The dual checkpoint blockade in unresectable hepatocellular carcinoma: opportunities emerging in clinical trials

To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale.In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early-phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages.The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.