Response-focused analyses of the impact of circadian rhythm on efficacy of first-line immunotherapy in melanoma.

Abstract

9520 Background: Several retrospective studies have associated better clinical outcomes with morning infusions of immune-checkpoint inhibitors (ICI), attributing the same to circadian differences in T-cell activity. However, these studies have largely focused on survival endpoints, which are susceptible to confounding by skewed cohort distributions, treatment heterogeneity or other unknown variables. In this study, we explore the impact of timing of ICI infusions by primarily focusing on objective response as a more direct and immediate measure of immunologic activity, and possibly less susceptible to confounding variables. Methods: We conducted a single center, retrospective study of patients with advanced melanoma with response-evaluable disease and treated with an ICI regimen in the first-line setting. We recorded baseline patient and tumor characteristics and the start time of the first ICI infusion. Based on the median start time (~1:00 PM) of all ICI infusions in our clinic, we classified patients into “Early” (before 1:00 PM) and “Late” cohorts (1:00 PM & after). We analyzed objective response rate (ORR) per RECIST v1.1, time-to-response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS), comparing endpoints between cohorts using logistic or Cox regression, with adjustments for variables including age, sex, ECOG score, and disease stage. Results: We identified 216 eligible patients treated between 2014 - 2025, including 78 in the Early cohort and 138 in the Late cohort. Median age was 64 years (range 19 - 95) and 69% were male. Median follow-up duration was 27 months (range 6 days - 12 years). There were no significant differences in baseline patient and tumor characteristics between the two cohorts. ORR for the Early cohort was 64.1% (50/78; complete response [CR] - 34.6%, partial response [PR] - 29.5%) and for the Late cohort was 61.6% (85/138; CR - 28.3%, PR - 33.3%) [p = 0.71]. There were no significant differences in TTR and DOR between the cohorts. The distribution of first ICI infusion start-time in the responders mirrored that of all ICI infusions in all patients with melanoma. Adjusted PFS and OS were also similar between the cohorts (see Table). Conclusions: Our response-focused analyses do not suggest an association of early timing of ICI infusion to better efficacy outcomes, in contrast to findings from other studies. Our findings are consistent with the known long terminal half-life of ICI agents, which should provide steady availability of ICI antibodies to immune cells throughout the day. Our results do not support implementing time-based ICI infusion strategies in the oncology clinics. Endpoint Early cohort Late cohort Hazard ratio (95% CI) P-value PFS, Median months (95% CI) 12 (9, NR) 16 (9, 28) 1.01 (0.68, 1.50) 0.97 OS, Median months (95% CI) 82 (66, NR) 88 (62, NR) 1.07 (0.61, 1.89) 0.82 CI = Confidence interval; NR = Not reached.