Josep M. Llovet and Charissa Chang, Icahn School of Medicine at Mount Sinai, New York, NY; Josep M. Llovet and Jordi Bruix, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) -Hospital Clinic, University of Barcelona, Barcelona, Spain; Thomas Decaens, University of Paris-Est, and Institut National de la Santé et de la Recherche Médicale, Creteil; Jean-Luc Raoul, Institut Paoli Calmette, Marseille; Eveline Boucher, Service d'Oncologie Médicale, Central Eugene Marquis, Rennes; Eric Assenat, Hôpital Saint Eloi, Montpellier; Valerie Boige, Institut Gustave Roussy, Villejuif; Philippe Mathurin, Hôpital Claude Huriez, Lille; Laetitia Fartoux, Hôpital Saint Antoine, Paris; Jean-Frederic Blanc, Saint-Andre Hospital, Bordeaux, France; Masatoshi Kudo, Kinki University School of Medicine, Osaka, Japan; Yoon-Koo Kang, Asan Medical Center; Ho-Yeong Lim, Samsung Medical Center, Seoul; Won-Young Tak, Kyungpook National University Hospital, Daegu; Joong-Won Park, National Cancer Center, Goyang, Republic of Korea; Deng-Yn Lin, Chang Gung Memorial Hospital and Chang Gung University; Yee Chao, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Ronnie T. Poon, University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China; Morris Sherman, Toronto General Hospital, Toronto, Ontario, Canada; Richard S. Finn, University of California at Los Angeles, Los Angeles, CA; and Rana Ezzeddine, David Liu, and Ian Walters, Bristol-Myers Squibb, Wallingford, CT.
Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib.
PATIENTS AND METHODS:
In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety.
Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%).
In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.