Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after
sorafenib failure in patients with unresectable
hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis,
tumor proliferation, spread, and
metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in
carcinogenesis and
tumor growth. In this review, we discuss rationale and evidence supporting
regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after
sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of
regorafenib in emerging combined treatment approach with
immunotherapy strategies using
immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.