Role of Regorafenib as Second-line Therapy and Landscape of Investigational Treatment Options in Advanced Hepatocellular Carcinoma

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the ONA take:

The tyrosine kinase inhibitor sorafenib is the only systemic agent approved for the treatment of advanced hepatocellular carcinoma (HCC) and is the standard systemic treatment option for locally advanced HCC not amenable to locoregional treatment and metastatic disease. Various trials have sought to evaluate other kinase inhibitors in comparison with sorafenib for the first-line treatment of HCC, but none have been shown to be superior to sorafenib. In addition, there is no established second-line treatment for patients who have progressed on or after first-line sorafenib.

The phase 3 RESOURCE trial recently demonstrated that regorafenib after sorafenib significantly improved overall survival compared with best supportive care in patients with unresectable hepatocellular carcinoma. A contributing factor for these positive findings may have been the inclusion of only patients who could tolerate sorafenib, as opposed to other clinical trials that included patients irrespective of the cause of sorafenib failure. The findings suggest that regorafenib may become the standard of care for this subpopulation of patients with HCC.

Another kinase inhibitor that holds potential in HCC is lenvatinib, which is approved for kidney and thyroid cancer. Recent data from a phase 1b dose-escalation study showed an encouraging response rate of 15% with tumor shrinkage in 70% of patients with advanced HCC. A phase 3 study ( Identifier: NCT01761266) is comparing the efficacy and safety of lenvatinib with that of sorafenib in the first-line treatment of patients with unresectable HCC.

Journal of Hepatocellular Carcinoma
Journal of Hepatocellular Carcinoma

Abstract: Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.

Keywords: hepatocellular carcinoma, receptor tyrosine kinase inhibitor, sorafenib, regorafenib, lenvatinib, tivantinib, cabozantinib, ramucirumab, immunotherapy, anti-CTLA-4, anti-PD-1, oncolytic virus 
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