A large phase 3 clinical trial has found that adding immunotherapy and anti-angiogenic therapy to standard transarterial chemoembolization (TACE) significantly improves progression-free survival in patients with unresectable hepatocellular carcinoma. The EMERALD-1 study, published on January 8, 2025 in The Lancet, evaluated the efficacy and safety of combining durvalumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) with TACE compared to TACE alone.
This multicenter, randomized, double-blind, placebo-controlled study was conducted at 157 sites across 18 countries. Funded by AstraZeneca, EMERALD-1 enrolled 616 adult patients with unresectable hepatocellular carcinoma that was amenable to embolization but not eligible for curative therapies like resection, ablation, or transplantation. Patients were required to have Child-Pugh A-B7 liver function, ECOG performance status of 0-1, and at least one measurable intrahepatic lesion. Those with major portal vein thrombosis or previous systemic therapy were excluded.
Participants were randomized 1:1:1 to receive TACE plus either durvalumab and bevacizumab, durvalumab and placebo, or placebo alone. The primary endpoint was progression-free survival assessed by blinded independent central review. Key secondary endpoints included overall survival and quality of life measures.
The study population was predominantly male (78%) and Asian (61%), with a median age of 65 years. Most patients had BCLC stage B disease (57%) and Child-Pugh A liver function (98%). Baseline characteristics were generally well-balanced between groups, though there were slightly more patients with higher albumin-bilirubin grade in the durvalumab plus placebo arm.
After a median follow-up of 27.9 months, the trial met its primary endpoint. Median progression-free survival was significantly longer with durvalumab plus bevacizumab (15.0 months) compared to placebo (8.2 months), with a hazard ratio of 0.77 (95% CI 0.61-0.98, p=0.032). The durvalumab plus placebo arm did not show a significant benefit over placebo (10.0 vs 8.2 months, HR 0.94, p=0.64).
Objective response rates were higher with durvalumab plus bevacizumab (44%) and durvalumab plus placebo (41%) versus placebo alone (30%). Median duration of response was also longest in the durvalumab plus bevacizumab group at 22.1 months. The progression-free survival benefit with durvalumab plus bevacizumab was generally consistent across key subgroups.
Regarding safety, adverse events of any grade occurred in 98% of patients receiving durvalumab plus bevacizumab, 93% receiving durvalumab plus placebo, and 93% receiving placebo alone. Grade 3-4 adverse events were more common with durvalumab plus bevacizumab (45%) compared to durvalumab plus placebo (28%) or placebo alone (23%). The most frequent grade 3-4 events with durvalumab plus bevacizumab were hypertension, anemia, acute kidney injury, and proteinuria.
No new safety signals were identified. While participants receiving durvalumab plus bevacizumab had higher rates of serious adverse events and discontinuations, this was likely related to longer treatment exposure. Importantly, there were no treatment-related deaths in the durvalumab plus bevacizumab group.
The authors concluded that adding durvalumab and bevacizumab to TACE significantly improved progression-free survival with a manageable safety profile in this population of patients with unresectable hepatocellular carcinoma amenable to embolization. They suggest this combination has the potential to become a new standard of care, though longer follow-up for overall survival is needed.
Some limitations of the study include the heterogeneity of TACE practices across regions, which may impact generalizability. The study also did not recruit patients from some high-incidence areas like Africa. Additionally, progression-free survival as a primary endpoint may be confounded by competing risk of death from cirrhosis in this population.
Nonetheless, EMERALD-1 represents the first phase 3 trial to show a significant improvement in a clinically relevant endpoint by adding systemic therapy to TACE in hepatocellular carcinoma. If overall survival data are positive, this approach could substantially change clinical practice for intermediate-stage disease.
The combination of immunotherapy and anti-angiogenic therapy with TACE has strong biological rationale. TACE increases tumoral PD-L1 and VEGF expression, potentially enhancing the efficacy of targeted inhibition. This synergy may explain the lack of benefit seen with durvalumab alone or in previous studies of single-agent systemic therapies added to TACE.
For clinicians, these results suggest that patients with unresectable hepatocellular carcinoma who are candidates for TACE may benefit from the addition of durvalumab and bevacizumab. However, careful patient selection will be important given the potential for increased toxicity. Management of immune-related adverse events and close monitoring for bleeding risk, especially in patients with varices, will be critical.
Looking ahead, final overall survival results from EMERALD-1 will be crucial to fully establish the role of this regimen. Cost-effectiveness analyses will also be needed to determine the value proposition, especially in resource-limited settings. Further research may help identify biomarkers to select patients most likely to benefit from the addition of immunotherapy and anti-angiogenic therapy to TACE. Ultimately, EMERALD-1 opens new possibilities for improving outcomes in intermediate-stage hepatocellular carcinoma, a population with limited treatment options to date.
References
Sangro B, Kudo M, Erinjeri JP, et al. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2025;405(10474):216-232. doi:10.1016/S0140-6736(24)02551-0
