Chronotherapy in metastatic melanoma: Retrospective outcomes of immunotherapy administration timing in a community practice.

Abstract

e21580 Background: Circadian rhythms influence immune cell trafficking and PD-1/PD-L1 signaling, suggesting a potential relationship between timing of immune checkpoint inhibitor (ICI) administration and therapeutic response. Although prior studies have reported improved outcomes with morning ICI administration, findings remain inconsistent. This study evaluates whether ICI infusion timing is associated with differences in clinical outcomes among patients with metastatic melanoma treated at a community oncology practice, providing real-world data on chronotherapy in routine care. Methods: A retrospective cohort study of 69 patients diagnosed between 2020 and 2025 with stage IV melanoma was conducted at the Cancer Center of Kansas. Patients were categorized based on timing of their treatments: AM (8:00–12:00) or PM (12:00–17:00). Baseline characteristics, comorbidities, melanoma subtype, and metastatic burden were compared using χ² and Mann–Whitney U tests. Survival outcomes, including progression-free survival (PFS) and time to next treatment (TTNT), were our primary endpoints. Kaplan–Meier estimates with log-rank testing and multivariable Cox proportional hazards models were performed adjusting for age, sex, ECOG performance status, BRAF mutation, and metastatic burden. Treatment-related toxicities (CTCAE v5.0) were analyzed by timing group. Results: Sixty-nine patients were included (AM: n=33; PM: n=36). Median age was higher in the AM group (75 vs. 66 years; p=0.04), while sex, BRAF mutation, and comorbidities were generally balanced. Cutaneous melanoma predominated (AM: 84.8%; PM: 97.1%). Median PFS was numerically longer in the AM group (30.0 vs. 25.5 months; log-rank p=0.859), as was median TTNT (29.0 vs. 14.3 months; p=0.752), though neither difference reached statistical significance. Toxicity rates were comparable (AM: 45.5% vs. PM: 33.3%; p=0.303). On multivariable Cox regression, ECOG PS (HR 5.72 for poor PS; p=0.005) and higher metastatic burden (≥4 sites: HR 9.5–13.0; p<0.01) remained dominant prognostic factors for shorter PFS, whereas infusion timing was not independently associated with outcome after adjustment. Conclusions: Despite biologically plausible circadian effects, morning ICI administration showed a numerical but not statistically significant improvement in PFS and TTNT in our modest-sized community-based cohort. These findings complement and partially contrast with selected prior studies reporting morning infusion advantages. A larger, ongoing multi-center study across additional practices in Kansas is currently expanding the sample size with the goal of improving statistical power and better defining the impact of chronotherapy on melanoma outcomes.