A Multicenter Randomized Phase III Trial Comparing MET Tyrosine Kinase Inhibitors vs. Immune Checkpoint Inhibitors With or Without Chemotherapy as First-Line Treatment for Patients With Advanced Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutations: JCOG2506 (DECIDE-MET).

BACKGROUND: MET exon 14 skipping (METex14) mutations represent a rare subset of non-small cell lung cancer (NSCLC) for which MET tyrosine kinase inhibitors (MET-TKIs) are recommended as first-line therapy. Patients with METex14-mutant NSCLC are often older and frequently exhibit high programmed death-ligand 1 (PD-L1) expression, providing a rationale for considering immune checkpoint inhibitor (ICI)-based therapy. Retrospective studies indicate that ICI-based therapy may offer survival outcomes comparable to, or potentially exceed those of, MET-TKIs, with possible tolerability advantages. However, without direct comparisons, it remains unclear which treatment offers more favorable outcomes in this population. PATIENTS AND METHODS: This is an open-label, multicenter, randomized phase III trial to evaluate the efficacy of ICI-based therapy compared with MET-TKIs for overall survival (OS) in patients with previously untreated advanced METex14-mutant NSCLC. Eligible patients are randomly assigned in a 1:1 ratio to receive either MET-TKIs (tepotinib or capmatinib) or ICI-based therapy, consisting of pembrolizumab monotherapy for patients with PD-L1 tumor proportion score (TPS) ≥ 50% or pembrolizumab plus platinum-based chemotherapy for those with PD-L1 TPS < 50%. The primary endpoint is OS, with secondary endpoints including progression-free survival, objective response rate, duration of response, adverse events, and quality of life. Enrollment of 100 patients is planned over 4 years. The trial was initiated in June 2026 and registered in the Japan Registry of Clinical Trials (study number: jRCT1031260225). CONCLUSION: This trial aims to provide evidence to inform optimal first-line treatment strategies for advanced METex14-mutant NSCLC and to address an evidence gap in this rare population.