Does the time-of-day administration of immune checkpoint inhibitors affect efficacy in patients with metastatic renal cell carcinoma? A single-center study.

Abstract

681 Background: Immune checkpoint inhibitors (ICI) are the standard of care for metastatic renal cell carcinoma (mRCC). Circadian rhythm drives organisms to properly predict and react to cyclical changes in the environment, and also affects the adaptive immune response. Here, we study the relationship between time-of-day ICI administration and outcomes in mRCC patients (pts). Methods: This is a single-center retrospective study of ICI-treated mRCC pts diagnosed from January 2014 to March 2022. Day and time of each ICI infusion (inf) for each pt were obtained from the pharmacy records. Proportion of ICI inf administered after 4:30 pm (ICI430) was calculated based on a prior publication (Quian, Lancet Oncol 2021). The primary outcome was overall survival (OS), and secondary endpoints were time on treatment (TOT), time to next treatment (TNT), and overall response rate (ORR). The proportion of ICI430 as a continuous variable, and the dichotomized data (≥20% and ≥50%) were correlated with OS, TOT and TNT by Kaplan-Meier analysis and Cox regression, and with ORR by logistic regression. Results: Overall, 104 pts and 1763 inf were analyzed (Table). 48 pts were treated with 1st line (1L) ICI. 903 inf were administered (median 12 inf per pt, 1 - 111), 146 (15.6%) after 4:30 pm. 12 (25%) and 2 (4.2%) pts received ≥ 20% and ≥ 50% ICI430. Due to the small number of events (5 deaths and 15 progressions), of ICI430, and heterogeneity of treatments in 1L, we focus on pts treated with 2nd line (2L) ICI. 56 pts were treated with ICI in ≥2L. 860 inf were administered (median 8 inf per pt, 1 - 123), 180 (20.9%) after 4:30 pm. 15 (34.1%) and 9 (20.5%) pts received ≥20% and ≥50% ICI430. Pts who received ≥20% after 4:30pm, received fewer inf (7 vs. 16, p=0.022), had a worse TOT (4.3 vs. 9 m, HR 2.5, p=0.013), a trend to a worse TNT (6.3 vs. 10.5 m, HR 1.9, p=0.06) and a worse OS (16.9 vs. 56.1 m, HR 3.1, p=0.01). Similar results were obtained when using ≥ 50% ICI430 as the cut-off (TOT, 2 vs. 9m, p=0.007; TNT 4.7 vs. 10.5m, p=0.05; OS 16.9 vs. 36.6m, p=0.1), as well as higher frequency of progressive disease (85.7 vs. 21.9%, p=0.006). A significant association with OS (HR 1.02, p=0.03) was shown when analyzing ICI430 as a continuous variable, meaning a 16% increase in the risk of death for each 10% increment of ICI inf after 4:30 pm. Conclusions: Administration of ≥2L ICI after 4:30 pm is associated with poor overall survival. Our results could have a direct impact on pt survival and organization of outpatient clinics, but further research is needed. [Table: see text]

Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis

“…A pragmatic approach was used in five studies which selected 12:00, 39 12:54, 26 13:00, 30 , 31 , 37 or 14:00 32 as cut-off points corresponding to the median time of the per-patient median times of reported ICI infusions. The percentage of courses associated with a weaker ICI efficacy after the ToD ‘cut-off’ was 50% in one study 38 and 25% in another. 37 In two studies, ToD groups differed as a function of whether patients received one to four of the initial four ICI infusions before 12:00 or 13:00 versus all four initial infusions after 12:00 or 13:00.…”

“…The search found 16 studies, including 8 articles in peer-reviewed international journals 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 and 8 congress abstracts, which were presented as poster communications at major international congresses. 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Three abstracts were discarded because the data 40 were updated in a subsequently published article, 26 or detailed HR data were not reported. 34 , 35 All 13 retained study reports consisted of retrospective evaluations of ToD ICI administration effects.…”

“… 34 , 35 All 13 retained study reports consisted of retrospective evaluations of ToD ICI administration effects. They involved patients receiving ICIs for metastatic lung cancer, 26 , 27 , 28 , 36 , 39 malignant melanoma, 25 , 30 , 32 urothelial cancer, 33 renal cell carcinoma, 29 , 37 , 38 and esophageal carcinoma. 31 ICIs were anti-PD-1 and/or anti-PD-L1, which were combined with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) ipilimumab for some patients in five studies 25 , 29 , 30 , 32 , 37 ( Supplementary Figure S1 , available at https://doi.org/10.1016/j.esmoop.2023.102220 ).…”

“…The percentage of infusions administered after this threshold that was associated with a weak efficacy of ICIs also differed from 20% to 75% between studies. Most studies considered all the immunotherapy cycles, 25 , 26 , 27 , 28 , 29 , 31 , 33 , 36 , 37 , 38 but a few studies only considered the initial ones. 30 , 31 , 39 …”

“…The ToD ‘cut-off’ was 16:00 for one study 36 and 16:30 for six others. 25 , 27 , 28 , 29 , 33 , 38 For those seven studies, the early ToD groups consisted of patients receiving fewer than 20% of their ICI infusions after the cut-off time. The patients in the late ToD groups received at least 20% of their ICI infusions after that cut-off time.…”