Multicenter single-arm phase II trial of lenvatinib in patients with advanced hepatocellular carcinoma after progression on first-line atezolizumab plus bevacizumab

Abstract

Background & aims: Atezolizumab plus bevacizumab (atezo-bev) is the global standard first-line therapy for unresectable hepatocellular carcinoma (uHCC). However, most patients eventually experience disease progression and optimal second-line strategies after atezo-bev failure remain unclear. Prospective evidence supporting multikinase inhibitors in this context is limited. Methods: This investigator-initiated, multicenter, single-arm study (KCSG HB23-04) enrolled 50 patients with uHCC who progressed after first-line atezo-bev across 13 sites between August 2023 and May 2024. Patients received second-line lenvatinib at 12 mg or 8 mg daily, depending on body weight, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate, disease control rate, duration of response, and safety. Results: Of the 50 patients enrolled, the median age was 66 years, and 72% had a viral etiology. The median time to progression with atezo-bev was 6.5 months. During a median follow-up of 12.6 months, the median progression-free survival was 5.4 months (95% CI 4.2-7.1) (>4.5 months), meeting the prespecified primary endpoint. Median overall survival was 9.8 months (95% CI 8.1-NR). The objective response rate was 14.0%, and the disease control rate was 82.0%. The median duration of response was 9.4 months. Survival outcomes were different according to the objective response with lenvatinib, but not by time to progression on atezo-bev or HCC etiology. The most common adverse events were diarrhea (42.0%), hypothyroidism (32.0%), and anorexia (30.0%). Grade >= 3 adverse events occurred in 46.0% of patients. Conclusions: Lenvatinib demonstrated promising efficacy and a manageable safety profile as a second-line treatment for patients with HCC progressing on atezo-bev. These findings offer prospective evidence supporting lenvatinib as a viable treatment option in the post-atezo-bev context. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).