Targeting MET in 2025: From Exon 14 Skipping to MET-Amplified Acquired Resistance in Non-Small Cell Lung Cancer.

MET pathway alterations have evolved from a niche translational interest into one of the most clinically actionable axes in non-small cell lung cancer (NSCLC). Three biologically distinct lesions-MET exon 14 (METex14) skipping mutations, focal high-level MET amplification, and c-Met protein overexpression-are now individually targetable, each with its own diagnostic prerequisites and therapeutic class. Selective type Ib MET tyrosine kinase inhibitors (capmatinib, tepotinib) anchor first-line therapy for METex14, while next-generation agents and type II inhibitors are being developed to address on-target D1228 and Y1230 resistance mutations. In parallel, MET amplification has emerged as a leading mechanism of acquired resistance to osimertinib in EGFR-mutated NSCLC, with the SAVANNAH, SACHI, and INSIGHT 2 trials providing biomarker-guided combination strategies. The 2025 accelerated approval of telisotuzumab vedotin for c-Met-overexpressing tumors expanded the therapeutic armamentarium beyond kinase inhibition. Despite these advances, lineage plasticity, polyclonal bypass signaling, and inconsistent diagnostic thresholds for MET amplification continue to limit durable benefit. This review integrates the molecular biology, current clinical evidence, resistance mechanisms, and a proposed 2025 treatment algorithm for MET-altered NSCLC, with emphasis on the translational interface between mutation class, drug class, and emerging combinatorial approaches. As a narrative review, it synthesizes peer-reviewed literature and pivotal trial and regulatory data through early 2026, identified by structured searches of PubMed and major oncology congress proceedings, and prioritizes sources that link mutation class to drug class and resistance mechanism.