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

Sep 29, 2026

Immune checkpoint inhibitors have driven interest in earlier use for hepatocellular carcinoma (HCC), particularly when combined with locoregional therapy. The EMERALD-1 trial randomized 616 patients to durvalumab plus bevacizumab plus TACE, durvalumab plus placebo plus TACE, or placebo plus TACE, improving progression-free survival versus TACE alone. The LEAP-012 trial likewise showed longer progression-free survival with lenvatinib plus pembrolizumab plus TACE versus TACE alone. Both combinations increased grade 3–4 treatment-related adverse events, and overall survival data remain immature.

LanguageEnglish

CategoryHealthcare

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Pages9

Reading Time23 min

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Introduction

Current management of intermediate-stage HCC

Keypoints

Review Impact of LEAP-012 and EMERALD-1 in the management of HCC Amit G. Singal1 ,* ,†, Kirema Garcia-Reyes2 ,†, Robin K. Kelley3 ,‡, Edward Kim2 ,‡ Summary 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. © 2025 The Author(s) . Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL) . This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). Introduction Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally and one of the few cancers with a 5-year survival rate that has remained below 20% .1 Although patients with early-stage HCC can achieve a median survival exceeding 10 years with curative-intent therapies, patients with larger tumour burden are treated with palliative therapies and have a median survival of 2-3 years.2 Transarterial therapies including chemoembolisation (TACE) and radioembolisation (TARE) are the recommended therapies for most patients with intermediate-stage HCC that is too extensive for curative therapies.3 ,4 Recent advances in treatment options, particularly the introduction of immune checkpoint inhibitors (ICIs), have significantly improved prognosis for patients with advancedstage HCC.5 Activity in advanced stages of HCC has spurred interest in evaluating ICIs in earlier lines of therapy, including inpatients with intermediate-stage disease. Herein, we review results of the LEAP-012 and EMERALD-1 trials evaluating the combination of ICIs with TACE and discuss how these results can be applied to the management of patients with intermediate-stage HCC. Current management of intermediate-stage HCC The management of intermediate-stage HCC has evolved to incorporate interventional techniques aimed at improving patient outcomes.6 TACE has demonstrated safety and efficacy in treating HCC, with improved overall survival (OS) compared to best supportive care.7 ,8 Based on small randomised controlled trials (RCTs) and meta-analyses, TACE has been a mainstay of therapy for patients who are not candidates for surgical resection or ablation for over two decades and is includ

FAQs

What did the EMERALD-1 trial show about progression-free survival in HCC?

Durvalumab plus bevacizumab plus TACE significantly prolonged progression-free survival versus TACE alone, with a hazard ratio of 0.77 (95% CI 0.61–0.98). Durvalumab plus TACE did not show the same significant benefit versus TACE alone.

What did the LEAP-012 trial demonstrate for patients receiving locoregional therapy?

Lenvatinib plus pembrolizumab plus TACE significantly improved progression-free survival compared with TACE alone, with a hazard ratio of 0.66 (95% CI 0.51–0.84).

How do the trials compare on safety and overall survival data?

Both trials reported increased grade 3–4 treatment-related adverse events in combination arms versus TACE alone, including events leading to treatment discontinuation. Overall survival data are immature and the follow-up analyses did not achieve statistical significance for a survival benefit versus TACE alone.

Sep 29, 2026

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