Does timing of Immune checkpoint inhibitors (ICIs) administration in first line Metastatic Renal Cell Carcinoma (mRCC) have impact in survival outcomes?

Background: Recent data in metastatic melanoma patients shows that time-of-day infusion of ICIs may directly impact on the efficacy based on the dependence of the adaptive immune system on circadian rhythm. ICIs either as single agents or in combinations, are now considered the backbone systemic treatment of mRCC pts. There is a strong biological rational showing that “Clock genes”, particularly PER2, TIMELESS and TIPIN have an altered expression in RCC compared with normal tissue. We conducted a retrospective analysis in pts with mRCC receiving ICIs-based therapies in order to determinate whether timing of ICIs administration has an impact on survival outcomes. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 3 in Italy to describe the outcome of all pts who received ICIs-ICIs or ICIs-TKI treatment for the first line setting of mRCC in daily standarc practice related to the timing of administration. We selected 16.30h as the time-limit and identified the pts receiving more than 20% of the treatment infusion after that time. Pts were treated and evaluated according to institutional local guidelines. Pts characteristics, efficacy and treatment-related toxicities were gathered. A Cox regression analysis was conducted to explore the association of baseline variables. Results: From 2019, 61 pts received either Nivolumab/Ipilimumab (N = 46, 75.4%) or pembrolizumab/axitinib (N = 15, 24,6%) for the upfront mRCC treatment. 52 (85.2%) pts (17 ICI+TKI and 25 ICI+ICI) received less than 20% of the ICIs combination treatment infusion after 16.30h compared with 9 (14.8%) pts (3 ICI+TKI and 6 ICI+ICI) who received more than 20% of the treatment infusion after 16.30h. Median follow up was 14.6 months (m). Pts who received most treatment before 16.30h had a significantly longer median PFS compared with those pts with the latest administration (12.3 vs 5.6m; HR 2.28: 95%CI 1.1-5.15; p = 0.048). Overall Survival (OS) data were immature but showed a tend to a better survival for those patients with earlier infusion administration (HR 2.33 p = 0.16). Corticosteroids concomitant administration or immune-related adverse events did not seem to have an impact on these results. Conclusions: Consistently to the melanoma findings, we also identified a potential survival impact from timing of IO administration in mRCC pts receiving ICIs-based combinations in first line treatment. Despite these promising results, there are study limitations such as number of patients and heterogeneous treatment groups. Larger prospective and randomized data are needed to assess the robustness of this hypothesis in the clinic.