Sorafenib, a multikinase inhibitor targeting Raf kinase and vascular endothelial growth factor receptor, became the first approved systemic agent for hepatocellular carcinoma (HCC) in 2007.? In Taiwan, the National Health Insurance Program has started to reimburse the treatment of sorafenib for patients with advanced HCC, defined as the presence of extrahepatic metastasis or vascular invasion, and with Child-Pugh liver function since Aug 2012.
　　Although the approval of sorafenib has stimulated a lot of efforts in developing therapeutics for HCC, the progress has been very limited.? Until 2015, multiple phase III trials have been conducted but none of them have proven superior or sufficient efficacy at the first-line and second-line settings of advanced HCC.
　　Nevertheless, the results of RESORCE trial, a multicenter phase III study of regorafenib in HCC patients whose disease has progressed after treatment with sorafenib, were reported at the European Society for Medical Oncology (ESMO) 18th World Congress on Gastrointestinal Cancer in Jun2016. RESORCE trial demonstrated that patients treated with regorafenib, compared with those treated with placebo, had significantly improved overall survival (OS) [median OS 10.6 months vs 7.8 months, with hazard ratio =0.62, 95% confidence interval = 0.50–0.78, P < 0.001). Regorafenib may soon become another therapeutic agent approved for the treatment of HCC.
　　Moreover, immunotherapy especially blockade of immune checkpoints including programmed cell death protein-1 (PD-1) pathway has recently emerged as a new paradigm of cancer therapy.? Immune checkpoint inhibitors have demonstrated impressive clinical activities in melanoma, lung cancer, urothelial cancer, and a wide variety of solid cancers. CheckMate-040 is a phase I/II trial of nivolumab, a monoclonal antibody against PD-1, in advanced HCC patients who have progressed ? one line of systemic therapy.? Nivolumab as a monotherapy resulted in an objective tumor response rate as high as 16%, and the tumor response was seen across patients with different etiologies. This promising data has prompted marked enthusiasm for developing immunotherapy in HCC.? Large randomized trials of nivolumab and other immune checkpoint inhibitors as first-line and second-line therapy for advanced HCC are under active investigation.