The study’s senior author discusses how the combined mechanisms of action produced benefit in progression-free survival.
Results presented today at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) found that a combination of durvalumab, bevacizumab, and TACE offered a significant advantage in progression-free survival (PFS) over TACE alone in eligible patients with unresectable hepatocellular carcinoma (HCC). TACE, or transcatheter arterial chemoembolization (TACE), has been the current standard of care for 20 years for patients with uHCC who can receive embolization.1
To gain insight into the results from EMERALD-1 presented at ASCO GI, The American Journal of Managed Care® (AJMC) put several questions to the study’s senior author, Bruno Sangro, MD, who is director, Liver Unit, and coordinator of the HPB Oncology Area at Clínica Universidad de Navarra in Pamplona, Spain. Sangro is also professor of Internal Medicine and leads an active research group in the Spanish Network for Biomedical Research on Hepatic and Digestive Diseases, focused on liver cancer.
AJMC: Can you discuss unmet need in unresectable HCC? How is unmet need impacted by rising levels of liver cancer among younger women?
Sangro: Liver cancer, of which HCC is the most common type, is the third-leading cause of cancer death with an estimated 900,000 people worldwide diagnosed each year. Mortality figures stand not far below incidence. There are, therefore, many unmet needs across tumor stages. Immunotherapy has changed the way we treat patients in the more advanced stage.
An important need is to improve the outcome of patients that are treated with embolization (not less than one third of all HCC patients). Embolization is a catheter-based procedure that blocks the blood supply to the tumor and can also deliver chemotherapy or radiation therapy directly to the tumors. Despite being the standard of care in this setting for more than 20 years, most patients who receive embolization experience disease progression or recurrence within 8 months.
Women exposed to the main causes of HCC (chronic viral hepatitis and chronic fatty liver disease associated with alcohol or the metabolic syndrome), have around 5 times lower risk of developing HCC than men across geographical regions. Yet, the incidence rate of liver cancer among women has been increasing 2% per year, while it has stabilized in men since 2015 (according to the recent American Cancer Society Cancer Facts and Figures 2024).2 This is likely the result of a higher exposure to causative factors.
AJMC: Durvalumab (Imfinzi, AstraZeneca) with bevacizumab plus TACE produced the best PFS results among the 3 arms in the trial. Can you discuss why combining a checkpoint inhibitor with the targeted therapy worked well in HCC?
Sangro: The primary end point for EMERALD-1 is PFS for the combination of TACE with durvalumab plus bevacizumab. Durvalumab is PD-L1 inhibitor, that induces and strengthens cytotoxic T cell responses against tumor cells. In the advanced stage, durvalumab induced objective responses and proved to be noninferior to sorafenib. Bevacizumab is a VEGF inhibitor that prevents the formation of new blood vessels and promotes T-cell activation in the liver, contributing to the antitumor response through immune activation and inhibition of blood flow to tumor cells. In the Study 22 Phase II trial, durvalumab plus bevacizumab was well tolerated and showed promising clinical activity in patients with advanced HCC with a confirmed objective response rate of 21.3%. TACE itself may induce immunogenic tumor cell death and certainly induces tumor hypoxia. Hence, the dual mechanism of action of the combination of durvalumab and bevacizumab helps explain the best results observed when combined with TACE.
AJMC: The abstract does not break out results by age. Were there any differences in results by age? Were there differences in PFS based on the stage of the cancer?
Sangro: The median age was around 65 years and similar in all 3 cohorts. This is the expected age for HCC patients. A specific assessment of outcomes by age was not preplanned for this initial analysis.
Pre-planned subgroup analyses show a very consistent PFS benefits across subgroups, including patients with different etiologies of HCC, geographical location, tumor burden and stage, liver function or performance status, and α-fetoprotein levels. Importantly, patients participating in EMERALD-1 represent all categories of HCC patients treated with embolization around the globe, something that is very relevant when one considers the applicability to daily clinical practice.
AJMC: Other data being presented at ASCO GI examine use of combination therapy without TACE in unresectable HCC. What are the specific advantages of using therapy with TACE for these patients?
Sangro: TACE is the standard of care for patients who are not amenable to radical therapies such as liver transplantation or resection or thermal ablation, are free from extrahepatic disease, and have relatively preserved liver function and performance status. It is recommended by all clinical practice guidelines around the globe. Combination therapies with immune checkpoint inhibitors and other agents including antiangiogenics or tyrosine-kinase inhibitors are being tested mostly in patients at advanced stages. Advanced here means patients that are not eligible for embolization.
EMERALD-1 has shown that combining TACE with treatment durvalumab and bevacizumab reduced the risk of disease progression or death by 23% compared to TACE alone. Median progression-free survival (PFS) was 15 months in patients treated with the durvalumab plus bevacizumab combination versus 8.2 months with TACE alone. It also produced objective responses in 43.6% of patients. And did so while showing a safety profile that was generally manageable and consistent with the known profile of each agent. Grade 3 and 4 adverse events occurred in 45.5% of patients treated with TACE in combination with durvalumab plus bevacizumab and 23% of patients treated with TACE alone. All these are clinically relevant benefits that have been observed for the first time in this population and may change the way we approach the treatment of patients with embolization-eligible HCC.