Durable Disease Control with Local Therapy following the Identification of an Acquired Resistance Mechanism in Oligo-Progressive KRAS G12C-mutated Non-small Cell Lung Cancer: A Case Report

KRAS G12C-mutated non-small cell lung cancer (NSCLC) is relatively uncommon in East Asian populations, and mechanisms of acquired resistance remain incompletely defined. We report a patient with metastatic KRAS G12C–mutated NSCLC who received frontline treatment with sotorasib, a KRAS G12C inhibitor. After 7 months of therapy, oligo-progression occurred at the primary tumor site. Repeat next-generation sequencing identified KRAS amplification as the putative resistance mechanism. The lesion was treated with stereotactic body radiation therapy, after which sotorasib was continued. The patient has remained free of progression for an additional 12 months to date. This case report highlights KRAS amplification as a possible on-target resistance mechanism and underscores the utility of local therapy in selected patients with oligo-progressive disease. Integrating molecular profiling and site-directed therapy may extend the clinical benefit beyond progression on tyrosine kinase inhibitors.