Systemic therapy sequence and outcomes in unresectable hepatocellular carcinoma: results from the multicenter Tokai...

To clarify the optimal sequencing strategy of systemic therapies for unresectable hepatocellular carcinoma that maximizes efficacy and patient outcomes.

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.

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%).

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.