Patients with unresectable hepatocellular carcinoma have a poor prognosis, and treatments with long-term benefits remain an important need. In this setting, anti-PD-L1 or anti-PD-1 plus anti-VEGF or anti-CTLA-4 double combinations are validated first-line systemic immunotherapies.

The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial evaluated survival outcomes and safety with the triple combination of atezolizumab, bevacizumab, and ipilimumab in the first-line setting for patients with previously untreated unresectable hepatocellular carcinoma.

The article, titled “Addition of ipilimumab to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma (PRODIGE 81-FFCD 2101-TRIPLET HCC): phase 2 results from a randomised, multicentre, open-label, phase 2–3 trial,” was published online in The Lancet Gastroenterology & Hepatology on June 22, 2026.

Authors: Philippe Merle, Jean-Frederic Blanc, Karine Le Malicot, Jean-Marie Peron, Vincent Bourgeois, Mohamed Bouattour, Yann Touchefeu, Carole Vitellius, Faiza Khemissa Akouz, Alexandra Heurgué, Paul Girot, Eric Assenat, Eric Nguyen-Khac, Jean-Pierre Bronowicki, Juliette Viaud, Meher Ben Abdelghani, Sylvain Manfredi, Julien Edeline, and Jean-Marc Phelip, for the TRIPLET-HCC study investigators.

Trial Design

PRODIGE 81-FFCD 2101-TRIPLET-HCC was a randomised, multicentre, open-label, phase 2–3 trial conducted at 36 hospitals in France.

The trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma and no previous systemic therapy. Eligible patients had at least one measurable untreated lesion according to RECIST version 1.1, Child–Pugh class A disease, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive atezolizumab plus bevacizumab plus ipilimumab or atezolizumab plus bevacizumab alone. Treatment was given intravenously every 3 weeks for up to 2 years. Atezolizumab was given at 1200 mg and bevacizumab at 15 mg/kg. In the experimental group, ipilimumab was given at 1 mg/kg for up to four doses.

The preplanned phase 2 analysis was non-comparative. The primary endpoint was investigator-assessed objective response, defined as complete or partial response, within the first 24 weeks of treatment by RECIST version 1.1. For the trial to progress to phase 3, 35 patients in the experimental group needed to have an objective response at week 24.

You can also read about Atezolizumab Plus Bevacizumab in Child-Pugh B Hepatocellular Carcinoma on OncoDaily.

Patient Population

Between March 9, 2023, and September 20, 2024, 229 patients were randomly assigned to treatment, and 226 received at least one dose of study medication. Overall, 113 patients received atezolizumab plus bevacizumab plus ipilimumab, and 113 received atezolizumab plus bevacizumab. Among treated patients, 206 were male and 20 were female.

Efficacy Results

At 24 weeks, objective response was reported in 34 patients in the atezolizumab plus bevacizumab plus ipilimumab group, corresponding to 30%, and in 31 patients in the atezolizumab plus bevacizumab group, corresponding to 27%. The predefined threshold of 35 responses in the experimental group was not met. The trial was stopped and did not progress to phase 3.

Safety

The most common investigator-assessed treatment-related grade 3–4 adverse events reported in more than 2% of patients in the triplet group were colitis, confusional syndrome, arterial hypertension, and asthenia.

In the atezolizumab plus bevacizumab group, the most common investigator-assessed treatment-related grade 3–4 adverse events reported in more than 2% of patients were acute renal failure, proteinuria, gastrointestinal bleeding, arterial hypertension, increased aspartate aminotransferase, increased alanine aminotransferase, and increased lipasaemia.

Serious adverse events were reported in 55 patients, corresponding to 49%, in the triplet group and in 48 patients, corresponding to 42%, in the atezolizumab plus bevacizumab group.

Treatment-related adverse events resulting in death occurred in 6 patients, corresponding to 5%, in the triplet group and in no patients in the atezolizumab plus bevacizumab group.

Takeaway

The addition of ipilimumab to atezolizumab plus bevacizumab did not show benefit in patients with previously untreated unresectable hepatocellular carcinoma.

These results do not support the addition of low-dose ipilimumab, at 1 mg/kg, to atezolizumab plus bevacizumab as first-line treatment in this setting.

The full article is available in The Lancet Gastroenterology & Hepatology.