Immunotherapy, TACE-based regimen may reshape HCC treatment landscape

In the EMERALD-1 trial, durvalumab plus bevacizumab (D+B) combined with transarterial chemoembolization (TACE) improved progression-free survival (PFS) in individuals with unresectable hepatocellular carcinoma (HCC) eligible for embolization.

“EMERALD-1 met its primary endpoint,” said Dr Riccardo Lencioni from the University of Pisa School of Medicine, Pisa, Italy, at ASCO GI 2024. “This is the first phase III study to demonstrate statistically significant and clinically meaningful improvement in PFS with an immunotherapy and TACE-based regimen [in this patient setting].”

D+B plus TACE had the upper hand over placebo-TACE in terms of median PFS, nearly doubling that observed with the latter (15.0 vs 8.2 months; hazard ratio [HR], 0.77; p=0.032).

“[This was] one of the best reported [PFS] results for TACE,” Lencioni said. “The curves started separating at around 4 or 5 months. A clear separation was maintained for >30 months, with clear benefits at 12 and 18 months.”

The PFS benefit with D+B plus TACE was generally consistent across key subgroups.

Without bevacizumab however, durvalumab and placebo did not appear to differ significantly when added to TACE, with only a modest improvement in median PFS with the former vs the latter (10.0 vs 8.2 months; HR, 0.94; p=0.638).

Median time to progression improved with D+B vs placebo (22.0 vs 10.0 months; HR, 0.63) but not without bevacizumab (11.5 vs 10.0 months; HR, 0.89).

In terms of objective response rate, improvements were seen with durvalumab vs placebo, with (43.6 percent vs 29.6 percent; odds ratio [OR], 1.87) or without bevacizumab (41.0 percent vs 29.6 percent; OR, 1.67).

Adverse events (AEs) were consistent with the known safety profiles of D, B, and TACE. “The incidence of grade 3/4 AEs was relatively low across all arms, with no new or unexpected safety signals,” said Lencioni. The most common grade 3/4 AEs with D+B plus TACE were hypertension (5.8 percent), anaemia (4.5 percent), and acute kidney injury and proteinuria (3.9 percent each).

Setting a new standard

For over 20 years, TACE has been standard of care (SoC) for embolization-eligible unresectable HCC. [Ann Oncol 2012;23:vii41-vii48; Lancet 2002;359:1734-1739; J Clin Oncol Prac 2022;18:35-41] However, median PFS for TACE recipients remains at about 7–8 months which, according to Lencioni, represents a large unmet need. [Lancet Gastroenterol Hepatol 2017;2:565-575]

“This is a strong rationale to support the combination of TACE with ICIs* and VEGF inhibitors,” he said. “[It is] hypothesized that immunotherapy + anti-VEGF therapy + TACE may induce enhanced antitumour activity via immune activation and inhibition of tumour neovascularization.”

The team thus sought to evaluate TACE plus anti-PD-L1 immunotherapy (durvalumab) with or without an anti-VEGF (bevacizumab) for unresectable HCC eligible for embolization. All 616 participants received DEB** or conventional TACE (1–4 procedures within 16 weeks). While on TACE, 411 patients were also given durvalumab 1,500 mg Q4W, while 205 were on placebo.

The combination regimens commenced after the final TACE procedure. Participants then received durvalumab 1,120 Q3W with (n=207) or without bevacizumab 15 mg/kg (n=204) or placebo (n=205). Median age was around 65 years, more than three-quarters of the population were men, and over half were Asian (non-Japanese).

“[The findings suggest] that D+B in combination with TACE has the potential to set a new SoC in unresectable HCC eligible for embolization,” Lencioni concluded.

Hope at the early disease stages

In a press release, Lencioni noted that the results have “the potential to reshape the treatment of this complex disease with a poor prognosis by showing, for the first time, that adding an immunotherapy combination to TACE significantly improves PFS.” [https://www.astrazeneca.com/media-centre/press-releases/2023/imfinzi-combination-improves-pfs-in-liver-cancer.html]

The high rates of progression and recurrence in embolization-eligible liver cancer patients limit their chances for early intervention with effective systemic therapies. “These positive results for a [durvalumab]-based treatment … may bring the potential of immunotherapy to patients with earlier stages of liver cancer,” said Dr Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca.

“We look forward to discussing these data with regulatory authorities and seeing the survival data mature over time, which will be important as we aim to bring this novel treatment option to patients,” Galbraith continued.