A multicenter pilot study of nivolumab with drug-eluting bead transarterial chemoembolization in patients with liver-limited hepatocellular carcinoma

Abstract

Background Drug-eluting bead transarterial chemoembolization (deb-TACE) is a standard for liver-limited, locally advanced hepatocellular carcinoma (HCC) and may enhance response to immune checkpoint inhibition through tumor immune microenvironment modulation. We evaluated nivolumab combined with deb-TACE. Patients and methods This phase I, multicenter trial used a 3 + 3 design with expansion, evaluating three nivolumab schedules relative to deb-TACE. Eligible patients had unresectable, liver-limited HCC. Patients underwent deb-TACE and received nivolumab 240 mg i.v. every 2 weeks for up to 1 year, according to cohort-specific schedules. The primary outcome was safety. Secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory immune outcomes included peripheral T-cell subsets and cytokines. Results Nineteen patients were treated. One dose-limiting toxicity (grade 3 transaminitis) resolved without intervention and did not recur with rechallenge. Common treatment-related adverse events were fatigue (53%), transaminase elevation (42%), and fever (37%). The ORR was 21% [95% confidence interval (CI) 6% to 44%]. With a median follow-up time of 72.7 months, median PFS and OS were 5.9 months (95% CI 3.6-23) and 23 months (95% CI 19-62), respectively. Transient immune changes occurred but were not statistically significant and without persistent effects. Conclusion Nivolumab combined with deb-TACE demonstrated acceptable tolerability across dosing schedules but did not enhance antitumor activity beyond historical benchmarks for deb-TACE alone. In the context of recent phase III trials that have yet to demonstrate an overall survival benefit for TACE plus immune checkpoint inhibitor combinations, these findings underscore the need for hypothesis-driven trial designs incorporating improved patient selection criteria and rational combinatorial strategies.