Lights and shadows of time-of-day administration of immune checkpoint inhibitors in solid tumors: a comprehensive review with exploratory analyses

Background Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for several solid tumors. Among the mechanisms investigated to explain variability in ICIs efficacy, the potential effect of the time-of-day (ToD) at which ICIs are administered has emerged as an area of interest. This review summarizes the evidence on the impact of ToD administration of ICIs in solid tumors. Materials and methods A comprehensive manual search of two leading international databases, PubMed/MEDLINE and Scopus/ELSEVIER, was conducted to identify relevant studies. An exploratory pooled analysis of the included studies was performed. The pooled effect size was expressed as HR with 95%CIs for either PFS or OS, according to random-effect meta-analysis. Results Our research led to the selection of 21 relevant retrospective and prospective studies evaluating the effect of ToD infusion of ICIs across several solid tumor types. The predominantly retrospective design of the studies and the absence of a standardized ToD threshold limit the reliability of the available data. In our pooled, exploratory analysis, earlier administration was associated with better PFS and OS. Conclusion Although ICIs morning administration may be associated with favorable survival trend, the available evidence is too heterogeneous to support a widespread adoption of a chrono-modulated approach. Additional prospective, reproducible clinical trials using standardized administration windows and clearly defined treatment regimens are necessary to further explore this path.