A Systematic Review and Meta-analysis of Clinical Trials in ALK-positive Non-small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed in a subset of patients with non-small cell lung cancer (NSCLC). Since the approval of crizotinib, which was the first ALK tyrosine kinase inhibitor (TKI), the treatment landscape has rapidly evolved with the development of multiple next-generation TKIs and investigational agents. A structured review of clinical trials registered on ClinicalTrials.gov was conducted to identify studies evaluating therapies in ALK-positive NSCLC, including phase I-IV trials in adult populations, regardless of recruitment status. Trials were screened for ALK-specific relevance and key outcomes including progression-free survival (PFS) and objective response rate (ORR) were extracted. Central nervous system (CNS) activity and resistance mutation profiles were collected from published literature when available. A meta-analysis of ORR was conducted on a subset of 41 trials comprising 66 evaluable cohorts with sufficient efficacy data. Studies evaluated first- through third-generation ALK TKIs, combination regimens, and experimental agents. Meta-analysis of 6,382 patients showed a pooled ORR of 58.5% [95% confidence interval=57.3-59.7], with higher response rates in treatment-naive versus pretreated cohorts (71.8% vs 48.4%). Weighted median PFS was 13.8 months in treatment-naive and 9.8 months in pretreated cohorts. CNS activity, summarized from published reports, indicated superior intracranial efficacy of later generation TKIs. ALK-targeted therapies have significantly improved outcomes in ALK-positive NSCLC. However, CNS progression, acquired resistance, and optimal treatment sequencing continue to limit outcomes. This review synthesizes current evidence to guide clinical practice and future investigations.