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Type: Journal article
Title: Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: The NCIC clinical trials group and AGITG co.
Author: Siu, L.
Shapiro, J.
Jonker, D.
Karapetis, C.
Zalcberg, J.
Simes, J.
Couture, F.
Moore, M.
Price, T.
Siddiqui, J.
Nott, L.
Charpentier, D.
Liauw, W.
Sawyer, M.
Jefford, M.
Magoski, N.
Haydon, A.
Walters, I.
Ringash, J.
Tu, D.
et al.
Citation: Journal of Clinical Oncology, 2013; 31(19):2477-2484
Publisher: Amer Soc Clinical Oncology
Issue Date: 2013
ISSN: 0732-183X
Statement of
Lillian L. Siu, Jeremy D. Shapiro, Derek J. Jonker, Chris S. Karapetis, John R. Zalcberg, John Simes, Felix Couture, Malcolm J. Moore, Timothy J. Price, Jehan Siddiqui, Louise M. Nott, Danielle Charpentier, Winston Liauw, Michael B. Sawyer, Michael Jefford, Nadine M. Magoski, Andrew Haydon, Ian Walters, Jolie Ringash, Dongsheng Tu and Chris J. O'Callaghan
Abstract: PURPOSE The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. PATIENTS AND METHODS Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m2 intravenous loading dose followed by weekly maintenance of 250 mg/m2 plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). RESULTS A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. CONCLUSION Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
Keywords: Humans
Colorectal Neoplasms
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Disease-Free Survival
Treatment Failure
Drug Administration Schedule
Odds Ratio
Drug Resistance, Neoplasm
Genes, ras
Middle Aged
Protein-Tyrosine Kinases
Kaplan-Meier Estimate
Antibodies, Monoclonal, Humanized
Rights: © 2013 by American Society of Clinical Oncology
DOI: 10.1200/JCO.2012.46.0543
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