A multiregional, randomised, double-blind, placebo-controlled, phase III EMERALD-1 study reported positive results for its primary efficacy endpoint, with a significant improvement in progression-free survival (PFS) observed with durvalumab plus bevacizumab plus transarterial chemoembolisation (TACE) versus placebo plus TACE in patients with unresectable hepatocellular carcinoma (HCC). The findings were published by Prof. Bruno Sangro of the Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra and CIBEREHD in Pamplona, Spain and colleagues on 8 January 2025 in The Lancet.
A multicentre, randomised, double-blind, phase III LEAP-012 study met the primary endpoint, with a significant improvement in PFS for patients with unresectable, non-metastatic HCC, who received lenvatinib plus pembrolizumab with TACE compared to dual placebo plus TACE. The findings were reported by Prof. Josep M Llovet of the Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, USA and colleagues on 8 January 2025 in The Lancet.
The EMERALD-1 study
TACE is standard-of-care for patients with unresectable HCC that is amenable to embolisation; however, median PFS is still approximately 7 months. The phase III EMERALD-1 study was designed to assess the efficacy and safety of durvalumab with or without bevacizumab, in combination with TACE, in a global population of patients with unresectable HCC amenable to embolisation. Due to safety considerations, the study was designed to avoid concurrent bevacizumab and TACE; durvalumab was allowed with TACE, while bevacizumab was only started after completion of TACE. The study investigators reported the results from the final PFS analysis.
In EMERALD-1 study, the adult patients aged 18 years or older with unresectable HCC amenable to embolisation, an ECOG performance status of 0 or 1 at enrolment, and at least one measurable intrahepatic lesion per modified RECIST were enrolled at 157 medical sites including research centres and general and specialist hospitals in 18 countries. Eligible patients were randomly assigned 1:1:1, stratified by TACE method, region, and portal vein invasion to TACE plus either durvalumab plus bevacizumab, durvalumab plus placebo, or placebo alone. Patients, investigators, and those assessing outcomes were masked to treatment assignment until data analysis.
The primary endpoint was PFS by blinded independent central review (BICR), and per RECIST v1.1, with durvalumab plus bevacizumab versus placebo alone in the intention-to-treat population (ITT). Key secondary endpoints were PFS by BICR per RECIST v1.1 with durvalumab plus placebo versus placebo alone, overall survival (OS), and time to deterioration in select patient-reported outcomes (PROs). Patients continue to be followed-up for OS, and OS and PROs will be reported in a later publication. Safety was assessed in the safety analysis set, which included all patients assigned to treatment who received any study treatment. This study is closed to accrual.
Between 30 November 2018 and 19 July 2021, 887 patients were screened, of whom 204 were randomly assigned to durvalumab plus bevacizumab, 207 to durvalumab plus placebo, and 205 to placebo alone. Median age was 65.0 years (interquartile range, IQR 59.0–72.0), 135 of 616 patients (22%) were female, 481 (78%) were male, 375 (61%) were Asian, 176 (29%) were White, 22 (4%) were American Indian or Alaska Native, nine (1%) were Black or African American, one (<1%) was native Hawaiian or other Pacific Islander, and 33 (5%) were other races.
As of data cut-off on 11 September 2023, median follow-up for PFS was 27.9 months (95% confidence interval [CI] 27.4–30.4), median PFS was 15.0 months (95% CI 11.1–18.9) with durvalumab plus bevacizumab, 10.0 months (95% CI 9.0–12.7) with durvalumab, and 8.2 months (95% CI 6.9–11.1) with placebo. Hazard ratio (HR) for PFS was 0.77 (95% CI 0.61–0.98; two-sided p = 0.032) for durvalumab plus bevacizumab versus placebo, and 0.94 (0.75–1.19; two-sided p = 0.64) for durvalumab plus placebo versus placebo.
The most common maximum grade 3–4 adverse events were hypertension in patients who received durvalumab and bevacizumab (6%), anaemia in patients who received durvalumab and placebo (4%), and post-embolisation syndrome in patients who received placebo alone (4%). Study treatment-related adverse events that led to death occurred in none of 154 patients who received durvalumab and bevacizumab, three of 232 (1%) who received durvalumab and placebo (1 for arterial haemorrhage, liver injury, and multiple organ dysfunction syndrome), and three of 200 (2%) who received placebo alone (1 for oesophageal varices haemorrhage, upper gastrointestinal haemorrhage, and dermatomyositis).
With additional follow-up of the EMERALD-1 study, future analyses, including the final OS data and PROs, will help to further characterise the potential clinical benefits of durvalumab plus bevacizumab plus TACE in patients with HCC amenable to embolisation.
The LEAP-012 study
In LEAP-012 study, patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic HCC not amenable to curative treatment, but with tumours amenable to TACE, ECOG performance status of 0 or 1, and Child-Pugh class A disease. Eligible patients were randomly assigned 1:1, stratified by study site, alpha-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden to receive TACE and either oral lenvatinib plus intravenous pembrolizumab or matched dual placebo (oral and intravenous).
Primary endpoints were PFS (threshold one-sided p = 0.025) per RECIST v1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by BICR, and OS (threshold one-sided p = 0.0012) in the ITT population. Safety was assessed in the as-treated population. The study investigators reported results from the first interim analysis (final analysis for PFS). This study is active, but not recruiting.
Between 22 May 2020 and 11 January 2023, 847 patients were screened, of whom 480 (57%) were enrolled: 237 randomly assigned to receive TACE plus lenvatinib plus pembrolizumab and 243 to receive TACE plus dual placebo. Median age was 66 years (IQR 58–73), 82 of 480 patients (17%) were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native.
Median follow-up as of data cut-off on 30 January 2024 was 25.6 months (IQR 19.5–32.4). Median PFS was 14.6 months (95% CI 12.6–16.7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10.0 months (95% CI 8.1–12.2; 154 events [eight deaths and 146 progressions]) with placebo (HR 0.66, 95% CI 0.51–0.84; one-sided p = 0.0002).
A total of 69 of 237 patients (29%) in the lenvatinib plus pembrolizumab group and 82 of 243 (34%) from the placebo group died, with a 24-month OS rate of 75% (95% CI 68–80) in the lenvatinib plus pembrolizumab group and 69% (95% CI 62–74) in the placebo group (HR 0.80, 95% CI 0.57–1.11; one-sided p = 0.087).
Grade 3 or worse treatment-related adverse events occurred in 169 of 237 patients (71%) in the lenvatinib plus pembrolizumab group and in 76 of 241 (32%) in the placebo group, the most common of which were hypertension (24% versus 7%) and platelet count decreased (11% versus 6%). Deaths due to treatment-related adverse events occurred in four (2%) patients in the lenvatinib plus pembrolizumab group (1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage).
The study investigators concluded that TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in PFS in patients with unresectable, non-metastatic HCC compared with TACE plus placebo. The numerical improvement in OS is encouraging, but longer follow-up is necessary.
In an accompanied comment, Drs. Florian P Reiter and Andreas Geier of the Division of Hepatology, Department of Medicine II, University Hospital Würzburg in Würzburg, Germany wrote that in the era of rapidly evolving therapies for HCC, the association between OS and specific study treatments is particularly susceptible to confounding factors, including multi-stage treatment strategies, post-progression therapies, and therapy crossovers. These factors further underscore the appropriateness of PFS as a primary endpoint.
They postulated that the results of both studies could have practice-changing effects. As a result of these findings, clinicians could introduce immune checkpoint inhibitor therapy combinations at earlier stages, when they might enhance tumour control with a lower symptom burden compared with their current use in more advanced stages with a higher symptom load.
These encouraging results not only offer new opportunities for patients with early-stage HCC, but also raise important questions about how to proceed with systemic therapy after progression to an advanced stage under early immune checkpoint inhibitor-based and TACE-based combination therapies. Considering these results, future research might need to acknowledge that immune checkpoint inhibitor-based systemic therapy could, from now on, become part of the treatment for patients with HCC that is amenable to TACE according to the commentators.
The EMERALD-1 study was funded by AstraZeneca.
The LEAP-012 study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.
References
- Sangro B, Kudo M, Erinjeri JP, et al. on behalf of the EMERALD-1 Investigators. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. The Lancet; Published online 8 January 2025. DOI: https://doi.org/10.1016/ S0140-6736(24)02551-0
- Kudo M, Ren Z, Guo Y, et al. and the LEAP-012 investigators. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. The Lancet; Published online 8 January 2025. DOI: https://doi.org/10.1016/ S0140-6736(24)02575-3
- Reiter FP, Geier A. TACE plus immune checkpoint inhibitor-based systemic therapies for hepatocellular carcinoma. The Lancet; Published online 8 January 2025. DOI: https://doi.org/10.1016/S0140-6736(24)02680-1