By Lynda Williams, medwireNews Reporter
medwireNews: Progression-free survival (PFS) findings from two phase 3 clinical trials support the use of targeted therapies in combination with transarterial chemoembolisation (TACE) for the treatment of patients with unresectable, nonmetastatic hepatocellular carcinoma.
The authors of an accompanying comment in The Lancet say these results may have “practice-changing effects”, writing that early immune checkpoint inhibitor (ICI) therapy use “might enhance tumour control with a lower symptom burden compared with their current use in more advanced stages with a higher symptom load.”
However, Florian Reiter and Andreas Geier, both from University Hospital Würzburg in Germany, say the findings “also raise important questions about how to proceed with systemic therapy after progression to an advanced stage under early [ICI]-based and TACE-based combination therapies.”
LEAP-012 – an international randomised, double-blinded trial – included 480 patients with liver-only multinodular large tumours, or early-stage disease unsuitable for potentially curative therapies, and Child-Pugh class A disease.
After a median follow-up of 25.6 months, median PFS was 14.6 months for the 237 patients randomly assigned to receive a weight-based dose of the multikinase inhibitor lenvatinib (8 or 12 mg daily) plus up to 2 years of the ICI pembrolizumab given at a dose of 400 mg every 6 weeks. Treatment was started 2–4 weeks before the patients underwent up to two conventional or drug-eluting bead TACE procedures with epirubicin, doxorubicin or cisplatin.
This compared with a median PFS of 10.0 months for the 243 patients who instead received double placebo plus TACE, giving a significant hazard ratio (HR) for progression or death of 0.66 in favour of the ICI therapy arm.
The 24-month overall survival rates in the ICI and placebo arms were 75% and 69%, with a nonsignificant HR for death of 0.80, which the researchers say is “encouraging”.
Grade 3 and more severe treatment-related adverse events (TRAEs) were reported in 71% of patients given ICI and 32% of controls, most commonly hypertension (24 vs 7%) and platelet count decreases (11 vs 6%). Treatment-related deaths were reported in 2% of the patients given ICI therapy and less than 1% of controls.
“Although longer follow-up is necessary to definitively identify whether there is a survival benefit, these first interim results from LEAP-012 support the use of lenvatinib plus pembrolizumab plus TACE compared with TACE alone in this setting”, say Josep Llovet (Icahn School of Medicine at Mount Sinai, New York, USA) and co-authors.
“Based on these data, lenvatinib plus pembrolizumab plus TACE could be a new option for patients with unresectable, non-metastatic hepatocellular carcinoma.”
The EMERALD-1 investigators too reported a PFS benefit in their double-blinded study comparing two to four TACE procedures alone or in combination with the ICI durvalumab, with or without the vascular endothelial growth factor (VEGF)-A inhibitor bevacizumab. The 616 participants all had at least one measurable intrahepatic lesion and Child-Pugh class A–7B disease.
Durvalumab was initiated in 204 patients at a dose of 1500 mg every 4 weeks for the first 16 weeks, beginning from at least 1 week after first TACE, before decreasing to a dose of 1120 mg every 3 weeks. Bevacizumab was then begun 14 days after the final TACE, at a dose of 15 mg/kg every 3 weeks.
This staggered regimen was chosen to avoid previously reported septic and vascular side effects with TACE plus bevacizumab; the commentators note this delay was effective “because the study authors report that the adverse event profile of durvalumab plus bevacizumab with TACE was similar to that found with immunotherapy and anti-VEGF combinations without TACE.”
After a median of 27.9 months of follow-up, median PFS was 15.0 months for the patients given durvalumab plus bevacizumab with TACE, significantly longer than the 8.2 months achieved by 205 patients given double placebo with TACE (HR=0.77). The 10.0-month PFS achieved by 207 patients given durvalumab plus placebo with TACE was not significantly longer than the PFS with double placebo plus TACE.
Grade 3–4 TRAEs occurred in 27% of patients given durvalumab, bevacizumab and TACE, most commonly hypertension (6%). In addition, TRAEs of this severity occurred in 6% of both the durvalumab plus TACE and the double placebo arms, most commonly anaemia (4%) and post-embolisation syndrome (4%), respectively. Treatment-related deaths occurred in 1% of the durvalumab plus placebo arm and 2% of the double placebo arm.
The EMERALD-1 study was designed with “purposefully broad” inclusion criteria so “to be truly reflective of real-world care”, say Bruno Sangro (Clínica Universidad de Navarra, Pamplona, Spain) and fellow authors.
They continue: “In the context of a standard of care that has remained unchanged for over 20 years, we found that a systemic therapy and TACE combination improved on the efficacy of TACE alone for the first time.
“These progression-free survival results, combined with the manageable safety profile, represent a positive risk–benefit profile for the EMERALD-1 regimen. Durvalumab plus bevacizumab plus TACE is a potential new standard of care for people with unresectable hepatocellular carcinoma that is amenable to embolisation.”
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group
Lancet 2025; doi:10.1016/S0140-6736(24)02575-3
Lancet 2025; doi:10.1016/S0140-6736(24)02551-0
Lancet 2025; doi:10.1016/S0140-6736(24)02680-1
https://pubmed.ncbi.nlm.nih.gov/39798578