title: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
abstract: OBJECTIVE
  The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.
  
  
  METHODS
  Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.
  
  
  RESULTS
  The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.
  
  
  CONCLUSIONS
  The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.
authors.affiliation: University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. eric.vancutsem@uz.kuleuven.ac.be
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: István
authors.initials: I
authors.lastname: Láng
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.forename: Marek P
authors.initials: MP
authors.lastname: Nowacki
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Igor
authors.initials: I
authors.lastname: Shchepotin
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Michael
authors.initials: M
authors.lastname: Schlichting
authors.forename: Angela
authors.initials: A
authors.lastname: Zubel
authors.forename: Ilhan
authors.initials: I
authors.lastname: Celik
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; 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; D002166:Camptothecin