Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma

Sorafenib, which was shown to improve survival in the SHARP [1] and Asia-Pacific [2] trials, has been the standard therapy for unresectable hepatocellular carcinoma (HCC) since 2007. Since then, several first-line clinical trials have been conducted with the aim of developing molecular targeted agents showing better efficacy or safety than sorafenib [3] (Table (Table1).1). A superiority trial comparing sorafenib with sunitinib (SUN1170 trial) showed that sunitinib is not superior but rather significantly inferior to sorafenib regarding the primary endpoint of overall survival (OS) [4]. The BRISK-FL and LiGHT trials showed that brivanib and linifanib are not superior and, moreover, not noninferior, despite the fact that the trial designs allowed for assessment of noninferiority [5, 6]. A superiority trial of sorafenib plus erlotinib (SEARCH trial) [7], a superiority trial of sorafenib plus doxorubicin (CALGB808028 trial), and a trial investigating sorafenib plus hepatic arterial infusion chemotherapy (HAIC) (SILIUS trial) [8] all failed. The results of two superiority trials comparing sorafenib with radioembolization called SARAH (SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma) [9] and SIRveNIB (Study to Compare Selective Internal Radiation Therapy [SIRT] Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma [HCC]) were also reported at EASL 2017 and ASCO 2017, although these trials failed as well [10]. These results highlight the difficulties associated with conducting clinical trials of first-line HCC drugs using OS as the endpoint, and demonstrate the superiority of sorafenib for improving survival compared with other drugs. Table 1 Phase III clinical trials of advanced-stage HCC