Beating the clock: Immunotherapy timing, early immune modulation, and clinical outcomes in hepatocellular carcinoma.

Abstract

322 Background: Circadian regulation of immune function is closely linked to hepatic physiology and may influence response to immune checkpoint inhibitors (ICIs). Whether the timing of ICI administration affects early systemic immune modulation and clinical outcomes in hepatocellular carcinoma (HCC) remains unclear. Methods: We conducted a prospective observational study of patients with advanced HCC treated with ICIs. Based on infusion records, treatment timing was categorized as morning (08:00–11:59) or non-morning (≥12:00) administration. Neutrophil–lymphocyte ratio (NLR) was assessed at baseline and prior to cycle 2. Early immune modulation was defined as a directional decrease in NLR. Associations between infusion timing and early NLR change were evaluated using Fisher’s exact test. Progression-free survival (PFS) was estimated using the Kaplan–Meier method and compared using the log-rank test. Results: A total of 42 patients were included; 24 (57%) received morning infusions and 18 (43%) received non-morning infusions. An early decrease in NLR was observed in 25 patients (60%). Early NLR decrease was more frequently observed among patients receiving morning ICI administration compared with non-morning administration (75% vs 39%; p = 0.027). Progression-free survival was significantly longer in patients demonstrating early NLR decrease (Group 1) compared with those without early NLR decrease (Group 2). Median PFS was 402 days (13.2 months; 95% CI 187–NR) in Group 1 versus 125 days (4.0 months; 95% CI 77–197) in Group 2. Kaplan–Meier analysis demonstrated a significant difference in PFS between the two groups (log-rank p = 0.00054). The 12-month PFS rate was 50.1% in Group 1 compared with 11.8% in Group 2. Conclusions: In this observational cohort of patients with hepatocellular carcinoma treated with immune checkpoint inhibitors, early favorable modulation of neutrophil–lymphocyte ratio was strongly associated with prolonged progression-free survival. Morning administration of immunotherapy was associated with a higher likelihood of early NLR decrease. These findings describe a clinically relevant association between immunotherapy timing, early immune biomarker dynamics, and outcomes, and support prospective evaluation of chronotherapy-informed immunotherapy strategies in HCC.