Donafenib in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global healthcare problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Sorafenib demonstrated its efficacy as the first therapeutic agent for unresectable HCC in 2007. Since then, other multitarget tyrosine kinase inhibitors have demonstrated efficacy in HCC patients. Still, the tolerability of these drugs remains an unsolved problem, with 5-20% of patients permanently discontinuing their therapies due to adverse events. Donafenib is a deuterated form of sorafenib exploiting the increased bioavailability derived from the deuterium-for-hydrogen replacement. In the multicenter, randomized, controlled phase II-III trial ZGDH3, donafenib outperformed sorafenib in terms of overall survival, with favorable safety and tolerability. As a result, donafenib was approved as a possible first-line treatment of unresectable HCC by the National Medical Products Administration (NMPA) of China in 2021. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of donafenib.