Mutations in the KRAS gene are the most common gain-of-function mutations found in lung adenocarcinomas. The most common mutation, KRAS G12C, is present in 13% of lung adenocarcinomas. Sotorasib (AMG-510) is an irreversible small molecule inhibitor targeting KRAS G12C. In preclinical studies, treatment with sotorasib led to the regression of KRAS G12C-mutated tumors, and clinical efficacy in NSCLC was demonstrated in clinical trials. In May 2021, sotorasib received US FDA approval for treatment of KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy. In this report, we present a case with metastatic, KRAS G12C-mutated NSCLC who responded favorably to sotorasib as first-line therapy. The efficacy of sotorasib as first-line treatment in this patient was remarkable, which supports further study of sotorasib as first-line therapy for KRAS G12C-mutated NSCLC, especially in fragile patients with comorbidities.