A TRIPLE immunotherapy regimen showed no added benefit in patients with unresectable hepatocellular carcinoma (HCC), the most common form of liver cancer, according to phase 2 results from the PRODIGE 81-FFCD 2101-TRIPLET-HCC trial. The findings do not support adding low-dose ipilimumab to atezolizumab plus bevacizumab as a first-line treatment in this setting.
HCC is the most common primary liver cancer and is often diagnosed at an advanced stage when surgery is no longer an option. Patients with unresectable disease generally have a poor prognosis, making effective first-line systemic therapies a continuing clinical priority.
Triple Immunotherapy Misses Phase 3 Threshold
The randomised, open-label phase 2 study evaluated whether adding ipilimumab to atezolizumab plus bevacizumab could improve objective response rates in patients with previously untreated, unresectable HCC.
To progress to the planned phase 3 stage, at least 35 patients in the experimental arm were required to achieve a complete or partial response within 24 weeks. That threshold was narrowly missed, with 34 patients (30%; 80% CI, 24-36) receiving atezolizumab, bevacizumab and ipilimumab achieving an objective response. In comparison, 31 patients (27%; 80% CI, 22-34) treated with atezolizumab plus bevacizumab achieved an objective response.
As the predefined efficacy target was not met, the trial did not advance to phase 3.
Study Included 229 Randomised Patients
The study enrolled adults with unresectable HCC across 36 hospitals in France. Eligible patients had received no previous systemic therapy, had at least one measurable untreated lesion, Child–Pugh class A disease and an Eastern Cooperative Oncology Group performance status of 0 or 1.
Between March 2023 and September 2024, 229 patients were randomly assigned to treatment, with 226 receiving at least one dose of study medication. Each treatment group included 113 treated patients. Overall, 206 participants (91%) were male and 20 (9%) were female.
Triple Therapy Linked to More Serious Toxicity
The addition of ipilimumab was associated with a higher burden of serious adverse events.
Serious adverse events were reported in 55 patients (49%) receiving the triple combination compared with 48 patients (42%) treated with atezolizumab plus bevacizumab alone. Treatment-related adverse events resulting in death occurred in six patients (5%) receiving triple therapy and in no patients receiving the doublet regimen.
The most common investigator-assessed grade 3-4 treatment-related adverse events in the triple-therapy group were arterial hypertension, asthenia, colitis and confusional syndrome.
Findings Do Not Support First-Line Triple Immunotherapy
The phase 2 findings indicate that adding low dose ipilimumab to atezolizumab plus bevacizumab did not improve objective response rates sufficiently for the trial to progress to phase 3.
For healthcare professionals managing unresectable liver cancer, the results suggest that intensifying first-line immunotherapy with low-dose ipilimumab increased toxicity without demonstrating a clinically meaningful improvement in tumour response.
Reference
Merle P et al. 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. Lancet Gastroenterol Hepatol. 2026;DOI:10.1016/S2468-1253(26)00115-9.
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