Abstract
BACKGROUND: It remains unknown what is the optimal front-line choice for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion. METHODS: We conducted a systematic review and network meta-analysis of randomized phase III clinical trials comparing two or more treatments as the front-line setting for patients with advanced ALK-positive NSCLC. RESULTS: Nine phase III randomized clinical trials with 2367 patients were included. As to efficacy, lorlatinib had the most favorable progression-free survival [PFS; surface under the cumulative ranking curve (SUCRA) = 98.4%] in the first-line setting, with noticeable outcome benefits versus chemotherapy [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.08-0.19], crizotinib (HR: 0.28; 95% CI: 0.19-0.41), ceritinib (HR: 0.22; 95% CI: 0.13-0.37), and brigatinib (HR: 0.58; 95% CI: 0.35-0.96), as well as beneficial trends when compared with alectinib (HR: 0.66; 95% CI: 0.41-1.04) and ensartinib (HR: 0.62; 95% CI: 0.36-1.08). Meanwhile, alectinib showed the optimal overall survival (OS; SUCRA = 91.2%), with significant improvements over chemotherapy (HR: 0.47; 95% CI: 0.30-0.72) and crizotinib (HR: 0.58; 95% CI: 0.41-0.82). Similarly, brigatinib also displayed prolonged OS compared with crizotinib after adjustment for crossover by the marginal structural model (HR: 0.54; 95% CI: 0.31-0.92). In terms of safety, alectinib had the fewest grade 3-5 adverse events (SUCRA = 98.9%), with marked advantages versus crizotinib [odds ratio (OR): 0.67; 95% CI: 0.46-0.97], ceritinib (OR: 0.21; 95% CI: 0.10-0.43), brigatinib (OR: 0.37; 95% CI: 0.20-0.69), ensartinib (OR: 0.48; 95% CI: 0.27-0.89), and lorlatinib (OR: 0.30; 95% CI: 0.16-0.54). CONCLUSIONS: Lorlatinib may have advantageous PFS compared with other agents but a greater risk of severe toxicity. Second-generation inhibitors, including alectinib, brigatinib, and ensartinib, provide major efficacy with less toxicity and remain appropriate regimens in the front-line setting.