Association between time-of-day of the immune checkpoint inhibitor (ICI) infusion and disease outcomes among patients with metastatic renal cell carcinoma (mRCC).
Authors: Dizman Nazli , Govindarajan Ameish , Zengin Zeynep Busra , Meza Luis A , Tripathi Nishita , Sayegh Nicolas , Castro Daniela V. , Chan Elyse H. , Lee Kyle O. , Prajapati Sweta R. , Feng Matthew I. , Loo Vivian , Pace Makala , O'brien Shea , Bailey Erin B. , Barragan-Carrillo Regina , Chehrazi-Raffle Alex , Li Xiaochen , Agarwal Neeraj , Pal Sumanta Monty 
Published: March 2023

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Background: Recent studies have suggested an association between the time-of-day of ICI infusions and disease outcomes, including progression free survival and overall survival, among patients with cancer. (Qian et al Lancet Oncology 2021). We sought to identify whether such an association exists in patients with mRCC receiving ICIs. Methods: Patients with mRCC treated with nivolumab alone, or in combination with ipilimumab, in either first- or second-line treatment were retrospectively identified. Patients who received <25% of infusions after 4:30 pm were assigned to the early time of infusion (TOI) sub-cohort while patients who received ≥ 25% of infusions after 4:30 pm were assigned to the late TOI sub-cohort. Objective response rate (ORR, per RECIST 1.1), time to treatment failure (TTF, defined as time from the date of first ICI infusion to time of treatment discontinuation), and overall survival (OS) were compared across the two groups using Cox proportional hazard models before and after adjustment for potential confounders (age, gender, line of treatment, IMDC risk, and histologic subtype). Results: A total of 145 mRCC pts (M:F,102:43) were included in the analysis. Median age was 64 (range 31-89) years, 81.4% had clear cell histology, and 75.9% had intermediate/poor risk disease. Early TOI sub-cohort included 110 (75.9%) patients while late TOI sub-cohort included 35 (24.1%) patients. Baseline characteristics were comparable across the two groups. Median OS for the entire cohort was 41.7 months (95% CI, 33.0 – Not reached [NR]), with a median TTF of 6.5 months (95% CI, 5.0 – 10.8). ORR was 32.7% in early TOI sub-group versus 25% in late TOI sub-group (p=0.60). Median TTF for the early TOI sub-cohort was 8.3 months (95% CI 6.0 – 12.6), as compared to 4.4 months (95% CI 2.1 - 10.8) among the late TOI group with a hazard ratio (HR) of 0.79 (95% CI, 0.50 – 1.25; p=0.32). Multivariate analysis showed a HR of 1.55 (95% CI, 0.98 – 2.57; p=0.06) after adjustment for potential confounders. The median OS was 46.3 months (95% CI, 32.2 – NR) in early TOI sub-cohort versus 41.7 months (95% CI, 16.7 – NR) in late TOI sub-group with a HR of 0.67 (95% CI 0.37 – 1.23; p=0.20) in univariate analyses and 0.61 (95% CI 0.33 – 1.15; p=0.13) in multivariate analyses. Conclusions: Our results demonstrated a numerical increase in ORR, TTF and OS with early TOI compared to late TOI, with the TTF difference approaching significance after adjustment for potential confounders. Larger randomized and controlled investigations are warranted to examine the impact of chronomodulation on the efficacy of ICIs in cancers, including mRCC.