ANN ARBOR, MI — Does synchronizing immune checkpoint inhibitor (ICI) dosing with morning peaks in immune activation improve clinical outcomes?
Circadian biology suggests, but well-powered studies using appropriate causal inference methodology are sparse, according to a new study To help answer the questions, researchers led by the University of Michigan and the VA Ann Arbor, MI, Healthcare System emulated a pragmatic randomized controlled trial of AM versus PM ICI infusions using VHA records from 2010 to 2024.
The study team explained in the Journal for ImmunoTherapy of Cancer that, 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 researchers defined the primary outcome as overall survival (OS) and explained that 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, they said.1
Overall, 4,688 patients were eligible for the emulated trial; of these, 1,171 received their first three infusions in the AM and 794 in the PM. Over median follow-up of 4.7 years, median survival was 10.3 months (AM) vs 8.1 months (PM). Results indicated that PM dosing was associated with worse overall survival (HR for PM vs. AM 1.15, 95% CI 1.04 to 1.26, p=0.004). In 7,951 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), however.
The authors noted that results were robust in sensitivity analyses, concluding, “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.”
- Gonzalez RT, Datta R, Rehmani S, Strohbehn GW, Ramnath N, Jalal S, Dykstra MP, Nieto J, Elliott D, Schipper MJ, Bryant AK. Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer. J Immunother Cancer. 2026 May 14;14(5):e013830. doi: 10.1136/jitc-2025-013830. PMID: 42134900.