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.
In this adult randomised phase 2 trial of unresectable hepatocellular carcinoma, adding low-dose ipilimumab to first-line atezolizumab plus bevacizumab failed to meet the prespecified response threshold and was associated with six treatment-related deaths versus none with the doublet.
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In this adult randomised phase 2 trial of unresectable hepatocellular carcinoma, adding low-dose ipilimumab to first-line atezolizumab plus bevacizumab failed to meet the prespecified response threshold and was associated with six treatment-related deaths versus none with the doublet.
Research significance
The trial provides evidence against adding ipilimumab 1 mg/kg to atezolizumab plus bevacizumab in the studied adult first-line HCC population; any inference that this result should guide pediatric liver-tumor treatment would be unsupported because no pediatric patients or pediatric-specific tumor biology were evaluated.
Source abstract
BACKGROUND: Patients with unresectable hepatocellular carcinoma have a poor prognosis and treatments with long-term benefits are needed. Anti-PD-L1 or anti-PD-1 plus anti-VEGF or anti-CTLA-4 double combinations are validated, first-line, systemic immunotherapies. We report the preplanned phase 2 results of the phase 2-3 PRODIGE 81-FFCD 2101-TRIPLET-HCC trial investigating the survival outcomes and safety profile of a triple combination of atezolizumab, bevacizumab, and ipilimumab in a first-line setting. METHODS: This randomised, open-label, phase 2-3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 36 hospitals in France. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1), Child-Pugh class A disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to receive intravenous treatment every 3 weeks for up to 2 years with atezolizumab 1200 mg plus bevacizumab 15 mg/kg (plus ipilimumab 1 mg/kg for up to four doses), or atezolizumab plus bevacizumab alone. Subsequent follow-up was for a further 2 years. Randomisation was done centrally by the study funder, via an electronic case report form, using the minimisation method, and stratified by centre, ECOG performance status, macrovascular invasion or extrahepatic spread (or both), and baseline α-fetoprotein. We report the non-comparative phase 2 results with a primary endpoint of objective response (complete or partial) within the first 24 weeks of treatment, assessed per investigator by RECIST v1.1, in patients who received at least the first dose of study medication (modified intention-to-treat population); 35 patients in the experimental group needed to have had an objective response at week 24 for the trial to progress to phase 3. Missing data were not replaced. The trial is registered with ClinicalTrials.gov (NCT05665348) and is complete. FINDINGS: Between March 9, 2023, and Sept 20, 2024, 229 patients were randomly assigned to treatment and 226 received at least one dose of study medication; 113 patients received atezolizumab plus bevacizumab plus ipilimumab and 113 received atezolizumab plus bevacizumab. 206 (91%) patients were male and 20 (9%) were female. At 24 weeks, 34 (30% [80% CI 24-36]) patients in the atezolizumab plus bevacizumab plus ipilimumab group had an objective response as had 31 (27% [22-34]) patients in the atezolizumab plus bevacizumab group. The trial was therefore stopped and did not progress to phase 3. The most common (>2% of patients) investigator-assessed treatment-related, grade 3-4 adverse events in the atezolizumab plus bevacizumab plus ipilimumab group were colitis (four [4%] patients), confusional syndrome (three [3%]), arterial hypertension (11 [10%]), and asthenia (six [5%]); the most common in the atezolizumab plus bevacizumab group were acute renal failure (three [3%] patients), proteinuria (four [4%]), gastrointestinal bleeding (six [5%]), arterial hypertension (13 [12%]), increased aspartate aminotransferase (three [3%]), increased alanine aminotransferase (three [3%]), and increased lipasaemia (three [3%]). Serious adverse events were reported in 55 (49%) patients in the atezolizumab plus bevacizumab plus ipilimumab group and in 48 (42%) patients in the atezolizumab plus bevacizumab group. Treatment-related adverse events resulting in death occurred in six (5%) patients in the atezolizumab plus bevacizumab plus ipilimumab group and none in the atezolizumab plus bevacizumab group. INTERPRETATION: The addition of ipilimumab to atezolizumab plus bevacizumab did not show any benefit in patients with previously untreated, unresectable hepatocellular carcinoma. These results do not support the addition of low-dose (1 mg/kg) ipilimumab to atezolizumab plus bevacizumab as a first-line treatment in this setting. FUNDING: Fédération Francophone de Cancérologie Digestive.