrospective data of patients with advanced KRAS G12C–mutated NSCLC treated with either sotorasib (Lumakras) or adagrasib (Krazati) to assess the effect of co-mutations on clinical outcomes. Investigators found that patients who harbored co-alterations in the tumor suppressor genes KEAP1, SMARCA4, and CDKN2A/2B had significantly shorter progression-free survival.

Data were gathered from 20 academic institutions across the United States and Europe. Patients included in the study were required to have baseline genomic profiling prior to starting treatment with a KRAS G12C inhibitor therapy. Profiling was allowed to be conducted with commercially available assays or any assay run through a certified laboratory, Skoulidis says.

Based on the findings from this study, future research could include expansion to a larger cohort of patients who have undergone broad, comprehensive genomic profiling, which could increase understanding of less prevalent molecular determinants of KRAS G12C inhibition in patients with NSCLC, Skoulidis expands.

Beyond co-mutational determinants of sensitivity, other determinants at the transcriptional and proteomic level could also play a role on the effect of this treatment, Skoulidis explains. The tumor microenvironment is hypothesized to play an important role in modulating response, sensitivity, and resistance to KRAS G12C inhibitors, and future research could help address this possibility, Skoulidis concludes.