The addition of durvalumab and bevacizumab to transarterial chemoembolization (TACE) significantly improved progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC) eligible for embolization.
In the EMERALD-1 trial, median PFS, the primary end point, was nearly double among patients randomized to durvalumab plus bevacizumab compared with placebo (15 vs 8.2 months).
The trial is the first global phase 3 trial to demonstrate improved clinical outcomes for immunotherapy-based combinations with TACE in such patients, and as a result, “durvalumab plus bevacizumab in combination with TACE has the potential to set a new standard of care in unresectable HCC eligible for embolization,” said lead investigator Riccardo Lencioni, MD, who presented the results at the 2024 ASCO Gastrointestinal Cancers Symposium.
“For more than 20 years, TACE has been the standard of care for this patient population, although the median PFS after TACE does not exceed 7 to 8 months, representing a large unmet need,” he said, providing the rationale for testing the combination of TACE with immune checkpoint inhibitors and VEGF inhibitors. EMERALD-1 evaluated TACE plus durvalumab, with or without bevacizumab, in patients with unresectable HCC eligible for embolization.
Immunotherapy plus anti-VEGF therapy plus TACE is hypothesized to induce enhanced antitumor activity via immune activation and inhibition of tumor neovascularization, he added.
The 616 patients enrolled in EMERALD-1 were randomized equally into 3 arms. All arms received TACE as the standard of care, combined with either durvalumab alone, durvalumab and bevacizumab, or placebo. Those with macrovascular invasions, indicating advanced disease, were eligible for inclusion.
Treatment was divided into 2 parts. In the first part, patients received 1 to 4 TACE procedures within 16 weeks, with the number and timing of TACE at the discretion of the investigators. Durvalumab or placebo was started 1 week after the first day.
The second part of the treatment started upon completion of all TACE cycles. In the second part, patients received durvalumab, bevacizumab, or placebos until progression or unacceptable toxicity. There was no concurrent use of TACE and bevacizumab as a result of this regimen.
Imaging was conducted at 12 weeks and every 9 weeks thereafter.
Most patients received 1 or 2 TACE procedures. The number of patients who reached the dosed TACE treatment phase was similar across the 3 arms, as was the number of patients still receiving therapy at the time of the database lock and the number of patients who discontinued treatment. However, the number of patients who discontinued treatment because of progression of the tumor was lower in the durvalumab plus bevacizumab plus TACE treatment arm.
Most patients received 1 or 2 TACE procedures. The number of patients who reached the dosed TACE treatment phase was similar across the 3 arms.
The hazard ratio (HR) for improvement in median PFS with the addition of durvalumab and bevacizumab was 0.77 (P=.032), and this benefit was consistent across clinical subgroups, including patients with limited disease and a more extensive tumor burden, said Dr Lencioni, from the University of Pisa, Italy.
Time to progression (TTP) in the durvalumab plus bevacizumab treatment arm was 22 months compared with 10 months in the control arm (HR, 0.63).
Modest but nonsignificant improvements in median PFS and TTP were realized with durvalumab monotherapy versus placebo.
At an interim overall survival (OS) analysis, the difference in OS between arms was not statistically significant. EMERALD-1 is ongoing for the final analysis of OS and remains blinded to investigators and participants.
The safety profile of durvalumab plus bevacizumab was manageable. The most common grade 3-4 adverse events (AEs) with the triplet were hypertension (5.8%), anemia (4.5%), acute kidney injury (3.9%), proteinuria (3.9%), postembolization syndrome (3.2%), hepatic encephalopathy (3.2)%, ascites (2.6%), hyponatremia (2.6%), and esophageal varices hemorrhage (2.6%).
The duration of exposure was longer in the post-TACE period and across the total study period in the durvalumab plus bevacizumab arm, consistent with the longer PFS in this arm, said Dr Leoncini. “So it’s not surprising that these patients with greater exposure experienced higher rates of serious AEs, grade 3-4 AEs, and AEs leading to discontinuation. Of interest, there were no AEs resulting in death in the combined durvalumab plus bevacizumab plus TACE arm,” he said.
In advanced HCC, from 27 phase 3 randomized controlled studies, PFS has a reliable surrogate for OS when the HR for PFS is <0.6, whereas PFS is an unknown surrogate for OS in intermediate HCC, noted Josep M. Llovet, MD, from Icahn School of Medicine at Mount Sinai, New York City, and the University of Barcelona in Spain. He added that bevacizumab appears to have an important role in combination with immunotherapies in HCC, acting on angiogenesis.