Cetuximab (brand name Erbitux) is a monoclonal antibody used in the treatment of metastatic colorectal cancer (mCRC) and cancer of the head and neck. Cetuximab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered as a weekly intravenous (IV) infusion, but in practice, is often given every other week to coincide with chemotherapy (for example, FOLFIRI or FOLFOX). Cetuximab has several off-label uses as well, which include non-small cell lung cancer, squamous cell carcinoma of the skin, and Menetrier’s disease.
Interestingly, for colorectal cancer, the location of the primary tumor influences whether an individual with mCRC will respond to anti-EGFR therapy, and influences prognosis. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, currently only the mutation status of the tumor, and not the location of the tumor, is discussed in the drug label’s dosing recommendations.
Resistance to cetuximab is associated with specific RAS mutations. The RAS family of oncogenes includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors.
The KRAS mutations often lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and are associated with resistance to anti-EGFR drugs such as cetuximab. In addition, mutations in NRAS and another gene, BRAF, have been associated with poor response to anti-EGFR therapy; however, BRAF mutation does not explicitly preclude anti-EGFR therapy. Combination therapies targeting both BRAF and EGFR have shown to improve survival for individuals with wild-type RAS and mutant BRAF.
The 2018 FDA-approved drug label for cetuximab states that for mCRC, cetuximab is indicated for K- and N-RAS wild-type (no mutation), EGFR-expressing tumors. The label states that an FDA-approved test must be used to confirm the absence of a RAS mutation (in either KRAS or NRAS) prior to starting cetuximab (Table 1) (1). While the FDA label also states that EGFR expression should also be confirmed by an approved test prior to starting therapy for mCRC, this is largely not implemented in practice, nor is it recommended by professional oncology society guidelines.
Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have mutations detected after extended RAS testing (Table 2) (2).
The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to cetuximab (and panitumumab) highly unlikely unless given a BRAF inhibitor (Table 3) (3).