Does the Timing of Immunotherapy Administration Influence Survival Outcomes in Advanced Cancers?
By: Wendy LaGrego
Posted: Friday, August 28, 2026
Circadian rhythms influence immune function, raising the possibility that the time of day when immune checkpoint inhibitors (ICIs) are administered may affect their efficacy. However, evidence examining this relationship has largely been retrospective, and previous reviews have included fewer studies and have not comprehensively evaluated differences across cancer types, ICI regimens, concomitant treatments, and definitions of early vs late administration. In a systematic review and meta-analysis published in JAMA Network Open, Shota Inoue, MD, of the Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Austria, and colleagues evaluated the association between time of day of ICI administration and oncologic outcomes in patients with advanced solid tumors.
Study Details
The investigators conducted a comprehensive search of MEDLINE, Embase, and Web of Science Core Collection in February 2026. Randomized clinical trials and prospective or retrospective cohort studies comparing early vs late time-of-day ICI administration and reporting overall survival (OS) or progression-free survival (PFS) were eligible. The primary outcomes were OS and PFS.
Of 7,892 records screened, 29 studies involving 6,129 patients were included. The evidence base consisted of one randomized clinical trial involving 210 patients with non–small cell lung cancer (NSCLC), one prospective cohort study involving 62 patients with head and neck squamous cell carcinoma, and 27 retrospective cohort studies involving 5,857 patients. Cancer types represented included NSCLC, melanoma, gastric cancer, renal cell carcinoma, esophageal cancer, small cell lung cancer, urothelial carcinoma, biliary tract cancer, hepatocellular carcinoma, and others.
Key Results
Across the included studies, earlier ICI administration was associated with improved OS (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.51–0.70) and PFS (HR = 0.62, 95% CI = 0.54–0.71). Cancer-specific analyses demonstrated significant associations with both improved OS and PFS in NSCLC (OS: HR = 0.58; PFS: HR = 0.60), gastric cancer (OS: HR = 0.61; PFS: HR = 0.62), renal cell carcinoma (OS: HR = 0.60; PFS: HR = 0.70), small cell lung cancer (OS: HR = 0.37; PFS: HR = 0.48), and biliary tract cancer (OS: HR = 0.62; PFS: HR = 0.55).
Exploratory analyses also found that both simple clock-time cutoffs and definitions based on the proportion of infusions administered before or after a specified time favored earlier administration, with no significant difference between approaches. Similarly, associations with improved outcomes were observed across single-agent, dual-agent, and mixed ICI regimens. Twenty studies reported adverse-event data, but inconsistent reporting precluded a pooled safety analysis, and no consistent relationship between administration time and adverse-event incidence or severity was identified.
The authors concluded: “In this systematic review and meta-analysis of studies including patients with advanced cancers, early immunotherapy administration was associated with improved outcomes. These findings suggest that treatment timing may have clinical relevance and warrant prospective evaluation to establish standardized timing strategies across cancer settings.”
DISCLOSURE: For full disclosures of the study authors, visit jamanetwork.com.
