Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Most patients with HCC have advanced disease at initial diagnosis, and sorafenib has been the only systemic treatment option for more than a decade in patients with advanced, unresectable HCC. However, there has been a dramatic change in the treatment algorithm in the last several years, given new drug approvals in the field. Most importantly, the combination of atezolizumab and bevacizumab has demonstrated clinically meaningful benefits in terms of response rate, progression-free survival, and overall survival compared to sorafenib in the first-line setting. Recently a phase III trial showed that the combination of durvalumab with a single dose of tremelimumab improved overall survival compared to sorafenib, while durvalumab monotherapy was found to be noninferior to sorafenib, making it an attractive alternative single agent in selected patient populations. As immunotherapy makes its way into the therapeutic landscape of HCC, other novel targeted therapies, such as lenvatinib, cabozantinib, ramucirumab, and regorafenib, have also been approved by regulatory authorities for treatment of advanced, unresectable HCC. This review article focuses on the first-line systemic treatment options for HCC while addressing some of the most important questions aimed at optimization of HCC treatment.