Impact of time-of-day administration of immunotherapy on overall survival among patients with metastatic renal cell carcinoma.
Authors: Arroyave Ramirez Andres Mauricio , Motola Daniel , Morales Garcia Mariana Guadalupe , Conde-Flores Emilio 
Published: June 2024

e16537

Background: Circadian rhythm influences adaptive immune response. In recent years, some studies have suggested a relationship between the time of day of immune checkpoint inhibitor (ICI) infusions and disease outcomes among cancer patients. Evening infusions (after 4:30 pm) are associated with shorter overall survival. This study aims to determine whether the time of day of immunotherapy infusion affects the efficacy of treatment in patients with metastatic renal cell cancer (mRCC) in a Mexican population. Methods: This is an observational, retrospective, single-center study that included patients with mCRC treated with Nivolumab plus Ipilimumab in first line diagnosed between 2018 and 2023. Patients who received <20% of infusions after 4:30 pm were assigned to early time of infusion (TOI) group, while patients who received ≥20% of infusions after that time were assigned to late TOI group. The primary end point was overall survival (OS), and the secondary end point was overall response rate (ORR). Both groups were compared using Kaplan-Meier analysis and Cox regression model. Results: 127 patients were included in the analysis. Most of the population were men (70.1%). Median age was 62 years. In addition, 100% had clear cell histology and 96% had intermediate/poor-risk disease. The early TOI group included 84 (66%) patients, while 43 patients were assigned to the late TOI group. In the overall population, median OS in the early TOI group was 64.8 months (95% CI, 53.4-68.8) versus 46.3 months (95% CI, 22.5-61.4) in the late TOI group, with a hazard ratio (HR) of 0.67 (95% CI, 0.51-0.83; p=0.03). Improvement in OS with early administration of therapy was seen across all subgroups that were evaluated. The impact of time of day of ICI administration was greater in patients with intermediate/poor-risk disease (median OS 56.4 months [95% CI 41.4-67.2] in the early TOI group versus 36.8 months [95% CI 18.9-51.3] in the late TOI group, HR 0.52 [95% CI 0.37-0.85]; p=0.002). In the overall population, the ORR was higher in the early TOI group (32.8% versus 22.4%; p= 0.04), with similar results in patients with intermediate and high-risk disease (34.5% versus 21.6%, and 30.5% versus 24.8% respectively). In the multivariate analysis, time-of-day administration of immunotherapy was an independent prognostic factor for death. Conclusions: Our results demonstrated improved OS and ORR in ICI-treated patients who received most infusions before 4:30 pm, particularly in patients with intermediate/poor-risk mRCC, in line with the findings of previous analyzes showing that chronomodulation influences the efficacy of immunotherapy. This is the first work in a Mexican population. Although larger prospective and controlled studies are necessary, early ICI infusion is a practical, safe and reasonable strategy that could be considered in the treatment of Mexican patients with metastatic renal cell cancer.