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

Abstract 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 chemoembolization (TACE) is believed to increase neoantigen release and local tumor PD-L1 expression, suggesting potential for increased anti-tumor responses if combined with ICIs. The EMERALD-1 Trial randomized 616 patients with Child Pugh A-B7 and localized HCC (including 6-8% with Vp1-Vp2 vascular invasion) to durvalumab plus bevacizumab plus TACE, durvalumab plus placebo plus TACE, and placebos plus TACE. The primary endpoint, progression-free survival (PFS), was significantly longer with durvalumab plus bevacizumab plus TACE versus TACE alone (HR 0.77, 95%CI 0.61 – 0.98) but not durvalumab plus TACE versus TACE alone (HR 0.94, 95%CI 0.75 – 1.19). The LEAP-012 Trial randomized 480 patients with Child Pugh A and liver-localized HCC to lenvatinib plus pembrolizumab plus TACE versus placebos plus TACE. PFS was significantly longer with lenvatinib plus pembrolizumab plus TACE arm versus 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 arms versus TACE alone, including those leading to treatment discontinuation. Early data from LEAP-012 suggested a trend toward overall survival benefit (HR 0.80, 95%CI 0.57 – 1.11), although data from both trials are immature. Both trials have not yet reported other outcomes including quality of life. Clinicians should emphasize individualized patient selection when deciding between TACE plus ICI versus TACE alone in HCC patients eligible for locoregional therapy.