Liquid biopsy-based detection of acquired MET resistance enables sequential targeted therapy in MET fusion-positive NSCLC.

Oncogenic alterations in MET represent therapeutically actionable driver alterations in non-small cell lung cancers (NSCLC). Among these, MET fusions are rare, occurring in approximately 0.1%-0.3% of NSCLC. We report the case of a 52-year-old woman with metastatic, TTF1-positive lung adenocarcinoma harboring a KIF5B::MET fusion. After progression on chemotherapy and immunotherapy, she achieved a durable response lasting nearly five years on third-line treatment with the type Ia MET inhibitor crizotinib. At the time of suspected disease progression, two tissue re-biopsies were non-diagnostic due of insufficient tumor cell content. Circulating tumor DNA (ctDNA) analysis identified two newly acquired on-target resistance mutations within the MET kinase domain (L1213V and Y1248C) in addition to the known KIF5B::MET fusion. After re-evaluation by the institutional molecular tumor board, both alterations were considered mediators of resistance to type I MET inhibitors, with available data indicating preserved sensitivity to type II inhibitors. Based on these findings, the patient was switched to cabozantinib, a multikinase type II MET inhibitor, resulting in a radiographic disease stabilization accompanied by a marked decline in tumor marker levels. This case illustrates the clinical utility of liquid biopsy for molecular resistance monitoring, particularly when tissue re-biopsy is not feasible, supports its integration into clinical decision-making, and underscores the therapeutic relevance of MET inhibitor class-switch strategies in MET fusion-positive disease.