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      Review article: systemic treatment of hepatocellular carcinoma

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          Summary

          Background

          The approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first‐ and second‐line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.

          Aim

          To summarise the evolving field of systemic therapy of hepatocellular carcinoma.

          Methods

          We reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.

          Results

          We discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.

          Conclusions

          The tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib‐experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib‐experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

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          Most cited references 80

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          Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

          Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.
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            Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

            Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.
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              Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.

              VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.
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                Author and article information

                Contributors
                matthias.pinter@meduniwien.ac.at
                markus@peck.at
                Journal
                Aliment Pharmacol Ther
                Aliment. Pharmacol. Ther
                10.1111/(ISSN)1365-2036
                APT
                Alimentary Pharmacology & Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                0269-2813
                1365-2036
                23 July 2018
                September 2018
                : 48
                : 6 ( doiID: 10.1111/apt.2018.48.issue-6 )
                : 598-609
                Affiliations
                [ 1 ] Division of Gastroenterology & Hepatology Department of Internal Medicine III Medical University of Vienna Vienna Austria
                [ 2 ] Liver Cancer (HCC) Study Group Vienna Medical University of Vienna Vienna Austria
                [ 3 ] Department of Internal Medicine and Gastroenterology (IMuG) Hepatology, Endocrinology, Rheumatology & Nephrology Central Emergency Medicine (ZAE) Klinikum Klagenfurt am Wörthersee Klagenfurt Austria
                Author notes
                [* ] Correspondence: Matthias Pinter, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Gürtel 18‐20, A‐1090 Vienna, Austria ( matthias.pinter@ 123456meduniwien.ac.at ) and Markus Peck‐Radosavljevic, Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology & Nephrology, Central Emergency Medicine (ZAE), Klinikum Klagenfurt am Wörthersee, Feschnigstraße 11, 9020 Klagenfurt am Wörthersee, Austria ( markus@ 123456peck.at )
                Article
                APT14913
                10.1111/apt.14913
                6120553
                30039640
                © 2018 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 2, Tables: 3, Pages: 12, Words: 9883
                Product
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                apt14913
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:03.09.2018

                Pharmacology & Pharmaceutical medicine

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