Association between time-of-day of the immune checkpoint inhibitor (ICI) infusion and disease outcomes among patients with metastatic renal cell carcinoma (mRCC).

Abstract

678 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.

Immunotherapy around the Clock: Impact of Infusion Timing on Stage IV Melanoma Outcomes

“…In metastatic melanoma, the MEMOIR retrospective study first documented a potential effect of circadian timing of the administration of immunotherapy (specifically ipilimumab, nivolumab, and pembrolizumab). The authors find that patients who received more than 20% of infusions after 4:30 p.m. had worse OS outcomes (HR of 2.04) [ 28 ]. Karaboué et al analyzed the impact of nivolumab administration timing in NSCLC using the median clock hour of a patient’s treatments and dichotomizing patients into AM (morning) and PM (afternoon) groups according to the period in which they received the most treatments.…”

“…Our findings support these results while also providing evidence that allocation to a treatment group is balanced across observables and is, therefore, unlikely to be driving our results. Finally, in metastatic renal cell carcinoma, a correlation has been found between daytime administration of immunotherapy and OS favoring morning infusions [ 28 , 29 ].…”

“…In non-small cell lung cancer (NSCLC), Kabaroué et al [ 27 ] report a retrospective study in metastatic NSCLC that indicates a major OS difference according to the immunotherapy infusion timing, with patients receiving morning infusions showing a four-fold OS increase compared to those receiving afternoon infusions. In metastatic renal cell carcinoma, two concurrent retrospective studies [ 28 , 29 ] showed that morning immunotherapy infusions were again associated with better objective response rates, time to treatment failure, and OS. A small-sample, pan-cancer retrospective study did not find significant OS differences between performing ICI infusions in the morning or late afternoon [ 30 ].…”

Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

“…Those patients receiving 20% or more ICI infusions after 16:30 experienced worse OS (HR = 3.1 [1.27-7.36] (p = 0.01), shorter time on treatment (HR = 2.5 [1.21-4.99] (p = 0.013) and shorter time to next treatment line (HR = 1.9, [0.96-3.71] (p = 0.067) as compared to those who received less than 20% of the infusions after 16:30. In 145 patients treated with nivolumab alone, or in combination with ipilimumab as firstor second-line treatment for metastatic RCC, Dizman et al [28] showed consistent trends towards improved response rate, prolonged time-to-treatment failure, and OS among those patients receiving less than 25% of ICI infusions after 16:30.…”

Readily available drugs and other interventions to potentially improve the efficacy of immune checkpoint blockade in cancer

“…Additional retrospective studies on melanoma, NSCLC, squamous cell carcinoma of the esophagus, and renal cell carcinoma provide additional information on the role of the circadian rhythm in immunotherapy efficacy. Later infusion times have been associated with worse outcomes in renal cell carcinoma ( 92 ). One study on renal cell carcinoma found a continuous association with the number of treatments, finding a 16% increased risk of death for every 10% of infusions after 4:30 PM ( 93 ).…”