For Unresectable Liver Cancer, the Addition of Durvalumab and Bevacizumab Boosts Efficacy of Transarterial Chemoembolization

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Patients with unresectable hepatocellular carcinoma derived significant benefit from the addition of the monoclonal antibody durvalumab and the angiogenesis inhibitor bevacizumab to transarterial chemoembolization (TACE), which alone has been a standard of care for 20 years. Investigators of the phase III randomized EMERALD-1 trial reported these results at the 2024 ASCO Gastrointestinal Cancers Symposium.1

“The EMERALD-1 trial met the primary endpoint. It is the first global phase III study to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival with an immunotherapy and TACE–based regimen in unresectable hepatocellular carcinoma eligible for embolization,” said Riccardo Lencioni, MD, of the University of Pisa School of Medicine in Italy. “Durvalumab plus bevacizumab in combination with TACE has the potential to set a new standard of care.”

Riccardo Lencioni, MD

Riccardo Lencioni, MD

Median progression-free survival was nearly doubled for patients receiving durvalumab plus bevacizumab in addition to TACE: 15.0 months vs 8.2 months with TACE plus placebo (hazard ratio [HR] = 0.77; P = .032). Patients who received durvalumab alone had a median progression-free survival of 10.0 months (HR = 0.94; P = .638), a nonsignificant difference from the placebo arm.

As background, Dr. Lencioni explained that with TACE alone, median progression-free survival is typically no more than 8 months, “representing a large unmet need.” It is believed that TACE may prime the tumor microenvironment, so immunotherapy and agents targeting the vascular endothelial growth factor (VEGF) might trigger neoantigen release and ischemia. “Immunotherapy plus anti-VEGF therapy plus TACE is hypothesized to induce enhanced antitumor activity via immune activation and inhibition of tumor neovascularization,” he said.


EMERALD-1 involved 616 patients with unresectable hepatocellular carcinoma, no extrahepatic disease, and Child-Pugh score A-B7, with baseline characteristics generally well balanced. Participants were randomly assigned to three groups: durvalumab plus TACE followed by durvalumab and placebo; durvalumab plus TACE followed by durvalumab and bevacizumab; or placebo plus TACE followed by placebo.

Patients underwent one to four TACE procedures within 16 weeks, at the investigator’s discretion. Durvalumab was given at week 1 of TACE and every 4 weeks during the TACE period; combination treatment, which was administered every 3 weeks, began after the final TACE, at a median of about 3 months from the start of TACE. The primary endpoint was progression-free survival for the comparison of durvalumab, bevacizumab, and TACE vs placebo and TACE.

Significant Findings and Toxicity

There was a 6.8-month absolute difference in progression-free survival favoring durvalumab, bevacizumab, and TACE vs TACE alone (P = .032). The landmark analysis favored the combination therapy at 12 months (55.5% vs 39.8%) and at 18 months (43.1% vs 28.3%), with benefits generally consistent across key clinical subgroups, Dr. Lencioni reported.

Median time to disease progression more than doubled with durvalumab, bevacizumab, plus TACE (22 months) vs placebo plus TACE (10 months), a 37% reduction in risk (HR = 0.63). Durvalu-mab plus TACE led to a numerically longer time to disease progression (11.5 months), but this did not substantially differ from the control arm (10 months; HR = 0.89). Overall survival was not statistically significant at the interim analysis.

“Overall response rate by blinded independent review was improved with both durvalumab, bevacizumab, and TACE and with durvalumab plus TACE,” Dr. Lencioni said. Rates (and odds ratios vs the placebo arm) were 43.6% with durvalumab, bevacizumab, and TACE (odds ratio = 1.87), 41.0% with durvalumab plus TACE (odds ratio = 1.67), and 29.6% with TACE alone.

Adverse events were reported in a similar proportion of patients across the groups. Grade 3 or 4 toxicities possibly related to treatment occurred in 26.6% of those given durvalumab, bevacizumab, and TACE and about 6% of patients in both other arms. Adverse events were more likely to lead to study discontinuation with the combination (24.7%) than with durvalumab plus TACE (12.1%) or TACE alone (7.0%). 

DISCLOSURE: Dr. Lencioni has received research support from and has served as a consultant for AstraZeneca.


1. Lencioni R, Kudo M, Erinjeri J, et al: EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract LBA432. Presented January 19, 2024.



EMERALD-1’s invited discussant was Josep M. Llovet, MD, PhD, founder and Director of the Liver Cancer Program and Professor of Medicine at Mount Sinai School of Medicine, and Professor of Research–ICREA in the Liver Unit, IDIBAPS–Hospital Clínic, University of Barcelona. He first provided some background to EMERALD-1, noting transarterial chemoembolization (TACE) has long been the standard of care for managing intermediate-stage hepatocellular carcinoma, based on a meta-analysis conducted 20 years ago.1

Josep M. Llovet, MD, PhD

Josep M. Llovet, MD, PhD

More recently, researchers have hypothesized that the addition of immunotherapy or targeted therapy might increase benefit; however, a series of randomized trials conducted between 2009 and 2019 found no value in adding tyrosine kinase inhibitors, in particular, sorafenib. “These trials were useful, however, in providing the modern outcomes for TACE—showing median survival of about 26 to 30 months, median progression-free survival of 7 to 8 months, and objective response rates of 45% to 55,” Dr. Llovet said.

Progression-Free Survival: A Reliable Surrogate of Overall Survival?

EMERALD-1 is the first trial to be reported among several ongoing trials evaluating immunotherapy plus agents targeting vascular endothelial growth factor (anti-VEGF) vs TACE alone. The inclusion criteria were “classic” for intermediate-stage hepatocellular carcinoma, but the study also enrolled patients with macrovascular invasion, a sign of more advanced disease, he noted. The median progression-free survival, 15.0 months with the combination vs 8.2 months with TACE alone, and the objective response rates of 43% vs 29% “align well” with expectations for this population, he said.

However, the question is whether progression-free survival is “a reliable surrogate” of overall survival in intermediate-stage hepatocellular carcinoma, “which we have been debating for the past decade,” Dr. Llovet emphasized.

An analysis of 27 phase III randomized trials in advanced hepatocellular carcinoma showed that the minimum threshold for surrogacy with progression-free survival is a hazard ratio (HR) < 0.60.2 This was not met in EMERALD-1, whose absolute difference in progression-free survival produced a hazard ratio of 0.77.

“In fact, all of the trials with hazard ratios below 0.6 have resulted in positive results in overall survival. Conversely, if the hazard ratio is above that, it is uncertain whether the trial will be positive or negative in terms of survival,” noted Dr. Llovet.

Despite the question of progression-free survival as a surrogate for overall survival, and the difficulty of capturing survival differences with patients exposed to additional lines of therapy, Dr. Llovet concluded: “EMERALD-1 is the first trial, well designed, that is positive for progression-free survival in 20 years. Bevacizumab has an important role in combination with immunotherapies in hepatocellular carcinoma. The implication is that durvalumab plus bevacizumab plus TACE may become the standard of care in intermediate-stage hepatocellular carcinoma.” 

DISCLOSURE: Dr. Llovet disclosed relationships with Eisai, Merck, Roche, Genentech, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Moderna, Glycotest, Exelixis, Sagimet, Boston Scientific, and Omega Therapeutics.


1. Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37:429-442, 2003.

2. Llovet JM, Villanueva A, Marrero JA, et al: Trial design and endpoints in hepatocellular carcinoma: AASLD Consensus Conference. Hepatology 73(suppl 1):158-191, 2021.