HILL: the efficacy and safety of hepatic arterial infusion chemotherapy with the FOLFOX regimen combined with lenvatinib and the PD-L1 inhibitor durvalumab in unresectable hepatocellular carcinoma: a prospective, single-arm, phase 2 clinical trial.

Despite numerous available treatment options, the overall prognosis for patients with unresectable hepatocellular carcinoma (uHCC) remains poor. This study aimed to evaluate the efficacy and safety of combining hepatic arterial infusion chemotherapy with FOLFOX (FOLFOX-HAIC), lenvatinib, and the PD-L1 inhibitor durvalumab in this population, with all uHCC patients receiving the triple-combination regimen as initial therapy. The primary objective was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From August 2021 to September 2023, 40 uHCC patients were enrolled, with a median follow-up of 23.1 months (95% confidence interval [CI], 19.0-23.8); 3 deaths and 12 disease progressions were recorded. The median PFS was 15.8 months (95% CI, 8.3-23.3) with a 6-month PFS rate of 77.5% (95% CI, 63-90%), and 1- and 2-year OS rates were 97.5% and 94.0%, respectively. Per modified RECIST criteria, ORR was 75.0% (9 CR/pCR, 21 PR) and DCR was 95.0% (8 SD); median time to response (TTR) was 2.2 months and median duration of response (DOR) was 10.4 months. Seven patients (17.5%) underwent R0 conversion surgery, 3 (42.9%) achieving pCR. Safety was favorable: 85.0% had grade 1-2 adverse events, with grade 3 elevated alanine aminotransferase and thrombocytopenia each occurring in 2 patients (5.0%). No grade 4 adverse events were observed. Collectively, the triple-combination therapy of FOLFOX-HAIC, lenvatinib, and durvalumab exhibits promising therapeutic efficacy, favorable disease control, and a well-tolerated safety profile, providing a potential new treatment option for patients with uHCC. Trial number: NCT04961918.