Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in fi rst-line treatment of advanced colorectal cancer with the aim of assessing eff ect on overall survival. Methods In this randomised controlled trial, patients who were fi t for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fl uoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fl uoropyrimidine therapy (capecitabine or infused fl uouroracil 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. Findings 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 diff er 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 eff ect on progressionfree 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 eff ects 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 diff ers 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). Interpretation This trial has not confi rmed a benefi t of addition of cetuximab to oxaliplatin-based chemotherapy in fi rst-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefi t 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 fi rstline chemotherapy in patients with widespread metastases cannot be recommended.
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