MET-Driven Resistance to Sotorasib in KRAS G12C-Mutant NSCLC and Response to Combined KRAS and MET Inhibition

KRAS G12C mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy. However, acquired resistance is inevitable. MET amplification has been described as a putative off-target resistance mechanism, although its clinical relevance remains incompletely understood.

We conducted a retrospective case series of patients with KRAS G12C-mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment biopsies were analyzed for resistance mechanisms using routine molecular diagnostics, including MET fluorescence in situ hybridization.

Nine patients with paired pre and posttreatment biopsies were identified. High-level MET amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with acquired MET amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy.

This study provides real-world evidence that MET amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate MET amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.