BACKGROUND: The approval of the tyrosine kinase inhibitor sorafenib in 2007 
marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib 
was the first systemic therapy to show a survival benefit in patients with 
advanced hepatocellular carcinoma. Since then many drugs failed in the first- 
and second-line setting and it took almost another decade until further tyrosine 
kinase inhibitors succeeded in phase III trials.
AIM: To summarise the evolving field of systemic therapy of hepatocellular 
carcinoma.
METHODS: We reviewed recently published studies identified from PubMed and data 
presented at recent meetings. Main search terms included hepatocellular 
carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint 
inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and 
nivolumab.
RESULTS: We discuss the evolution of targeted therapies since the approval of 
sorafenib including failures and recent advances. We also elaborate the unmet 
need of biomarkers to guide treatment decisions and discuss the emerging field 
of immunotherapy in hepatocellular carcinoma.
CONCLUSIONS: The tyrosine kinase inhibitors sorafenib (first line) and 
regorafenib (second line) have been approved for hepatocellular carcinoma, and 
the immune checkpoint inhibitor nivolumab obtained conditional approval for 
sorafenib-experienced patients in the United States. With lenvatinib in the 
first line, and cabozantinib and ramucirumab in sorafenib-experienced patients, 
three more targeted therapies reached their primary endpoint in phase III trials 
and may soon be added to the treatment armamentarium.