ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company (BMS) announced that the US Food and Drug Administration (FDA) has approved revisions to the US prescribing information for Erbitux (cetuximab) concerning the treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC).

The labelling revisions include a modification to the indication, which now includes a statement that retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumours had K-ras mutations in codon 12 or 13 and that the use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations. Revisions concerning the use of Erbitux in colorectal cancer tumours with K-ras mutations were also made to the clinical studies and clinical pharmacology sections of the product's prescribing information.

Recently, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network issued guidelines recommending that all mCRC patients be tested for K-ras gene mutations prior to treatment with an anti-EGFR monoclonal antibody therapy (mAb). Based upon these expert guidelines and the recent labelling update, ImClone Systems, Bristol-Myers Squibb and Lilly recommend that all patients should be tested for K-ras mutational status when considering treatment options for colorectal cancer patients.

In mCRC, Erbitux is approved by the FDA as: a single agent for the treatment of EGFR-expressing mCRC after failure of both irinotecan- and oxaliplatin-based regimens; a single agent for the treatment of EGFR-expressing mCRC in patients who are intolerant to irinotecan-based regimens; and in combination with irinotecan for the treatment of EGFR-expressing mCRC in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma. Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumours had K-ras mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations.

An estimated 40 per cent of patients with mCRC have K-ras mutations while the majority, approximately 60 per cent, has a wild-type K-ras gene. Signal transduction through the EGFR results in activation of wild-type K-ras protein. However, in cells with activating K-ras somatic mutations, the mutant K-ras protein is continuously active and appears independent of EGFR regulation.

"This revision is being included in the labelling of EGFR monoclonal antibody inhibitors with metastatic colorectal cancer indications in the US and is the result of a collaborative dialogue between the FDA, the industry and the public about the role of the K-ras biomarker in metastatic colorectal cancer patients being considered for therapy," said Eric K Rowinsky, executive vice president and chief medical officer of ImClone Systems.

This revision is based on retrospective analyses across seven randomized clinical trials that suggest anti-EGFR mAbs are not effective for the treatment of patients with mCRC containing K-ras mutations. In these trials, patients received standard of care (i.e., BSC or chemotherapy) and were randomized to receive an anti-EGFR antibody (cetuximab or panitumumab) or no additional therapy. In all studies, investigational tests were used to detect K-ras mutations in codon 12 or 13. The percentage of study populations for which K-ras status was assessed ranged from 23 to 92 per cent.

"The inclusion of K-ras as a biomarker in the Erbitux labelling helps physicians to better understand the most appropriate use of the drug in the management of patients with metastatic colorectal cancer," said Fouad Namouni, executive director, Erbitux, Oncology Medical Strategy for Bristol-Myers Squibb.

Erbitux (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumour cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1).