Clinical Summary:

• Design/Population: This single-arm, phase 2 study enrolled patients with liver-limited unresectable hepatocellular carcinoma, including a real-world population with prior locoregional therapy and selected Child-Pugh B7 liver function. Patients received induction ipilimumab plus nivolumab, followed by transarterial chemoembolization (TACE), then consolidation with cabozantinib plus nivolumab.
• Key Outcomes: The study evaluated progression-free survival at 6 months and complete response rate by mRECIST as dual primary endpoints, while also assessing overall efficacy, safety, and tolerability. Following the prespecified interim analysis, the study reached its planned futility analysis, prompting presentation of the available clinical results.
• Clinical Relevance: This trial explored a novel multimodality strategy designed to integrate immune checkpoint inhibition, targeted therapy, and locoregional treatment in patients with liver-limited unresectable hepatocellular carcinoma.

Farshid Dayyani, MD, PhD, University of California, Irvine, California, discusses the rationale and design of a phase 2 study evaluating induction ipilimumab plus nivolumab followed by transarterial chemoembolization (TACE) and consolidation with cabozantinib plus nivolumab in patients with unresectable hepatocellular carcinoma.

The study was designed to determine whether combining immunotherapy, targeted therapy, and locoregional treatment could improve outcomes by modifying the tumor microenvironment while enhancing local tumor control. The trial enrolled a broad, real-world patient population and provides important insights to guide future multimodality treatment strategies in liver-limited hepatocellular carcinoma.

These results were presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, California.

Transcript: 

My name is Dr Farshid Dayyani, I’m a professor of clinical medicine at the Chao Family Comprehensive Cancer Center at the University of California, Irvine. I would like to briefly discuss our clinical trial of ipilimumab and nivolumab in combination with TACE, followed by cabozantinib and nivolumab consolidation in patients with unresectable hepatocellular carcinoma (HCC) which was presented recently at ASCO GI 2026 as Abstract 542.

The background of the study, which we initiated in 2019, was recognizing the complex involvement of angiogenesis, the tumor microenvironment, and the new tools that were emerging, including next-generation small-molecule inhibitors, RTK inhibitors, as well as checkpoint inhibitors. We recognized the possibility of modulating the tumor microenvironment using dual checkpoint inhibition with ipilimumab and nivolumab to prime the tumor microenvironment, then treating the tumors within the liver with transarterial chemoembolization (TACE) which was standard about 6 or 7 years ago, and then attempting to consolidate that response with cabozantinib, which is a MET, AXL, and VEGF receptor tyrosine kinase inhibitor, plus nivolumab, an anti-PD-1 agent. 

The primary objective of this phase 2 trial was to estimate the efficacy of cabozantinib combined with ipilimumab and nivolumab priming and TACE in unresectable HCC. We had dual primary end points of progression-free survival at six months as well as complete response rate by mRECIST, along with standard secondary objectives of efficacy, safety, and tolerability. The study design included patients with liver-limited unresectable HCC diagnosed histologically or by radiographic criteria, Child-Pugh score A through B7, with albumin allowed. Patients were not candidates for resection or transplantation, were older than 18 years of age, had a performance status of 0 to 2, and had at least 1 measurable lesion. Importantly, prior locoregional treatment was allowed as long as it was completed more than 3 months prior to enrollment in the study. This resulted in a much more real-world patient population. As long as patients were eligible for TACE at the time of enrollment, vascular invasion was allowed.

The main exclusion criterion was extrahepatic metastatic disease, but otherwise any liver-limited patient was allowed to enroll in the trial. The design involved priming patients with 1 dose of ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg. Three weeks after this initial priming dose, patients underwent a TACE procedure, with the specific technique determined by the treating interventional radiologist. TACE was allowed to be repeated up to 2 additional times as needed, every 14 days. After completion of TACE, patients were started on consolidation therapy with cabozantinib 40 mg daily on a continuous basis, plus nivolumab 480 mg as a fixed dose once a month. Cabozantinib dose reductions were allowed based on adverse events, with 2 additional dose reduction levels: the first reduction to 20 mg daily, and the second reduction to 20 mg every other day.

We reached the prespecified interim analysis and the futility end point, and therefore decided to summarize the data at the ASCO GI Conference in 2026.

Source: 

Dayyani F, Valerin JB, Fernado D, et al. Phase 2 study of cabozantinib (Cabo) combined with ipilimumab (Ipi)/nivolumab (Nivo) and transarterial chemoembolization (TACE) in patients with liver limited unresectable hepatocellular carcinoma (uHCC).Presented at ASCO Gastrointestinal Cancers Symposium. January 8 - 12, 2026; San Francisco, California. Abstract 543