Impact of time-of-day atezolizumab plus bevacizumab combination therapy infusion for unresectable hepatocellular carcinoma: A retrospective multicenter study

Aim: This study aimed to evaluate the impact of infusion timing of time-of-day on clinical outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab combination therapy. Methods: A retrospective analysis was conducted using data from 751 unresectable HCC patients treated with atezolizumab plus bevacizumab between September 2020 and April 2024. Patients were categorized into morning (AM; n = 351) and afternoon (PM; n = 400) groups based on infusion timing of time-of-day. Outcomes, including progression-free survival (PFS), overall survival, objective response rate, and disease control rate, were assessed using Kaplan–Meier survival analysis and Cox regression analysis. Results: The PFS was significantly longer in the AM group (8.6 months, 95% CI 7.6–10.5) compared with the PM group (6.0 months, 95% CI 5.4–7.0; p = 0.006). In contrast, overall survival was similar between the groups (AM: 24.7 months vs. PM: 21.4 months; p = 0.99). Cox regression analysis revealed that morning infusion was an independent favorable predictor of PFS (HR 1.23, 95% CI 1.04–1.45). Additionally, the AM group demonstrated superior objective response rate and disease control rate compared with the PM group, suggesting better tumor control. Conclusion: Morning infusion of atezolizumab plus bevacizumab is associated with improved PFS and response rates in unresectable HCC patients, highlighting the potential for optimizing treatment outcomes through circadian timing.