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.

Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy

“…It can improve anti-tumor immune responses by regulating macrophages [ 43 ] and MDSCs [ 44 ], enhancing effector T-cell responses [ 45 ], and reducing Treg frequency [ 46 ]. Especially, regorafenib demonstrated anti-immunosuppressive properties, as well as promoting anti-tumor immunity [ 47 ]. In addition to improving DC and T cell responses, and modulating TAMs and Treg cells by VEGF inhibition, regorafenib has additional advantages in targeting immunosuppressive TIE2-expressing monocyte/macrophages and endothelial cells [ 47 ].…”

“…Especially, regorafenib demonstrated anti-immunosuppressive properties, as well as promoting anti-tumor immunity [ 47 ]. In addition to improving DC and T cell responses, and modulating TAMs and Treg cells by VEGF inhibition, regorafenib has additional advantages in targeting immunosuppressive TIE2-expressing monocyte/macrophages and endothelial cells [ 47 ]. Similarly, other TKIs such as lenvatinib and cabozantib can augment anti-tumor immune responses [ 48 ].…”

Function of N6-Methyladenosine Modification in Tumors

“…Cabozantinib exerts antitumor effects by targeting VEGFR-2 and inhibiting angiogenesis [ 36 ]. Regorafenib also inhibits tumor angiogenesis by acting on VEGF and has shown significant survival benefits as second-line therapy in treating hepatocellular carcinoma [ 37 ]. There are also classic drugs for solid tumor treatment, such as bevacizumab and ramucirumab, which work by acting on tumor angiogenesis [ 38 , 39 ].…”

Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib

“…Systemic therapy with regorafenib constitutes the recommended second-line treatment when sorafenib sensitivity is lost [30]. Among the anti-tumor effects of regorafenib, this TKI could modulate the autophagy pathway to counteract tumor cell survival [31], but the effect of regorafenib on FOXO3 and autophagy regulation in sorafenib-resistant HCC has not been studied yet.…”