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
Srivastava et al. (Thu,) studied this question.