The leverage of time of day on immune checkpoint inhibitors administration in survival of cancer patients: A systematic review and meta-analysis

Visakha Irawan; Kevin Dermawan

doi:10.22146/inajbcs.v57i3.Supplement.24317

Visakha Irawan Department of Internal Medicine, Mandaya Royal Hospital Puri, Tangerang, Banten, Indonesia
Kevin Dermawan Faculty of Medicine, University of Pelita Harapan, Tangerang, Banten, Indonesia

DOI: https://doi.org/10.22146/inajbcs.v57i3.Supplement.24317

Keywords: cancer, immune checkpoint inhibitors, survival, time of day, circadian rhythms

Abstract

Circadian rhythms influence the timing and function of immune cells, affecting their trafficking and activity. This allows for elucidation of how the timing of immune checkpoint inhibitors (ICIs) administration may impact outcomes in cancer patients. Several studies have explored the leverage of time of day (ToD) on ICIs administration, highlighting the potential benefits of earlier administration in cancer patients. To investigate the consistency of the leverage of ToD on ICI administration, a systematic review and meta-analysis were conducted. A systematic search of various databases through mid-2025 was conducted to identify cohort studies involving the leverage of ToD, either early or late, on ICIs administration in survival of cancer patients. Cohort studies involving cancer patients aged 18 years or older with adequate information on overall survival (OS) and progression-free survival (PFS) were eligible. Full-text studies were screened double-blind, followed by independent bias assessment. Using a random-effects model, pooled hazard ratios (HR) [95% confidence interval (CI)] were calculated, with OS as the primary and PFS as the secondary outcome. Eleven studies (n = 2,216) were included, median follow-up 9–42 months. Most participants were male (71.93%), and predominantly lung cancer (61.33%). The majority of participants (81.5%) received PD-1 inhibitors, and the others received PD-L1 inhibitors, CTLA- 4 inhibitors, or a combination. Cut-off of ToD ranged from 11:30 to 14:00 for seven studies, and 15:00 to 17:00 for four studies. Meta-analysis showed that the early ToD group had better OS (HR 0.53, 95% CI 0.45-0.64; p < 0.001) and PFS (HR 0.55, 95% CI 0.45-0.67; p < 0.001), compared with the late ToD group. Early ICI administration aligns with circadian rhythms and provides significant survival benefits. However, further studies are required to establish definitive recommendations.