title: Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.
abstract: BACKGROUND
  The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.
  
  
  METHODS
  A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.
  
  
  RESULTS
  Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.
  
  
  CONCLUSIONS
  Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Tormod Kyrre
authors.initials: TK
authors.lastname: Guren
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomsen
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Oncology, Tampere University Hospital, Tampere, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Österlund
authors.affiliation: Department of Oncology, Landspitali, Reykjavik, Iceland.
authors.forename: Fridbjörn
authors.initials: F
authors.lastname: Sigurdsson
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Inger Marie Bowitz
authors.initials: IMB
authors.lastname: Lothe
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Astrid Marie
authors.initials: AM
authors.lastname: Dalsgaard
authors.affiliation: Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Eva
authors.initials: E
authors.lastname: Skovlund
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kjell Magne
authors.initials: KM
authors.lastname: Tveit
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D055815:Young Adult
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil