A meta-analysis of the impact of different ALK variants on targeted therapy efficacy in advanced non-small cell lung cancer.

Background: Anaplastic lymphoma kinase (ALK) fusion is an important therapeutic targets in non-small cell lung cancer (NSCLC). Different ALK variants may affect the efficacy of targeted therapies. This meta-analysis systematically assesses the impact of different ALK variants on the clinical outcomes of ALK TKI treatment. Methods: By systematically searching PubMed, Embase, and Web of Science databases, we collected relevant studies published from January 1,1994 to September 30, 2025. The relationship between different ALK variations and treatment efficacy was evaluated by combining hazard ratio (HR) and 95% confidence interval (CI). The quality of studies was evaluated using tools such as the Newcastle-Ottawa Scale (NOS) and the Cochrane risk-of-bias tool. Results: A total of 30 studies involving 2737 patients with ALK-positive NSCLC were included. Comparison between EML4-ALK variant 1 (V1) and variant 3 (V3) showed that V3 was associated with shorter progression-free survival (PFS) in patients receiving ALK TKI treatment (HR = 1.53, 95%CI:1.17-1.99, p=0.002). Subgroup analysis showed that the adverse effect of V3 was more pronounced in patients treated with crizotinib (HR = 1.40, 95%CI: 1.00-1.96, p=0.049), in the first line treatment setting (HR = 1.83, 95%CI: 1.34-2.50, p<0.001), and in those assessed by NGS (HR = 1.67, 95%CI: 1.34-2.08, p<0.001). A significant association was also observed in the brigatinib-treated population (HR = 2.09, 95%CI: 1.33-3.28, p=0.001), although this finding was based on only two studies. When comparing V3 with non-V3 variants, V3 was associated with significantly worse PFS (HR = 1.78, 95%CI:1.38-2.30, p<0.001). When comparing V1 with non-V1 variants, V1 was associated with significantly better PFS (HR = 0.63, 95%CI:0.44-0.89, p=0.01); however, after excluding V3, no significant difference was found between V1 and other variants. No significant differences were observed between V1 and V3 in overall survival (OS) or objective response rate (ORR). Conclusion: EML4-ALK v3 may be an important negative prognostic factor for the efficacy of targeted therapy in ALK positive NSCLC. Subgroup analysis indicated that the poor prognosis associated with v3 was particularly evident in patients treated with crizotinib, in the first line setting, and in those assessed by NGS. However, due to limited data on newer generation ALK TKIs and the presence of heterogeneity in some of the comparison groups, definitive conclusions cannot be drawn. Prospective studies with standardized molecular subtyping are still needed before considering clinical stratification based on ALK variant types. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229641, identifier CRD420251229641.