There's a possible new standard of care on the horizon for unresectable hepatocellular carcinoma (HCC) after years of failed attempts to improve upon the outcomes of the current protocol — stand-alone transarterial chemoembolization (TACE).
In a phase 3, randomized clinical trial, investigators found that adding the checkpoint inhibitor durvalumab and the vascular endothelial growth factor (VEGF) blocker bevacizumab to TACE increased median progression-free survival from 8.2 months with TACE alone to 15 months (hazard ratio, 0.77; P = .032).
The 616-subject trial, dubbed EMERALD-1, was presented by lead investigator Riccardo Lencioni, MD, at the American Society of Clinical Oncology's 2024 Gastrointestinal Cancers Symposium.
Bevacizumab is already approved in combination with the checkpoint inhibitor atezolizumab for unresectable, locally advanced or metastatic HCC based on the IMbrave150 trial. In that trial, about half the patients had undergone previous TACE or other locally directed therapy. Progression-free survival with the combination was 6.8 months vs 4.3 months with the comparator, sorafenib.
In the EMERALD-1 trial, patients had more intermediate disease, with tumors confined to the liver. Also, systemic therapy was used in conjunction with TACE, not after the fact, Lencioni, a diagnostic and interventional radiologist at the University of Pisa, Italy, explained.
Adding durvalumab and bevacizumab to TACE could "become the standard of care in intermediate" unresectable HCC, said trial discussant, Josep Llovet, MD, PhD, a liver cancer specialist and researcher at Mount Sinai Hospital in New York City.
However, he noted, overall survival outcomes, which are pending in EMERALD, need to be reported first. He added that as was done in the trial, prospective patients will need a gastrointestinal endoscopy to screen out those with esophageal varices at a high risk for bleeding with bevacizumab.
TACE became the standard of care for unresectable HCC about 20 years ago, following a metanalysis led by Llovet that showed a benefit over other approaches.
Since then, there have been over 10 randomized trials, several of which tried adding sorafenib, that have failed to improve on the results of TACE alone.
With this first trial with positive results, "a new horizon is open," said Lencioni. "The data are very compelling that there is a meaningful benefit in starting early with immunotherapy and bevacizumab" in TACE patients.
There are several other ongoing trials combining TACE with systemic therapy, including pembrolizumab and the VEGF blocker lenvatinib. EMERALD was simply the first to report results, Llovet noted.
No Benefit With Durvalumab Alone
EMERALD subjects had embolization-eligible, unresectable HCC with Child-Pugh A to B7 liver function and no evidence of extrahepatic disease. Patients with microvascular invasion were included. Up to four TACE procedures were allowed; most patients had one or two.
Subjects were randomized equally to three groups: TACE alone (with placebo), TACE with durvalumab followed by durvalumab, and TACE with durvalumab followed by bevacizumab and durvalumab. Treatment continued until progression or unacceptable toxicity.
The progression-free survival curves between TACE plus placebo and TACE with bevacizumab and durvalumab arms started to separate at about 6 months, with a clear benefit for the combination at 12 and 18 months. The curves started converging at about 25 months and converged at 36 months.
The benefit of combination systemic therapy held across a number of subgroups, but the upper limit of hazard ratio confidence intervals crossed one in most cases.
There was no progression-free survival benefit when durvalumab was added to TACE by itself, which led Llovet to suspect that the benefit of combination systemic therapy came from the addition of bevacizumab, which limits blood flow to tumors by inhibiting VEGF.
Overall, the benefit seen in the trial was largely "an angiogenesis-driven response," he said.
Rates of grade 3/4 adverse events in the bevacizumab/durvalumab arm were more than double of those in the other two groups at 32.5%. The finding isn't surprising because the group also had the longest duration of treatment at a median of 13.75 months, Lencioni noted.
Grade 3/4 adverse events with the combination included hypertension (5.8%), anemia (4.5%), acute kidney injury (3.9%), hepatic encephalopathy (3.2%), and esophageal varices hemorrhage (2.6%). There were no treatment-related deaths in the bevacizumab/durvalumab arm.
EMERALD-1 was funded by AstraZeneca, maker of durvalumab. Lencioni is an AstraZeneca advisor and researcher. Llovet is also a consultant for AstraZeneca and many other companies, including Roche, maker of bevacizumab.
M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com