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
The Lancet,  Clinical Article

Maughan TS et al. – 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.

Methods

  • In this randomised controlled trial, patients 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)
  • Choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation
  • Randomization done centrally (via telephone) by MRC Clinical Trials Unit using minimization
  • Treatment allocation was not masked
  • Comparison of arms A and C is described in companion paper
  • Comparison of arm A and B, for which primary outcome was OS in patients with KRAS wild-type tumours
  • Analysis was by intention to treat
  • Further analyses with respect to NRAS, BRAF, and EGFR status done

Results
  • 1630 patients randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab)
  • Tumour samples from 1316 (81%) patients 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)
  • No effect on PFS (8·6 months [IQR 5·0—12·5] in control group vs 8·6 months [5·1—13·8] in cetuximab group; HR 0·96, 0·82—1·12, p=0·60)
  • ORR 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 increased with cetuximab (14 vs 114 and 67 vs 97 patients in control group vs cetuximab group with KRAS wild-type tumours)
  • OS 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)

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