Comparative efficacy and safety of protocol-defined 2-year versus indefinite immunotherapy strategies for advanced non-small-cell lung cancer: A systematic review and network meta-analysis

Abstract

The optimal duration of immune checkpoint inhibitor (ICI)-based therapy for advanced non-small-cell lung cancer (NSCLC) remains uncertain. To compare first-line ICI-based regimens with a protocol-defined maximum treatment duration of approximately 2 years versus indefinite treatment. Systematic review incorporating a restricted common-comparator indirect comparison and Bayesian network meta-analysis (NMA). We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov to November 2024 for randomized controlled trials in advanced NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR) and grade ≥3 adverse events (AEs). Thirty-two trials involving 20,378 patients were included. In the restricted indirect comparison, regimens with a protocol-defined 2-year duration showed a greater OS benefit relative to chemotherapy (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.64-0.75) than regimens designed for indefinite treatment (HR = 0.85, 95% CI: 0.80-0.91; Bonferroni-adjusted P = 0.0012). No significant duration-related interactions were observed for PFS or grade ≥3 AEs. In the NMA, protocol-defined 2-year ICI-plus-chemotherapy strategies were associated with a lower hazard of death than corresponding indefinite-treatment strategies (HR = 0.84, 95% credible interval [CrI]: 0.73-0.96). A significant PFS difference between corresponding duration strategies was observed only for dual-ICI regimens (HR = 0.67, 95% CrI: 0.46-0.98). No statistically significant between-strategy differences were observed for ORR or grade ≥3 AEs. Protocol-defined 2-year strategies were associated with a greater OS benefit relative to chemotherapy than indefinite-treatment strategies, while no clear duration-related differences were observed for PFS or severe AEs. These trial-level comparisons support the clinical feasibility of a planned 2-year strategy but do not establish that discontinuation at 2 years is superior.