Experience with regorafenib in the treatment of hepatocellular carcinoma

Abstract

Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.

Keywords: combination treatment; hepatocellular carcinoma (HCC); regorafenib; systemic treatment; tyrosine kinase inhibitor (TKI).

Figure 1.

a) Similarly to sorafenib, regorafenib is a bi-aryl urea class of drug. The sole difference between sorafenib and regorafenib is the presence of a fluorine atom in the latter (red arrow). Owing to a mechanism that has not yet been fully defined, this one unique difference produces a wider kinase inhibitory profile. In complement to the targets that are inhibited by sorafenib, regorafenib also blocks the signaling pathway of tyrosine-protein kinase receptor Tie2, the receptor for angiopoietin-2, a pro-angiogenic cytokine. b) M2 and M5 are the main active regorafenib metabolites.

Figure 2.

Regorafenib can inhibit several molecular pathways by targeting angiogenic, stromal, oncogenic and intracellular kinases. Regorafenib induces M1 macrophage polarization and increases CD8+ T cells proliferation and activation thus also acting on the tumor microenvironment and immunosuppression.

Figure 3.

Several TME components promote an immune suppressive environment. Regorafenib may modulate an immune-suppressive TME and promote anti-tumor immunity, blocking VEGFRs, TIE2, and CSF-1R. CTL, cytotoxic T lymphocyte; CSF-1R, colony-stimulating factor 1 receptor; DC, Dendric cells; EC, endothelial cell; TAM, tumor-associated macrophages; TEM, TIE2-expressing monocyte/macrophages; TME, tumor microenvironment; Treg, regulatory T cells; VEGFRs, vascular endothelial growth factor receptors.