Efficacy and Safety of Second‐Line Lenvatinib After First‐Line Durvalumab Plus Tremelimumab in Unresectable Hepatocellular Carcinoma

BACKGROUND: There is a paucity of data regarding the efficacy and safety of lenvatinib as a second-line treatment following first-line combination immunotherapy with durvalumab and tremelimumab (Dur + Tre). METHODS: This retrospective multicenter study included 14 patients with unresectable hepatocellular carcinoma who received lenvatinib after progression on Dur + Tre therapy, conducted at five institutions, including Hiroshima University. In cases where the multidisciplinary team determined that concurrent transcatheter arterial chemoembolization (TACE) would be beneficial, on-demand TACE was administered concomitantly with lenvatinib. The therapeutic response and safety profile of lenvatinib were evaluated in all enrolled patients, including those who underwent TACE. RESULTS: The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) for Dur + Tre and subsequent lenvatinib treatment were 14.3%/30.7%, 57.1%/61.5%, and 2.4/2.3 months, respectively. Five patients (35.7%) received combined lenvatinib and TACE therapy. Among these, one patient each with stable disease (SD) and progressive disease (PD) on Dur + Tre improved to partial response (PR) during lenvatinib therapy. Two patients (14.3%) remained on lenvatinib at the time of analysis. Six patients (42.9%) transitioned to subsequent lines of systemic therapy, all receiving atezolizumab combined with bevacizumab. Overall, five patients (35.7%) had died at the data cutoff, with a median overall survival (OS) of 18.4 months. Grade 3 or higher adverse events (AEs) were observed in 7 patients (50%) across both Dur + Tre and lenvatinib treatment phases. CONCLUSIONS: Lenvatinib administered after progression on Dur + Tre demonstrates promising efficacy and an acceptable safety profile in patients who tolerate the therapy. The integration of TACE in suitable candidates warrants further exploration, and timely transition to subsequent systemic therapies should be considered when adverse events or intolerance are encountered.