Real-world evidence for the impact of circadian clock on the benefit from immune checkpoint inhibitors in solid tumors

BACKGROUND: The circadian clock regulates tumor-immune interactions in a time-of-day-dependent manner, yet whether this translates to a clinically meaningful benefit across diverse solid tumors in real-world populations remains unclear. METHODS: We retrospectively analyzed 969 patients receiving anti-PD-1 or anti-PD-L1 therapy at UCI Health between 2018 and 2022. Patients were classified as early (before 12 PM) or late (12 PM or after) based on infusion time. The primary outcome was disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) per RECIST criteria. Unadjusted comparisons used the Pearson chi-square test. Multivariable logistic regression adjusting for disease stage, age, and ethnicity was performed in 806 patients with complete covariate data. Propensity score-matched analyses and sensitivity analyses using alternative exposure definitions were conducted. RESULTS: Early infusion was associated with significantly higher DCR compared with late infusion (49% vs. 40%, p = 0.007). This association persisted after multivariable adjustment (adjusted OR 1.18, 95% CI 1.02-1.38, p = 0.024). The effect was directionally consistent across subgroups defined by sex, age, stage, and ICI agent. In ethnicity-stratified analyses, the association was significant among non-Hispanic patients (adjusted OR 1.18, 95% CI 1.02-1.39) but was indeterminate among Hispanic patients due to limited sample size (adjusted OR 1.18, 95% CI 0.84-1.65); the ethnicity-by-TOD interaction term was non-significant (p = 0.958). Sensitivity analyses using alternative exposure definitions and propensity score matching yielded consistent results. CONCLUSIONS: In a large, heterogeneous real-world cohort spanning multiple tumor types and a diverse patient population, early ICI administration was independently associated with higher DCR. These findings support a chronotherapeutic effect of ICI timing and underscore DCR as a sensitive endpoint for its detection. Prospective validation across tumor types and demographic subgroups is warranted.