The largest clinical trial of epidermal growth factor receptor (EGFR)-targeted, first-line treatment of advanced colorectal cancer demonstrated negative results overall. Nevertheless, researchers identified possible subgroups of patients who may benefit from the addition of cetuximab (Erbitux) to oxaliplatin-based chemotherapy.

Findings of the study, the UK-based Medical Research Council's Cetuximab and Oxaliplatin (MRC COIN) trial, were presented at the 2010 ASCO Annual Meeting during the Gastrointestinal Cancer Oral Abstract Session.

No Benefit in Total Population

For the total population of 2,445 patients, the addition of cetuximab to the chemotherapy regimen did not change the overall survival (OS) or progression-free survival (PFS), according to principal investigator Timothy Maughan, MD, Professor of Cancer Studies, Cardiff University School of Medicine, Cardiff, United Kingdom.

"This result runs contrary to what we expected," Dr. Maughan said.

The investigators recruited patients from the United Kingdom and Ireland who had inoperable colorectal cancer and had never received chemotherapy. This study aimed to determine whether OS improves when the monoclonal antibody cetuximab is added to continuous chemotherapy with oxaliplatin and a fluoropyrimidine-either oral capecitabine (Xeloda) or infusional fluorouracil (5-FU) plus leucovorin.

Among the tumor samples that underwent gene mutation analysis, approximately 55% of the tumors expressed the normal wild-type form of the KRAS gene, 43% had KRAS mutations, 8% had BRAF mutations, and 4% had NRAS mutations. Among patients with wild-type tumors, the 2-year survival rate was similar between treatment arms: 40% in the control arm and 38.8% in the cetuximab arm, Dr. Maughan reported. He said it is unclear why survival was poor in both arms.

Patients with wild-type KRAS who received cetuximab had a better overall response rate than did the control arm (64% vs 57%, respectively), as assessed by the investigators. Furthermore, for the total population, fewer patients receiving cetuximab received second-line therapy than those in the control arm (56% vs 62%).

Predictive Covariates

Subgroup analyses showed improved survival with added cetuximab therapy for patients with one or fewer metastatic sites at baseline who had no KRAS, BRAF, or NRAS mutations, he said.

Independent of the use of cetuximab, the median survival in patients with any mutation was only 12.7 months compared with 19.9 months for all wild-type patients. According to Dr. Maughan, this difference showed a strong prognostic factor for KRAS status.

KRAS Analysis of Interest

Discussant Alan Venook, MD, called the results disappointing overall. He questioned the conclusions about the subgroup analyses and said the message from this trial is unclear.

"What's new and, I think, provocative is the analysis of KRAS mutations, that KRAS mutation may be prognostic and predicts nonresponse to EGFR antibodies," said Dr. Venook, Professor of Clinical Medicine at the University of California, San Francisco.

Merck Serono helped fund this study, as did the MRC and Cancer Research UK.

Reference

1. Maughan TS, Adams R, Smith CG, et al: Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial. 2010 ASCO Annual Meeting. Abstract 3502. Presented June 6, 2010.