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

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. Journal for immunotherapy of cancer. 2026 May 14; 14(5):DOI: 10.1136/jitc-2025-013830.

Related HSR&D Project(s)

• CDA 22-190 – Democratically Designed Optimal Dosing Regimens To Combat Overuse

Dimensions for VA is a web-based tool available to VA staff that enables detailed searches of published research and research projects.

If you have VA-Intranet access, click here for more information vaww.hsrd.research.va.gov/dimensions/

VA staff not currently on the VA network can access Dimensions by registering for an account using their VA email address.    Search Dimensions for VA for this citation
* Don't have VA-internal network access or a VA email address? Try searching the free-to-the-public version of Dimensions

Search for Abstract from PubMed

---

Abstract:

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.