Systemic therapy sequence and outcomes in unresectable hepatocellular carcinoma: results from the multicenter Tokai Post ICI Sequential Therapy Registry cohort

Aim To clarify the optimal sequencing strategy of systemic therapies for unresectable hepatocellular carcinoma that maximizes efficacy and patient outcomes. Methods We established a multicenter retrospective Tokai Post ICI Sequential Therapy Registry cohort across four Tertiary-Care Hospitals in Japan, enrolling patients who received first-line immune checkpoint inhibitor (ICI)-based therapy between October 2020 and May 2025. Tumor response was assessed every 2–3 months by Response Evaluation Criteria in Solid Tumors version1.1 as the primary outcome. Logistic regression models evaluated predictors of response with hospital-level mixed effects. Results A total of 368 patients were included [median age 74 years (interquartile range: 68–80 years); 303 (82%) male]; 307 (83.4%) received atezolizumab plus bevacizumab and 61 (16.6%) durvalumab plus tremelimumab. Following discontinuation, 151 (47.0%) proceeded to second-line therapy, predominantly lenvatinib ( n = 124, 82%). Second-line lenvatinib achieved objective response rates of 12–25% and disease control rates (DCRs) exceeding 60%, independent of prior ICI regimen or response. Of 56 patients receiving third-line therapy, the sequences of atezolizumab plus bevacizumab–lenvatinib–durvalumab plus tremelimumab and durvalumab plus tremelimumab–lenvatinib–atezolizumab plus bevacizumab ( n = 19, 28.6%) demonstrated significantly higher DCR compared with other sequences (52.6 vs. 29.7%) despite comparable liver function reserve and tumor burden. In addition, durvalumab plus tremelimumab following atezolizumab plus bevacizumab–lenvatinib showed numerically higher DCR compared with durvalumab plus tremelimumab directly after atezolizumab plus bevacizumab (53.3 vs. 29.4%). Conclusion Consistent efficacy of second-line lenvatinib and favorable outcomes with ICI–lenvatinib–ICI sequences may underscore the clinical importance of therapy sequencing in advanced hepatocellular carcinoma, warranting prospective evaluation of optimal strategies.