Cetuximab and panitumumab are monoclonal antibodies that bind with EGFR and inhibit its downstream signaling pathways. Cetuximab is a monoclonal antibody created from proteins derived from two different species, while panitumumab is a fully human monoclonal antibody. Both of these agents have been studied in combination with FOLFIRI (5-FU/LV + irinotecan) and FOLFOX (5-FU/LV + oxaliplatin) as initial therapy for the treatment of metastatic colorectal cancer. A meta-analysis of randomized controlled trials concluded that there is a clear benefit to the use of EGFR inhibitors in patients with RAS wild-type mCRC.

Several studies have shown that tumors with a mutation in codon 12 or 13 of the RAS (includes KRAS and NRAS) gene are essentially insensitive to EGFR inhibitors, such as cetuximab or panitumumab. Ordinarily, activation of EGFR results in activation of the RAS protein. EGFR inhibitors prevent this activation. However, in cells with certain RAS mutations, the mutant RAS protein is continuously active and appears independent of EGFR regulation. Thus, the involved cell-signaling pathway remains active, whether the EGFR is activated or not.

The NCCN guideline panel recommends RAS genotyping of primary or metastatic tumor tissue in all patients with mCRC. Those patients who prove to have RAS mutations should not be treated with EGFR inhibitors, either alone or in combination with other chemotherapeutic agents, because they are unlikely to benefit from the use of these agents and will be exposed to additional toxicity. The NCCN guideline recommendations related to cetuximab and panitumumab refer only to patients with CRC characterized by the RAS wild-type gene (ie, the gene without codon 12 or 13 mutations).