Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?

e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.