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.20 Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Princess Margaret Hospital, Toronto, ON, Canada. lillian.siu@uhn.ca
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Shapiro
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.forename: Chris S
authors.initials: CS
authors.lastname: Karapetis
authors.forename: John R
authors.initials: JR
authors.lastname: Zalcberg
authors.forename: John
authors.initials: J
authors.lastname: Simes
authors.forename: Felix
authors.initials: F
authors.lastname: Couture
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Price
authors.forename: Jehan
authors.initials: J
authors.lastname: Siddiqui
authors.forename: Louise M
authors.initials: LM
authors.lastname: Nott
authors.forename: Danielle
authors.initials: D
authors.lastname: Charpentier
authors.forename: Winston
authors.initials: W
authors.lastname: Liauw
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sawyer
authors.forename: Michael
authors.initials: M
authors.lastname: Jefford
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Magoski
authors.forename: Andrew
authors.initials: A
authors.lastname: Haydon
authors.forename: Ian
authors.initials: I
authors.lastname: Walters
authors.forename: Jolie
authors.initials: J
authors.lastname: Ringash
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Chris J
authors.initials: CJ
authors.lastname: O'Callaghan
mesh_terms: D000328:Adult; D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D011905:Genes, ras; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017211:Treatment Failure; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D014227:Triazines; C509922:brivanib; D011505:Protein-Tyrosine Kinases; D000409:Alanine; D000068818:Cetuximab