title: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.
abstract: BACKGROUND
  In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
  
  
  METHODS
  In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
  
  
  RESULTS
  1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3-29·2] in the control group vs 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all wild-type, 20·1 months (11·5-31·7).
  
  
  CONCLUSIONS
  This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.
  
  
  BACKGROUND
  Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Adams
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.forename: Angela M
authors.initials: AM
authors.lastname: Meade
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Seymour
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kenny
authors.forename: Edward
authors.initials: E
authors.lastname: Kay
authors.forename: Jenna K
authors.initials: JK
authors.lastname: Mitchell
authors.forename: Ayman
authors.initials: A
authors.lastname: Madi
authors.forename: Bharat
authors.initials: B
authors.lastname: Jasani
authors.forename: Michelle D
authors.initials: MD
authors.lastname: James
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: Bart
authors.initials: B
authors.lastname: Claes
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; 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; D003841:Deoxycytidine; D000069287:Capecitabine; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D005472:Fluorouracil