Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Abstract

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

Keywords: Hepatocellular carcinoma, Advanced-metastatic, Second-line, Third-line, Regorafenib, Cabozantinib, Ramucirumab, Angiogenesis, Multikinase inhibitor, MET, AXL, Vascular endothelial growth factor receptor 2

Core tip: During the last decade, sorafenib, a multikinase inhibitor, has emerged as the only systemic agent available for the treatment of patients with unresectable hepatocellular carcinoma. However, in recent years, lenvatinib, which is a different multikinase inhibitor, was shown to be non-inferior compared to sorafenib. Despite several negative phase III trials, novel drugs with similar, but not overlapping, properties have been recently shown to improve patient outcomes, thereby confirming the role of sustained anti-angiogenic inhibition in further lines of treatment. Here, we will discuss the results of the positive phase III trials of regorafenib, cabozantinib, and ramucirumab in patients failing sorafenib.