Cetuximab

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Cetuximab (Erbitux) belongs to a class of drugs known as monoclonal antibodies. It works by blocking the function of a protein called the epidermal growth factor receptor (EGFR).  The EGFR is found on the surface of many cancer cells as well as normal cells. It serves as an “antenna,” receiving signals from other cells and the environment that tell the cell to grow and divide. The EGFR plays an important role in growth and development prenatally and during childhood and helps to maintain normal replacement of old and damaged cells in adults. However, many cancer cells have unusually large amounts of the EGFR on their surface, or their EGFR has been altered by mutation of the DNA that carries the genetic code for the protein. The result is that the signals coming from the EGFR are much too strong, leading to excessive cell growth and division, a hallmark of cancer.

How does cetuximab work? 
Cetuximab binds tightly to the portion of the EGFR that extends outside of the cell to receive signals from the environment. Since cetuximab is a large protein molecule, it blocks the EGFR from receiving signals or interacting with other proteins that promote its normal function. EGFR molecules with cetuximab bound to them are removed from the surface of the cell and may be completely degraded. In addition, cetuximab bound to the EGFR on cancer cells ‘tags’ them for killing by cells of the immune system.

How is cetuximab currently used in the clinic?
Cetuximab was first approved by the United States Food and Drug Administration (FDA) in 2004 for use in combination with irinotecan to treat patients with metastatic colorectal cancer who did not respond to irinotecan alone. It was also approved at that time for use as a single agent for patients who did not tolerate therapy with irinotecan. Approval was restricted to use in patients with tumors that have detectable levels of the EGFR, which is expressed in abnormally high amounts in 60 to 80% of colorectal cancer patients.  

In 2006, the FDA approved cetuximab for use in combination with radiotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). Approval was also given for use of cetuximab as a single drug for SCCHN patients with recurrent or metastatic disease for whom prior therapy with platinum-based drugs (cisplatin or carboplatin) had failed. The EGFR is expressed in abnormally high amounts in >80% of SCCHN tumors, and clinical trials showed that cetuximab plus radiation therapy increased overall survival by 67% (from 29 months to 49 months) when compared to survival with radiation therapy alone. 

In 2011, approval was expanded for use of cetuximab in combination with platinum-based drugs and 5-fluorouracil as the first-line treatment for SCCHN patients who suffer from recurrent local disease or metastatic disease not curable by surgery or radiation. In this group of patients, the addition of cetuximab to chemotherapy increased overall patient survival by 36% (2.7 months). 

A new use for cetuximab in colorectal cancer was approved in 2012. In this case, cetuximab combined with FOLFIRI (chemotherapy with irinotecan, 5-fluorouracil, and leucovorin) was approved as first-line treatment of patients with metastatic colorectal cancer. In this case, the FDA specified that a patient’s tumor must not have a mutation in the gene for the protein KRAS, and it also approved a test to be used to check for KRAS mutations. KRAS mutations occur in about 30% of colorectal cancers, and clinical trials had shown that patients with these mutations did not respond well to cetuximab. For patients without KRAS mutations, adding cetuximab to FOLFIRI increased the response rate to 57.3% versus 39.7% and extended overall survival to 23.5 months from the 20.0 months obtained with FOLFIRI alone.

Patients taking cetuximab usually tolerate the drug quite well. The most common side effects are a skin rash and low magnesium levels in the blood. Cetuximab must be given by injection, and allergic-type reactions during the injection are also common. These can usually be prevented by treatment with an antihistamine before administering the drug.

In which patients is cetuximab most effective?
In all of its approvals, the FDA has specified that cetuximab should only be used for cancers that contain the EGFR. However, it is surprising that clinical studies have been unable to show that response to cetuximab is better for tumors with high levels of the EGFR than for tumors with low levels of the protein. Unlike the case of the tyrosine kinase inhibitors that block the EGFR (gefitinib, erlotinib, and afatinib), which work best on tumors that carry mutations in the gene for the EGFR, cetuximab works equally well on normal and abnormal EGFR proteins. As noted above, however, there is one group of patients who respond very poorly to cetuximab. These are patients with tumors that have a mutant form of KRAS. The KRAS protein plays an important role in transmitting signals from the EGFR to other proteins in the cell. The mutations of KRAS that lead to cetuximab resistance result in an overactive protein that is totally independent of the EGFR. Thus, in tumors bearing these mutations, blocking the EGFR with cetuximab has no effect.
 

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