Overcoming amplification-mediated resistance to sotorasib by dose re-escalation in <i>KRAS G12C</i> mutant NSCLC: a case report

Precision oncology has transformed non-small cell lung cancer (NSCLC) treatment by tailoring therapies to the genomic profile of the disease, significantly improving clinical outcomes. However, acquired resistance to molecularly targeted therapies remains a major challenge. This report details a 69-year-old woman with KRAS G12C-mutant metastatic NSCLC who developed resistance to sotorasib, a KRAS G12C inhibitor. Initially responding to the standard dose of 960 mg, the patient required a dose reduction to 480 mg due to liver toxicity. After 20 months, oligoprogression occurred, managed through surgical resection. Molecular analysis of the resected tissue identified KRAS amplification as a resistance mechanism. Following disease progression, re-escalation of sotorasib to 960 mg led to renewed tumor response without additional toxicity. This case highlights dose re-escalation as a potential strategy to address resistance in selected patients and underscores the critical role of molecular profiling and personalized approaches in optimizing targeted NSCLC treatments.