title: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials.
abstract: BACKGROUND
  The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.
  
  
  METHODS
  Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests.
  
  
  RESULTS
  In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p<0.001) and ORR (odds ratio 2.16; p<0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.
  
  
  CONCLUSIONS
  Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Hamburg, Germany. c.bokemeyer@uke.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeger
authors.forename: Michael
authors.initials: M
authors.lastname: Schlichting
authors.forename: Ilhan
authors.initials: I
authors.lastname: Celik
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018631:ras Proteins; D000068818:Cetuximab