Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer

Background: Circadian biology suggests that synchronizing immune checkpoint inhibitor (ICI) dosing with morning peaks in immune activation could improve clinical outcomes, but well-powered studies using appropriate causal inference methodology are sparse. Methods: We emulated a pragmatic randomized controlled trial of AM versus PM ICI infusions using Veterans Health Administration records from 2010 to 2024. In the emulated trial, stage IV non-small-cell lung cancer patients planned to undergo first-line or second-line ICI would have been randomized to receive the first three infusions in the AM (<12:00 PM) or PM (≥12:00 PM). The primary outcome was overall survival (OS). Marginal structural models with inverse probability of censoring weights estimated the per-protocol effect, accounting for baseline and longitudinal confounding. A historical chemotherapy cohort served as a negative control. Results: 4688 patients were eligible for the emulated trial; of these, 1171 received their first three infusions in the AM and 794 in the PM. Median follow-up was 4.7 years. Median survival was 10.3 months (AM) vs 8.1 months (PM). PM dosing was associated with worse OS (HR for PM versus AM 1.15, 95% CI 1.04 to 1.26, p=0.004). In 7951 chemotherapy controls (median follow-up 8.9 years), no time-of-day effect was detected (HR for PM vs AM 1.05, 95% CI 0.98 to 1.12, p=0.15). Results were robust in sensitivity analyses. Conclusions: Morning ICI infusions confer a modest but clinically meaningful survival benefit that is absent in chemotherapy controls, supporting a causal chronotherapeutic effect. Scheduling ICIs before noon represents a low-cost, immediately actionable strategy warranting prospective confirmation.