A systematic review and meta-analysis published in JAMA Network Open found that early time-of-day immunotherapy was associated with improved survival outcomes in patients with advanced cancers. According to Inoue et al, this association appeared to be particularly pronounced in non–small cell lung cancer (NSCLC), renal cell carcinoma, gastric cancer, small cell lung cancer, and biliary tract cancer.
Circadian rhythms influence immune function and may therefore affect the efficacy of immune checkpoint inhibitor therapy. The analysis appeared to support this hypothesis, with the investigators writing that their findings “suggest that treatment timing may have clinical relevance….”
Study Details
The investigators searched MEDLINE (via PubMed), Embase, and Web of Science Core Collection for randomized clinical trials and prospective or retrospective cohort studies comparing early vs late time-of-day immune checkpoint inhibitor administration and reporting overall and progression-free survival outcomes.
Twenty-nine studies comprising 6,129 patients with advanced solid tumors were included. Of these studies, one was a randomized clinical trial involving 210 patients with NSCLC, and one was a prospective cohort study including 62 patients with head and neck squamous cell carcinoma. The remaining 27 were retrospective cohort studies comprising 5,857 patients across a range of malignancies, including NSCLC, melanoma, gastric cancer, head and neck squamous cell carcinoma, renal cell carcinoma, esophageal cancer, small cell lung cancer, urothelial carcinoma, biliary tract cancer, and hepatocellular carcinoma.
Two reviewers independently extracted data and assessed risk of bias. Meta-analyses were conducted using random-effects models with the inverse-variance method.
Overall and progression-free survival were evaluated as primary outcomes.
Time-of-Day Immunotherapy and Outcomes
Earlier administration of immune checkpoint inhibitors was found to be associated with increased overall (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.51–0.70) and progression-free (HR = 0.62, 95% CI = 0.54–0.71) survival.
Subset analyses appeared to confirm significant improvements among patients with the following tumor types:
- NSCLC (overall: HR = 0.58 [95% CI = 0.46–0.74]; progression-free: HR = 0.60 [95% CI = 0.46–0.76])
- Gastric cancer (overall: HR = 0.61 [95% CI = 0.49–0.77]; progression-free: HR = 0.62 [95% CI = 0.43–0.89])
- Renal cell carcinoma (overall: HR = 0.60 [95% CI = 0.40–0.90]; progression-free: HR = 0.70 [95% CI = 0.50–0.98])
- Small cell lung cancer (overall: HR = 0.37 [95% CI = 0.26–0.53]; progression-free: HR = 0.48 [95% CI = 0.36–0.65])
- Biliary tract cancer (overall: HR = 0.62 [95% CI = 0.41–0.93]; progression-free: HR = 0.55 [95% CI = 0.38–0.79]).
“Although evidence from randomized clinical trials is currently limited to NSCLC, our findings highlight the potential relevance of administration timing as a modifiable factor in cancer immunotherapy,” the investigators concluded. “Prospective studies are needed to determine whether the observed associations are causal and to define standardized timing strategies across different cancer settings.”
Shahrokh F. Shariat, MD, of Medical University of Vienna, Austria, is the corresponding author of the article in JAMA Network Open.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
