Emulated randomized trial of morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small cell lung cancer

Circadian biology suggests that synchronizing immune checkpoint inhibitor (ICI) administration with morning peaks in immune activation could improve clinical outcomes. An emulated randomized trial using Veterans Health Adminstration records from 2010 to 2024 compared efficacy of first-line or second-line AM versus PM ICI infusions in patients with stage IV non-small cell lung cancer (NSCLC). The median follow-up was 4.7 years. Median overall survival was 10.3 months (AM) versus 8.1 months (PM) among patients receiving ICIs (HR 1.15; p=0.004), a difference that was not observed among control patients receiving chemotherapy (HR 1.05; p=0.15). Results were robust in sensitivity analyses. The authors conclude that morning ICI infusions confer a modest but clinically meaningful survival benefit over afternoon infusions that is absent in chemotherapy controls, supporting a causal chronotherapeutic effect.