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Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
Abou-Alfa, Ghassan K.,Meyer, Tim,Cheng, Ann-Lii,El-Khoueiry, Anthony B.,Rimassa, Lorenza,Ryoo, Baek-Yeol,Cicin, Irfan,Merle, Philippe,Chen, YenHsun,Park, Joong-Won,Blanc, Jean-Frederic,Bolondi, Luigi New England Journal of Medicine 2018 The New England journal of medicine Vol.379 No.1
<P>Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.</P>
Abou-Alfa, G.K.,Puig, O.,Daniele, B.,Kudo, M.,Merle, P.,Park, J.W.,Ross, P.,Peron, J.M.,Ebert, O.,Chan, S.,Poon, T.P.,Colombo, M.,Okusaka, T.,Ryoo, B.Y.,Minguez, B.,Tanaka, T.,Ohtomo, T.,Ukrainskyj, S Elsevier Science Publishers 2016 Journal of hepatology Vol.65 No.2
<P>Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FccRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Methods: Patients with advanced HCC who had failed prior systemic therapy, >= 18 years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2: 1 to biweekly codrituzumab 1600 mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. Results: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extrahepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p = 0.87), and 8.7 vs. 10 (hazard ratios 0.96, p = 0.82). Projected Ctrough at cycle 3 day 1 based exposure, high CD16/FccRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. Conclusions: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. Lay summary: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.</P>
Treatment options after sorafenib failure in patients with hepatocellular carcinoma
( Imane El Dika ),( Ghassan K. Abou-alfa ) 대한간학회 2017 Clinical and Molecular Hepatology(대한간학회지) Vol.23 No.4
Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma. (Clin Mol Hepatol 2017;23:273-279)