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.