Comparative effectiveness of ALK tyrosine kinase inhibitors in ALK-positive non–small cell lung cancer: A systematic review and network meta-analysis.

e20753 Background: Next generation ALK tyrosine kinase inhibitors (TKIs) have transformed ALK positive advanced non-small cell lung cancer (NSCLC). However, the relative efficacy of newer agents compared with established standards remains unclear. We conducted a network meta-analysis (NMA) to evaluate comparative effectiveness of firstline ALK-TKIs. Methods: We searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and oncology conferences for randomized trials evaluating ALK-TKIs or chemotherapy in advanced ALK positive NSCLC. The primary outcome was progression-free survival (PFS). A Bayesian random effects NMA was performed using crizotinib as reference. Results: Fifteen trials comprising 4,392 patients and nine ALK TKIs were included. All next-generation TKIs significantly improved PFS versus crizotinib. Lorlatinib ranked highest (HR 0.19, 95% CrI 0.13-0.27; SUCRA 0.91), followed by foritinib (HR 0.23) and iruplinalkib (HR 0.31). Alectinib showed consistent benefit with high-certainty evidence (HR 0.39, 95% CI 0.31-0.49). Lorlatinib demonstrated greatest intracranial efficacy (intracranial PFS HR 0.07). OS analyses were limited by crossover, though alectinib showed OS benefit versus crizotinib (HR 0.67, 95% CI 0.53-0.85). Risk of bias was low to moderate; certainty ranged from high to low across comparisons. Conclusions: Next-generation ALK-TKIs significantly outperform crizotinib. Lorlatinib demonstrated greatest PFS and intracranial benefit, while alectinib showed durable efficacy with high-certainty evidence, supporting current guidelines. First-line pfs network meta-analysis results. Treatment HR vs Crizotinib (95% CrI) SUCRA Lorlatinib 0.19 (0.13–0.27) 0.91 Foritinib 0.23 (0.14–0.38) 0.84 Iruplinalkib 0.31 (0.22–0.44) 0.72 Alectinib 0.39 (0.31–0.49) 0.61 Envonalkib 0.47 (0.34–0.64) 0.50 Brigatinib 0.49 (0.35–0.68) 0.48 Crizotinib Reference 0.24