Sorafenib: An Important Option for the Treatment of Hepatocellular Carcinoma (HCC)

Globally, the prevalence of hepatocellular cancer (HCC) is increasing. The leading cause of HCC is hepatitis C virus (HCV) infection in Europe, North America and Japan, and hepatitis B virus (HBV) infection in Asia and Africa. Non-viral risk factors for HCC include alcoholic cirrhosis, conditions such as hereditary haemochromatosis and nonalcoholic steatohepatitis. Advanced HCC has a poor prognosis and treatment options are limited. Sorafenib (Nexavar) was approved in the EU and the USA for use in HCC in 2007, and remains the only systemic agent approved for use in this indication. This article will briefly introduce the mechanism, and safety of sorafenib in HCC.^[1]

Figure 1. Mechanism of action of sorafenib.^[2]

Mechanism

Sorafenib is an orally administered multikinase inhibitor. It inhibits multiple cell surface tyrosine kinases [e.g.vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-β, KIT, FLT-3, RET, RET/PTC] and downstream intracellular serine/threonine kinases in the MAPK cascade [e.g. wild-type BRAF, mutant BRAF and CRAF (Raf-1)]. These kinases are involved in tumour cell signalling, proliferation, angiogenesis and apoptosis. In vitro, sorafenib inhibited the proliferation of HCC cells and induced their apoptosis, as well as inhibiting tumour growth, reducing tumour angiogenesis and inducing tumour cell apoptosis in animal models of HCC.

In brief, sorafenib affects several cell signalling pathways in addition to the MAPK pathway (e.g. downregulation of p-STAT3); this is of relevance given that various additional cell signalling pathways are implicated in the initiation and progression of HCC (e.g. the PI3K/Akt/mTOR, JAK/STAT, Wnt/β-catenin, cMET and IGF pathways). Sorafenib also induces tumour cell death via various MAPK-independent mechanisms, including downregulation of anti-apoptotic Bcl-2 proteins such as Mcl-1 and increased expression of p53-upregulatedmodulator-of-apoptosis (PUMA). It has also been suggested that sorafenib may have immunomodulatory effects, such as enhancing the activity of tumour-specific effector T cells and reducing suppressive immune cell populations.

Safety

Oral sorafenib was generally well tolerated in patients with advanced HCC, with a manageable adverse event profile. In the SHARP trial, drug-related adverse events of any grade occurring in significantly (p< 0.05) more sorafenib than placebo recipients included diarrhoea (39 vs.11%), hand-foot skin reactions (21 vs. 3%), anorexia (14 vs. 3%), alopecia (14 vs. 2%), weight loss (9 vs. 1%), dry skin (8 vs. 4%), abdominal pain (not otherwise specified) [8 vs. 3%] and voice changes (6 vs. 1%). Grade 3 drug-related adverse events reported in significantly (p < 0.05) more sorafenib than placebo recipients included diarrhoea (8 vs. 2%), hand-foot skin reactions (8 vs. <1%) and weight loss (2 vs. 0%). The only grade 4 drug-related adverse event reported among sorafenib recipients was fatigue (1 vs. <1% in placebo recipients). A similar tolerability profile was seen in the Sorafenib AP trial.

References

[1] Keating, G.M. Sorafenib: A Review in Hepatocellular Carcinoma. Targ Oncol 12, 243–253 (2017).

[2] Management of Common Adverse Events in Patients Treated With Sorafenib: Nurse and Pharmacist Perspective.
doi: 10.1053/j.seminoncol.2014.01.002