title: Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
abstract: OBJECTIVE
  The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated.
  
  
  METHODS
  Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points.
  
  
  RESULTS
  Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated.
  
  
  CONCLUSIONS
  Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.
authors.affiliation: Department of Oncology, Oslo University Hospital, 0407 Oslo, Norway. kjell.magne.tveit@ous-hf.no
authors.forename: Kjell Magne
authors.initials: KM
authors.lastname: Tveit
authors.forename: Tormod
authors.initials: T
authors.lastname: Guren
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.forename: Seppo
authors.initials: S
authors.lastname: Pyrhonen
authors.forename: Fridbjorn
authors.initials: F
authors.lastname: Sigurdsson
authors.forename: Elin
authors.initials: E
authors.lastname: Kure
authors.forename: Tone
authors.initials: T
authors.lastname: Ikdahl
authors.forename: Eva
authors.initials: E
authors.lastname: Skovlund
authors.forename: Tone
authors.initials: T
authors.lastname: Fokstuen
authors.forename: Flemming
authors.initials: F
authors.lastname: Hansen
authors.forename: Eva
authors.initials: E
authors.lastname: Hofsli
authors.forename: Elke
authors.initials: E
authors.lastname: Birkemeyer
authors.forename: Anders
authors.initials: A
authors.lastname: Johnsson
authors.forename: Hans
authors.initials: H
authors.lastname: Starkhammar
authors.forename: Mette Karen
authors.initials: MK
authors.lastname: Yilmaz
authors.forename: Nina
authors.initials: N
authors.lastname: Keldsen
authors.forename: Anne Berit
authors.initials: AB
authors.lastname: Erdal
authors.forename: Olav
authors.initials: O
authors.lastname: Dajani
authors.forename: Olav
authors.initials: O
authors.lastname: Dahl
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil