Impact of time-of-day of immune checkpoint inhibitor infusion on clinical outcomes in patients with metastatic renal cell carcinoma (mRCC).

Abstract

4552 Background: Emerging evidence suggests that circadian rhythms may influence the efficacy of immune checkpoint inhibitors (ICIs) by modulating immune cell activity and T-cell trafficking. This study evaluated whether the timing of ICI administration (early vs. late) affects progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Methods: We conducted a single-center retrospective study of 97 patients with Stage IV mRCC treated with first-line ICIs. Patients were categorized by infusion timing: "Early" (n=68) vs. "Late" (n=29), with the cutoff defined by the median infusion time of 2:00 PM. Treatment regimens included ipilimumab/nivolumab (37%), nivolumab (36%), and pembrolizumab (27%); 23% received ICI in combination with a VEGF-targeted tyrosine kinase inhibitor. Outcomes were analyzed using Kaplan-Meier curves and multivariable Cox regression models, adjusting for age and International Metastatic RCC Database Consortium (IMDC) risk scores. Results: The median age was 65 years (IQR 59–71), 77% of patients were male, and 88% had clear cell histology. IMDC risk categories were intermediate (56%), poor (27%), and favorable (18%). At a median follow-up of 54.8 months, early infusion was associated with significantly improved OS (median 54 vs. 29 months; adjusted HR 1.79; 95% CI 1.02–3.12; p = 0.041) and PFS (median not reached; adjusted HR 3.59; 95% CI 1.27–10.20; p = 0.016) after adjustment for age and IMDC risk. Landmark 60-month OS was 40% vs. 31%, and PFS was 79% vs. 60% for the early vs. late groups, respectively. The incidence of any-grade immune-related adverse events (irAEs) was similar (54% in the early group vs. 52% in the late group), and poor IMDC risk remained a significant predictor of OS in the multivariable model (HR 3.09; 95% CI 1.22–7.8; p = 0.017). Conclusions: In this mRCC cohort, ICI administration before 2:00 PM was associated with significant improvements in both PFS and OS, including a nearly two-fold increase in median overall survival compared to late-afternoon administration. These findings are hypothesis-generating and suggest that the timing of immunotherapy may be an immediately actionable, high-impact variable in optimizing mRCC treatment. Prospective validation is warranted.