Association of immune checkpoint inhibitor administration timing with toxicity and survival in uterine cancer: A real-world analysis.

Abstract

e17640 Background: Evolving data suggest the time of day (ToD) of immune checkpoint inhibitor (ICI) administration may influence toxicity and efficacy, with potentially greater effects in older adults and women. However, data in specific cancer populations, including uterine cancer (UC), remain limited. We evaluated associations between ToD of ICI administration and toxicity and survival outcomes in patients with UC. Methods: We conducted a retrospective cohort study of patients with UC treated with intravenous ICIs, with first dose administered between January 1, 2020, and November 10, 2025, within a statewide health system. Patients who received at least two ICI infusions were categorized as early (>50% of the first four infusions before 1 PM) or late (≤50% before 1 PM). The primary outcome was steroid-requiring immune-related adverse events (SRirAEs). Secondary outcomes included real-world progression-free survival (rwPFS), real-world overall survival (rwOS), and subgroup analyses based on population demographics. Survival was estimated using Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). This study was approved by the IRB of the University of North Carolina. Results: A total of 290 patients were included (186 early, 104 late). Baseline demographics were notable for: 42% endometrioid carcinoma, 90% stage III/IV disease, 97% pembrolizumab use, 52% receipt of ICI with chemotherapy, and 28% dMMR tumors. SRirAEs occurred less frequently in the early compared with the late group (16% vs 33%, p=0.001). No significant differences were observed in rwPFS (14.4 vs 15.6 mos; HR 1.02, 95% CI 0.74-1.41) or rwOS (42 vs 35 mos; HR 1.04, 95% CI 0.70-1.54). No differences in SRirAE rates or efficacy outcomes were observed based on MMR status or concurrent therapy (ICI monotherapy, chemotherapy, or lenvatinib). To further evaluate the increased SRirAE rate noted with later ICI administration, we completed a subgroup analysis of patients who received their first four infusions all before or all after 1 PM (n=132; 108 early, 24 late). Using this criterion, similar SRirAE rates were observed between groups (18% early vs 21% late, p=0.71), with no significant differences in rwPFS (26.7 vs 15.7 mos; HR 0.70, 95% CI 0.38-1.28) or rwOS (not reached vs 35.0 mos; HR 0.62, 95% CI 0.29-1.30). Conclusions: In patients with UC treated with ICIs, receipt of >50% of the first four infusions before 1 PM was associated with lower rates of SRirAEs, but this association varied depending on the time cutoff and number of infusions given around that cutoff. A specific time cutoff that may be predictive of ICI efficacy and toxicity remains unclear. These findings emphasize the need to evaluate toxicity in addition to efficacy in future prospective studies to optimize timing of ICI therapy.