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N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.

Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.

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From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (G.K.A.-A.); Royal Free Hospital and University College London, London (T.M.); National Taiwan University Hospital, Taipei (A.-L.C.), and the Department of Medical Oncology, Liouying Chi Mei Hospital, Tainan (Y.C.) - both in Taiwan; USC Norris Comprehensive Cancer Center, Los Angeles (A.B.E.-K.), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (A.P.V., R.K.K.), and Exelixis, Alameda (C.H., A.E.B.-H., G.S.) - all in California; Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano (L.R., T.P.), the Department of Medical and Surgical Sciences, University of Bologna, Bologna (L.B.), and Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padua (V.Z.) - all in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul (B.-Y.R., M.-H.R.), and the National Cancer Center, Goyang (J.-W.P.) - both in South Korea; Trakya University School of Medicine, Edirne, Turkey (I.C.); Groupement Hospitalier Nord, Lyon (P.M.), and Hôpital Haut-Lévêque, Centre Hospitalier Universitaire Bordeaux, Bordeaux (J.-F.B.) - both in France; the Department of Medical Oncology, Academic Medical Center, Amsterdam (H.-J.K.); and the Chinese University of Hong Kong, State Key Laboratory in Oncology in South China, Hong Kong (S.L.C.).



Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma.


A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate.


At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).


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. (Funded by Exelixis; CELESTIAL number, NCT01908426 .).

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