First-Line MET Tyrosine Kinase Inhibitors versus Immunotherapy ± Chemotherapy for Patients with MET Exon 14 Skipping Mutant Metastatic NSCLC

Abstract Purpose: First-line treatment options for MET exon 14 skipping–mutant metastatic non–small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy. Experimental Design: Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping–mutant non–small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics were performed. Results: Among 158 patients, 80 received MET TKI and 78 received ICI ± chemotherapy as first-line treatment. Baseline clinicopathologic features were balanced except for a higher proportion of patients with a history of smoking in the ICI ± chemotherapy group (P = 0.03). With a median follow-up of 37.9 months, no difference was observed in rwPFS (HR, 0.85; P = 0.4) or OS (HR, 0.97; P = 0.9) with first-line MET TKI versus ICI ± chemotherapy. In subgroup analyses, first-line ICI ± chemotherapy improved rwPFS in PD-L1 ≥80% (HR, 0.50; P = 0.03), whereas MET TKI improved rwPFS (HR, 0.40; P = 0.005) and OS (HR, 0.49; P = 0.03) in PD-L1 <50%, as well as rwPFS (HR, 0.39; P = 0.02) and OS (HR, 0.36; P = 0.03) in brain metastases and rwPFS (HR, 0.55; P = 0.01) in bone metastases. No significant differences were observed in the incidence of high-grade toxicity (P = 0.9) or rates of permanent treatment discontinuation (P = 0.2) between first-line MET TKI and ICI ± chemotherapy. Conclusions: First-line MET TKI improved outcomes in PD-L1 <50% and brain/bone metastases, whereas ICI ± chemotherapy prolonged PFS only in PD-L1 ≥80%, emphasizing the need for personalized treatment selection.