Multicenter 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. Impact and implications: This study provides the first prospective evidence for the use of lenvatinib as a second-line therapy for patients with unresectable hepatocellular carcinoma who have progressed after first-line atezo-bev treatment. The findings highlight the potential of lenvatinib as a viable therapeutic option in a clinical setting where few alternatives are available. The results are particularly important for healthcare professionals managing unresectable hepatocellular carcinoma, as they provide a robust framework for considering lenvatinib in second-line treatment protocols. Given the manageable safety profile, these findings could be translated into practical recommendations for clinical practice, offering physicians a treatment strategy to improve patient outcomes following atezo-bev failure while guiding future research into combination therapies and broader patient populations. Clinical trial number: NCT06138769.