First-line MET tyrosine kinase inhibitors versus immunotherapy ± chemotherapy for patients with MET exon 14 skipping mutant metastatic NSCLC

Purpose: First-line treatment options for MET exon 14 skipping (METex14) mutant metastatic non-small cell lung cancer (NSCLC) vary due to 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 METex14 mutant NSCLC receiving 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 clinicopathological characteristics were performed. Results: Among 158 patients, 80 received MET TKI and 78 ICI±chemotherapy as first-line. Baseline clinicopathologic features were balanced except for 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), while 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 in bone metastases (HR 0.55, p=0.01). No differences were observed in the incidence of high-grade toxicity (p=0.9) or rates of permanent 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, while ICI±chemotherapy prolonged PFS only in PD-L1≥80%, emphasizing the need for personalized treatment selection.