The study aims to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immune checkpoint inhibitors (ICIs) versus lenvatinib and ICIs for hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) refractoriness.

Patients with intermediate or advanced TACE‐refractory HCC who received lenvatinib and ICIs with or without HAIC between 2020 and 2022 were retrospectively reviewed. The tumor response, overall survival (OS), progression‐free survival (PFS), and treatment‐related adverse events (TRAEs) were evaluated and compared between the two groups. Factors affecting OS and PFS were identified with univariate and multivariate Cox regression analyses.

A total of 121 patients were enrolled, with 58 patients assigned to the HAIC‐Len‐ICI group and 63 patients assigned to the Len‐ICI group. A higher objective response rate and disease control rate were found in the HAIC‐Len‐ICI group than in the Len‐ICI group (48.30% vs 23.80%, P = 0.005; 87.90% vs 69.80%, P = 0.02, respectively). The median OS was 24.0 months in the HAIC‐Len‐ICI group and 13.0 months in the Len‐ICI group (P = 0.001). The median PFS was 13.0 months in the HAIC‐Len‐ICI group and 7.2 months in the Len‐ICI group (P < 0.001). Multivariable analyses suggested that the presence of cirrhosis, Child–Pugh B stage, and HAIC‐Len‐ICI therapy option were prognostic factors for OS and PFS. The incidences of any grade and grade 3/4 TRAEs were both comparable between the two groups.

HAIC combined with lenvatinib and ICIs yielded better OS, PFS, ORR, and DCR than lenvatinib‐ICI therapy in patients with HCC refractory to TACE, with manageable adverse events.