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Gefitinib (Iressa) belongs to a class of drugs known as tyrosine kinase inhibitors. 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 gefitinib work?
When the EGFR receives a signal, it transmits it into the cell by causing a chemical reaction that modifies other proteins. The portion of the EGFR protein that carries out this function is called the tyrosine kinase domain. The ability of the tyrosine kinase domain of the EGFR to modify other proteins is critical to the EGFR’s ability to signal cells to grow and divide. This led researchers to look for a drug that attaches to the EGFR tyrosine kinase domain, blocking its ability to function. Gefitinib does just that. 

How is gefitinib currently used in the clinic?
Gefitinib was approved by the United States Food and Drug Administration (FDA) in 2003 to be used alone for the treatment of patients with advanced non-small cell lung cancer who had relapsed after prior chemotherapy. Approval was based on clinical trials in which 9 to 18% of patients responded to the drug. In addition, the one year survival rate for the treated patients increased to 30% as compared to 5%, which was the usual outcome with standard therapy. Patients taking gefitinib tolerated the drug well. The most common side effects were a skin rash and diarrhea. Larger clinical trials, however, failed to show that gefitinib increased overall survival for lung cancer patients, and the FDA withdrew approval in 2005. Gefitinib is still used in Europe and Asia. In the United States, it has been largely replaced by erlotinib (Tarceva).

In which patients is gefitinib most effective?
Over the past decade, clinicians have gained considerable experience with tyrosine kinase inhibitors that block the EGFR. It has become increasingly clear that these drugs work best in a specific subgroup of lung cancer patients. These are patients whose lung cancer carries a particular kind of mutation that results in an abnormal EGFR protein. They are most likely to be of Asian descent, women, and never smokers with a form of lung cancer known as brochoalveolar adenocarcinoma. These findings make it clear that the best use of targeted therapies such as gefitinib requires an individualized approach to each patient, so that the therapy is designed to be just right for the precise characteristics of that patient’s cancer.


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