Impact of LEAP-012 and EMERALD-1 in the management of HCC

The introduction of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) has spurred interest in evaluating their use in earlier lines of therapy, including in combination with locoregional therapy for patients with intermediate-stage disease. Transarterial chemoembolisation (TACE) is believed to increase neoantigen release and local tumour PD-L1 expression, suggesting the potential for enhanced antitumour responses if combined with ICIs. The EMERALD-1 trial randomised 616 patients with Child-Pugh A-B7 and localised HCC (including 6-8% with Vp1-Vp2 vascular invasion) to durvalumab plus bevacizumab plus TACE, durvalumab plus placebo plus TACE, and placebo plus TACE. The primary endpoint, progression-free survival, was significantly longer with durvalumab plus bevacizumab plus TACE vs. TACE alone (hazard ratio [HR] 0.77, 95% CI 0.61-0.98) but not durvalumab plus TACE vs. TACE alone (HR 0.94, 95% CI 0.75-1.19). The LEAP-012 trial randomised 480 patients with Child-Pugh A and liver-localised HCC to lenvatinib plus pembrolizumab plus TACE vs. placebos plus TACE. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab plus TACE vs. TACE alone (HR 0.66, 95% CI 0.51-0.84). Both trials demonstrated increased grade 3-4 treatment-related adverse events in the combination vs. TACE alone arms, including those resulting in treatment discontinuation. Early data from LEAP-012 suggested a trend toward overall survival benefit (HR 0.80, 95% CI 0.57-1.11), although this failed to achieve statistical significance on follow-up analyses. Neither trial has yet reported on other outcomes, including quality of life. Clinicians should emphasise individualised patient selection when deciding between TACE plus ICI vs. TACE alone in patients with HCC eligible for locoregional therapy.