Time-of-Day of Initial Immune Checkpoint Inhibitor Administration and Its Impact on Outcomes in Metastatic Non–Small Cell Lung Cancer

Purpose Immune checkpoint inhibitors (ICIs) are integral to first-line treatment of metastatic non–small cell lung cancer (NSCLC). Circadian biology may influence antitumor immunity, raising the hypothesis that time-of-day of ICI administration could affect outcomes. We evaluated the association between initial and cumulative ICI administration time-of-day and clinical outcomes in metastatic NSCLC. Materials and Methods We conducted a retrospective cohort study of 778 patients with metastatic NSCLC treated with first-line ICI-containing therapy across Mayo Clinic sites between January 2021 and March 2024. Patients were stratified by time-of-day of first ICI administration: early (0700-1200) versus late (1201-2400). Primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end point was immune-related toxicity. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates. Exploratory analyses evaluated cumulative infusion time-of-day and alternative administration-time thresholds using spline and cut-point analyses. Results Of 778 patients, 277 received early and 501 received late initial ICI administration. Median OS was 1.33 versus 1.48 versus years and median PFS was 0.65 versus 0.67 years in the late and early groups, respectively. Time-of-day of initial ICI administration was not associated with OS (HR, 1.01 [95% CI, 0.85 to 1.20]) or PFS (HR, 1.03 [95% CI, 0.88 to 1.21]). Findings were unchanged after multivariable adjustment. Immune-related toxicity occurred in 26.9% and 24.2% of patients in the late and early groups, respectively ( P = .40). Cumulative infusion time-of-day was not associated with OS or PFS, and spline analyses identified no significant administration-time threshold associated with outcomes. Conclusion In this large real-world cohort of patients with metastatic NSCLC, neither initial nor cumulative ICI administration time-of-day was associated with survival or immune-related toxicity. Prospective studies incorporating chronotype and circadian biomarkers are warranted to further define the role of chronotherapy in immuno-oncology.