Many tumours contain mutations in the epidermal growth factor receptor (EGFR), a gene that encodes a tyrosine kinase that acts as a powerful oncogene and that is now a very important cancer drug target. In lung cancer, the efficacy of small-molecule EGFR inhibitors is limited to those tumours that carry mutations in this gene. In colorectal cancer, however, most success has been observed with antibodies directed against EGFR, and then only in patients without mutations in another gene in the EGFR pathway, KRAS.

 The COIN trial, set up by the UK’s Medical Research Council (MRC), is the largest clinical trial to date to test the addition of an anti-EGFR antibody, cetuximab, to standard chemotherapy regimens in the first-line treatment of advanced colorectal cancer. It had three arms: continuous standard chemotherapy, in this case a combination of oxaliplatin with a fluoropyrimidine (arm A); continuous chemotherapy combined with cetuximab (arm B); and standard chemotherapy with preplanned treatment interruptions (arm C). This first of a pair of papers by the MRC COIN trial investigators presents a comparison of arms A and B¹; the effect of treatment interruptions is described in a companion paper² and will be summarised separately. 

The complete protocol for the COIN trial is available on the MRC clinical trials website³. A total of 2445 patients with advanced colorectal cancer who had not received prior chemotherapy but were considered well enough to do so were assigned at random, without blinding, to the three equal arms. Tumour samples were obtained from all patients and assessed for EGFR expression and for commonly occurring mutations in KRAS and in two other genes in the EGFR pathway, NRAS and BRAF. The primary objective of the trial was to determine the effect of the treatments on overall survival in patients with wild-type KRAS; secondary objectives were to evaluate differences in overall survival in subgroups with mutations in all or any of these genes and in the whole cohort, and differences in progression-free survival, response, and toxicity.

Tumour samples from eighty-one percent of patients were suitable for mutation analysis. 43% of these samples carried mutations in KRAS, 8% in BRAF and 4% in NRAS. Eleven patients carried mutations in both KRAS and NRAS, and 44% of patients carried none. Differences in demographics and baseline characteristics between the patients randomised to all three arms were insignificant. The median follow-up period was 21 months for the control arm A and 23 months for arm B.

Surprisingly, and disappointingly, the COIN investigators found that the addition of cetuximab to conventional chemotherapy conferred no survival benefit, either in patients with wild-type KRAS – the sub-group that had been predicted to be the most likely to benefit – or in the complete cohort. In patients with wild-type KRAS, median survival was 17.0 months in the cetuximab group compared to 17.9 months in the control group (confidence interval 0·87–1·23, p=0·67). These results were mirrored in the whole cohort and in the other defined sub-groups, indicating that there was no group of patients, at least as defined by the tested genes, in which cetuximab conferred a survival benefit. Furthermore, no statistically significant differences were observed in progression-free survival. As expected, overall survival and progression-free survival times were significantly greater in patients who were wild-type in all three genes than in patients carrying any mutations, whichever treatment they received. The incidence of severe (Grade 3 and above) skin and gastro-intestinal toxicity was higher in the group receiving cetuzimab than in the control arm.

The COIN investigators concluded by emphasising that these results were unexpected and that some other trials have showed a benefit in combining an ant-EGFR antibody with chemotherapy for colorectal cancer patients with KRAS mutations. They attributed the lack of benefit in this trial largely to the particular chemotherapy drugs used, and suggested that although cetuximab cannot be recommended in combination with oxaliplatin and capecitabine in these patients, further trials of this drug in combination with other chemotherapy agents and in patient groups with different mutation profiles would be useful.

References

1. Maughan, T.S., Adams, R.A., Smith, C.G. and 18 others, on behalf of the MRC COIN Trial Investigators (2011) 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, published online ahead of print 4 June 2011.

2. Adams, R.A., Meade, A.M., Seymour, M.T. and 17 others, on behalf of the MRC COIN Trial Investigators (2011). Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial The Lancet Oncology, published online ahead of print 4 June 2011.