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Life sciences · Review
Frontiers in Oncology · November 4, 2026
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Background Primary non-small cell lung cancer (NSCLC) with mesenchymal-epithelial transition factor ( MET ) gene alterations, including exon 14 skipping mutations and amplification, represents a distinct molecular subtype with unique therapeutic challenges. While multiple tyrosine kinase inhibitor (TKI) strategies have been developed, their comparative efficacy and safety remain systematically unquantified, particularly across different MET alteration types. Methods We conducted a single-arm meta-analysis of clinical trials evaluating MET-targeted therapies in patients with primary MET -altered NSCLC. A systematic search of PubMed, Embase, Cochrane Library, and major conference proceedings was performed up to August 31, 2025. The primary outcome was progression-free survival (PFS), with secondary outcomes including overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Data were synthesized using R software (version 4.4.2). The protocol was registered with PROSPERO (CRD420251265925). Findings A total of 25 studies involving 1,636 participants were included. MET -TKIs demonstrated the highest pooled ORR of 49% (95% CI 46-52%) and DCR of 84% (95% CI 81-87%), significantly outperforming ALK / ROS-1 -TKIs (ORR 38%, DCR 66%) and other strategies. Subgroup analysis revealed that patients with MET amplification had consistently lower response rates compared to those with exon 14 skipping mutations across all TKI treatments (ORR 22% vs. higher in exon 14). Regarding safety, MET -TKIs were associated with a high incidence of any-grade AEs (90%), particularly peripheral edema. Notably, the combination of MET -TKI and programmed cell death protein 1 (PD-1) inhibitors carried the highest risk of severe (Grade ≥3) AEs (49%), primarily due to overlapping toxicities such as pneumonitis. Interpretation Selective MET-targeted therapies show robust clinical efficacy and represent a viable therapeutic strategy for NSCLC patients with MET exon 14 skipping mutations. However, current TKI strategies show limited efficacy for MET -amplified tumors, highlighting an unmet need for optimized approaches in this subgroup. While effective, MET -TKIs require careful management of adverse events, and their combination with immune checkpoint inhibitors warrants caution due to significant toxicity risks. Future research should focus on standardizing MET amplification definitions and exploring novel combination therapies to overcome resistance. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251265925, identifier CRD420251265925.