Molecular and Clinical Characteristics of Patients with Non–Small Cell Lung Cancer Harboring KRAS G12V Mutations

PURPOSE: KRAS G12V is among the most frequent KRAS mutations in non-small cell lung cancer (NSCLC), yet its clinical and molecular features remain poorly understood. EXPERIMENTAL DESIGN: In this retrospective study, we analyzed 636 patients with KRAS G12V-mutated NSCLC diagnosed between 2018 and 2023. Clinical, pathologic, and molecular characteristics, including co-mutations, smoking history, programmed cell death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, and treatment outcomes, were assessed. RESULTS: The majority of patients (94.2%) were current or former smokers, with a median tobacco exposure of 40 pack-years. Co-mutations were frequent, most commonly in TP53 (40.2%), STK11 (30.2%), and KEAP1 (29.3%). Heavy smokers exhibited significantly higher PD-L1 expression and more frequent TP53, KEAP1, and NTRK1-3 mutations than light smokers. CD8+ T-cell infiltration showed a nonsignificant trend toward higher values in G12V compared with non-G12V KRAS subtypes. Among 151 patients with advanced disease, those treated with immune checkpoint blockade (ICB) alone or in combination with chemotherapy had significantly higher response rates and improved real-world progression-free survival and real-world overall survival (rwOS) compared with chemotherapy alone. In patients with PD-L1 tumor proportion score ≥50%, ICB-based treatment achieved a median rwOS of 30 months. CONCLUSIONS: KRAS G12V-mutated NSCLC is characterized by a strong association with tobacco use, high co-mutation rates in clinically relevant genes, and a favorable response to PD-L1-based immunotherapy. The observed mutation landscape supports the potential for dual checkpoint blockade in a significant subset.