Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog 
(KRAS) is the most common oncogenic driver in advanced non-small cell lung 
cancer, 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 (G12C) composes 
approximately 44% of KRAS mutations in non-small cell lung cancer, 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 
modeling have led to the 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 the expression of programmed cell-death protein 
ligand 1, pathologists, medical oncologists, and community practitioners will 
need to incorporate routine testing for emerging biomarkers such as MET 
amplification, ERBB2 (alias HER2), and KRAS mutations, particularly KRAS G12C, 
considering the promising development of direct inhibitors of KRasG12C protein.