KRAS G12C-mutant non-small-cell lung cancer: biology, developmental therapeutics, and molecular testing.

Abstract KRAS mutation is the most common oncogenic driver in advanced non-small cell lung cancer (NSCLC), occurring in approximately 30% of lung adenocarcinomas. Over 80% of oncogenic KRAS mutations occur at codon 12 where the glycine residue is substituted by different amino acids, leading to genomic heterogeneity of KRAS-mutant tumors. The KRAS glycine-to-cysteine mutation (KRAS G12C) comprises approximately 44% of KRAS mutations in NSCLC, with mutant KRASG12C present in approximately 13% of all patients with lung adenocarcinoma. Mutant KRAS has been an oncogenic target for decades, but no viable therapeutic agents were developed until recently. However, advances in KRAS molecular modelling have led to development and clinical testing of agents that directly inhibit mutant KRASG12C. These agents include sotorasib (AMG 510), adagrasib (MRTX 849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for expression of PD-L1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRASG12C protein.