Study Evaluating the Benefit of Adding Ipilimumab to the Combination of Atezolizumab and Bevacizumab in Patients With Hepatocellular Carcinoma Receiving First-line Systemic Therapy

TRIPLET HCC is a phase II-III trial that assess the effectivness of addition of ipilimumab to the combination atezolizumab-bevacizumab, on global survival and response to the treatment, for patients with advanced or metastatic hepatocellular carcinoma. The theoretical duration of the study is 5 years. In the scope of this study, each patient will have 2 years of treatment and 2 years of follow-up from their enrollment date.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks fourth in terms of cancer-related mortality worldwide . Unfortunately, the diagnosis of HCC is often made late in the cure of the disease when the tumour has spread outside the liver parenchyma as portal vein invasion or distant metastases. In the history of HCC patients, a significant proportion will sooner or later face systemic therapies as they are no longer eligible for radical or locoregional therapies. Cytotoxic chemotherapy and hormonal therapies have never shown significant benefit on overall survival (OS) . The first systemic therapy to show a significant beneficial impact on HCC outcome was the tyrosine kinase inhibitor (TKI) sorafenib, an anti-angiogenic agent (AAA) with anti-proliferative properties on HCC . For nearly a decade, all systemic therapies tested in randomised controlled trials as first-line systemic therapy (1L) head-to-head with sorafenib, or as 2L after sorafenib failure have not shown significant benefit. In 2018, Kudo et al. showed that lenvatinib, another TKI with anti-angiogenic properties, was at least equivalent to sorafenib in 1L in the REFLECT non-inferiority trial \[5\]. Other AAA TKIs with anti-cancer properties on HCC cells have demonstrated efficacy in 2L: regorafenib after progression on sorafenib in 2017 , and cabozantinib after progression on or intolerance to sorafenib in 2018 . In addition, ramucirumab, a monoclonal antibody targeting VEGFR-2, has shown significant benefit in a specific subpopulation of HCC patients with high baseline alpha-fetoprotein levels ≥ 400 ng/ml . However, all these options were strictly palliative with no long-term survivors and lack of potential recovery. Immuno-oncology (IO) approaches have completely revolutionised the paradigm of systemic HCC therapies with nonetheless a significant increase in median OS in IO-based combination strategies, but also the emergence of the possibility of long-term survivors and, for some patients, hope for a complete response and possibly a final cure.