Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma

Background and aims Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systemic therapies for unresectable hepatocellular carcinoma (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching (PSM). The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p =0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p =0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p =0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p =0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p =0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p =0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT ( p =0.049) or TKIs-combined ( p =0.005) was also detected in term of PFS. Post progression treatment significantly improved PPS in both groups. The incidence of TRAEs was comparable between two groups. Conclusions The addition of TACE to ICI+TKI combination therapy did not result in a substantial improvement in efficacy and prognosis of patients. However, in selected uHCC patients (without preLRT or treated with lenvatinib as combination), ICI+TKI+TACE triple therapy may remarkably improve PFS.