K-Ras/B-Raf Mutations in Metastatic Colorectal Cancer

The KRAS gene encodes a protein centrally involved in EGFR signal transduction. Studies have shown that the anti-EGFR monoclonal antibody therapies do not work on colorectal and lung tumors that carry a mutant form of the KRAS gene.^1,2

In 2009, the US Food and Drug Administration updated the labels of two anti-epidermal growth factor receptor (EGFR) antibody drugs to include information about testing the KRAS gene for mutations.

Amgen's Vectibix® and ImClone/Bristol-Myers Squibb's Erbitux® labels now include the following statement: "retrospective analyses of metastatic colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13".

Labeling changes have been implemented in the INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, and CLINICAL STUDIES sections of both cetuximab and panitumumab product labels.

The following new information has been added to the cetuximab label:

The following new information has been added to the panitumumab label:

Statistical studies have shown that up to 40% of colorectal and 25% of non-small cell lung carcinoma tumors exhibit mutations in codons 12 and 13 of the KRAS gene.² Activating mutations in codon 61 account for another 1-4%.³ Mutations in BRAF, another key player in the EGFR signaling pathway, are found in approximately 10% of metastatic colorectal tumors.⁴

Retrospective studies have shown that tumors carrying any one of these mutations do not respond to anti-EGFR monoclonal antibody therapy.⁵ Since all of these mutations are mutually exclusive of each other, it is important to assess the mutation status of these genes prior to administering anti-EGFR therapy.

References

1. Amado et al., Journal of Clinical Oncology. 2008; 26:1626-1634
2. Cunningham et al., New England Journal of Medicine. 2004; 351:337-345
3. Edkins et al., Cancer Biol Ther. 2006; 5:928-932
4. Di Nicolantonio et al., Journal of Clinical Onology. 2008; 26:5705-5712
5. Loupakis et al., British Journal of Cancer. 2009; 101:715-21