Timing of immune checkpoint inhibitor administration and overall survival in advanced cancer

Overview

• retrospective cohort study evaluating whether time-of-day of immune checkpoint inhibitor (ICI) infusion affects overall survival (OS) in patients with advanced solid tumours
• cohort included 2,631 patients treated at a tertiary cancer centre between January 2018 and December 2023
• median follow-up was 32–38 months; median patient age was 68.2 years (61% male)
• cancer types: non-small cell lung cancer (45%), melanoma (23%), renal cell carcinoma (18%), head and neck cancer (9%), urothelial carcinoma (5%)

Study groupings and definition of timing

• overall median infusion time across all treatment cycles was 12:49 pm
• early group: patients receiving <50% of their total ICI cycles after 12:49 pm
• late group: patients receiving >=50% of their total ICI cycles after 12:49 pm

Primary findings

• median overall survival (OS):
  • early group: 21.4 months (95% CI 19.8 to 24.5)
  • late group: 13.1 months (95% CI 11.8 to 14.4)
• hazard ratio (HR) for OS (late vs. early):
  • standard Cox multivariate analysis: HR 1.48 (95% CI 1.33 to 1.63), indicating shorter survival in the late group
  • time-dependent Cox model (adjusting for immortal time bias): HR 1.30 (95% CI 1.16 to 1.44)
• subgroup variations by regimen:
  • significant survival association retained for monotherapy ICIs and ICIs combined with tyrosine kinase inhibitors (TKIs)
  • no significant survival difference observed in patients receiving combined ICI plus chemotherapy regimens

Proposed biological mechanism

• hypothesized to be driven by circadian rhythmicity of the host immune system, influencing T-cell activation, antigen presentation, and immune cell trafficking in response to checkpoint blockade

Clinical application and limitations

• key study strengths:
  • large real-world UK cohort; use of time-dependent models to account for potential immortal time bias
• confounding factors and unadjusted variables:
  • observational design cannot fully exclude confounding; frailer, more symptomatic patients, or those requiring hospital transport may experience treatment delays or routine afternoon scheduling
• current clinical recommendation:
  • findings are hypothesis-generating and should not immediately alter routine UK scheduling pathways until prospective, randomised clinical trials confirm the benefit

Reference:

1. Bosetti T, Kennedy OJ, Califano R, et al. Overall survival according to timing of immune checkpoint inhibitors administration in patients with advanced cancer: results from a large single-centre cohort analysis. Br J Cancer. 2026 Jul. doi: 10.1038/s41416-026-03494-y.