Advances in pharmacotherapeutics for hepatocellular carcinoma

Although hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, there are limited therapeutic options for the advanced stages. Sorafenib was the first tyrosine-kinase inhibitor (TKI) approved for unresectable HCC and remained the only effective choice for a decade. The horizon of systemic treatments drastically expanded in the latest years, opening new interesting possibilities.In this manuscript, the authors have analysed the recent advances in pharmacotherapy for HCC, discussing their mechanisms of action, the clinical efficacy and the safety profile of currently available first, second-and third-line treatments. The authors have also analysed the role of immune system modulators, in particular immune checkpoints inhibitors (ICIs), based on the limited data published so far.The emergence of new targeted therapies, such as lenvatinib, have changed the landscape of HCC therapy. Tumor extension, differences in objective response rates and adverse events profiles should be considered to tailor the choice of the first-line agent. Sorafenib remains the most studied drug, with much real-world data available. The efficacy of second line therapies has only been proven in non-responder or sorafenib-intolerant patients. Unfortunately, studies directly comparing the second-line agents regorafenib, ramucirumab and cabozantinib are still lacking.