Management of Hepatocellular Carcinoma after Progression on First-Line Systemic Treatment: Defining the Optimal Sequencing Strategy in Second Line and Beyond

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. It has a high mortality rate, especially when localized treatments fail. For about a decade, the only systemic treatment shown to improve survival was sorafenib. Recently, lenvatinib was found to be noninferior to sorafenib for overall survival, and combination atezolizumab–bevacizumab improved survival compared with sorafenib. Similarly, in the post-sorafenib setting, a number of recent positive clinical trials have been reported, and they indicate that regorafenib, cabozantinib, and ramucirumab are effective and safe in the second-line setting. With so many new options available, including immunotherapy, it is challenging to define the best sequence of systemic treatment for patients with hcc. In the present review, we introduce the current data for second-line systemic treatment and beyond in HCC. A treatment algorithm is also suggested, based on the best available evidence and expert opinion.