Sorafenib (
Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of
hepatocellular carcinoma. Monotherapy with
sorafenib prolongs overall survival and delays the time to progression in patients with advanced
hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization.
Sorafenib is generally well tolerated in patients with advanced
hepatocellular carcinoma. Thus,
sorafenib represents an important advance in the treatment of advanced
hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl
urea sorafenib is an oral multikinase inhibitor that inhibits cell surface
tyrosine kinase receptors (e.g.
vascular endothelial growth factor receptors and
platelet-derived growth factor receptor-beta) and downstream intracellular
serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these
kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with
sorafenib in human
hepatocellular carcinoma cells lines.
Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human
hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral
sorafenib. Metabolism of
sorafenib occurs primarily in the liver and is mediated via
cytochrome P450 (CYP) 3A4 and
uridine diphosphate glucuronosyltransferase 1A9. In advanced
hepatocellular carcinoma, differences in
sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant.
Sorafenib may be associated with drug interactions. For example,
sorafenib exposure was reduced by an average 37% with concomitant administration of the
CYP3A4 inducer rifampicin (
rifampin);
sorafenib concentrations may also be decreased by other
CYP3A4 inducers. Monotherapy with oral
sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced
hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between
sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination
therapy with
sorafenib plus
doxorubicin did not delay the median time to progression to a significant extent compared with
doxorubicin alone in patients with advanced
hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving
sorafenib plus
doxorubicin than in those receiving
doxorubicin alone. Combination
therapy with
sorafenib plus
tegafur/
uracil or
mitomycin also showed potential in advanced
hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral
sorafenib was generally well tolerated in patients with advanced
hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more
sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction,
anorexia,
alopecia,
weight loss, dry skin,
abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a
chemotherapy agent, the adverse event profile in patients with advanced
hepatocellular carcinoma who received combination
therapy with
sorafenib plus
doxorubicin differed somewhat to that seen with
sorafenib monotherapy in the SHARP trial. In patients receiving
sorafenib plus
doxorubicin, the most commonly occurring all-cause adverse events (all grades) included
fatigue,
neutropenia, diarrhoea, elevated
bilirubin levels,
abdominal pain, hand-foot skin reaction,
left ventricular dysfunction,
hypertension and
febrile neutropenia.