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Afatinib (Gilotrif) belongs to a class of drugs known as tyrosine kinase inhibitors. It works by blocking the function of two closely related proteins, the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2).  The EGFR and HER2 proteins are found on the surface of many cancer cells as well as normal cells. The EGFR serves as an “antenna,” receiving signals from other cells and the environment that tell the cell to grow and divide. 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 HER2 protein also contains a tyrosine kinase domain, although it lacks the EGFR’s ability to receive signals from outside of the cell. HER2 often works in concert with the EGFR to transmit signals within the cell. 

The EGFR and HER2 play important roles in growth and development prenatally and during childhood, and they help to maintain normal replacement of old and damaged cells in adults. However, many cancer cells have unusually large amounts of EGFR and/or HER2 on their surface. Alternatively, one or both proteins may be altered by mutation of the DNA that carries the genetic code for the protein. The result is that the signals are much too strong, leading to excessive cell growth and division, a hallmark of cancer.

How does afatinib work? 
The ability of the tyrosine kinase domains of the EGFR and HER2 to modify other proteins is critical to their ability to signal cells to grow and divide. This led researchers to look for a drug that attaches to the tyrosine kinase domain, blocking its ability to function. Usually, investigators try to find a drug that binds to and blocks the tyrosine kinase domain of only one protein. For example, gefitinib and erlotinib are tyrosine kinase inhibitors that strongly block only the EGFR. However, afatinib’s ability to block both the EGFR and HER2 might actually be an advantage, a possibility that is being investigated ongoing clinical trials.

How is afatinib currently used in the clinic?
Afatinib was approved by the United States Food and Drug Administration (FDA) as the first-line treatment for a subset of patients with advanced non-small cell lung cancer. The patients for which afatinib was approved have lung cancer that carries a particular kind of mutation that results in an abnormal EGFR protein. These patients are most likely to be of Asian descent, women, and never smokers with a form of lung cancer known as bronchoalveolar adenocarcinoma. Clinical experience with erlotinib and gefitinib has shown that these patients respond particularly well to tyrosine kinase inhibitors that block the EGFR. This proved to be true for afatinib as well, which increased the progression-free survival of this group of patients to 13.6 months as compared to only 6.9 months for patients treated with standard chemotherapy. Erlotinib is also approved in the United States as a first-line treatment for this subgroup of patients. Longer clinical experience will be needed to determine which drug is the best choice. Afatinib may be somewhat more potent than erlotinib, but its side effects, primarily rash and diarrhea, are also more severe.

How is afatinib different from gefitinib and erlotinib?
Afatinib is different from gefitinib and erlotinib in that it blocks HER2 in addition to the EGFR, rather than the EGFR alone. In addition, afatinib attaches permanently to the tyrosine kinase domain of the EGFR and HER2, so its effects are irreversible. This is different from both gefitinib and erlotinib, which attach to the EGFR in a reversible manner. The irreversible attachment of afatinib makes it a more potent drug than gefitinib or erlotinib. Afatinib can also attach to some mutant forms of the EGFR that are resistant to gefitinib and erlotinib.

How might afatinib be used in the future?
An overactive HER2 protein plays an important role in driving the out-of-control growth of some breast cancers. Afatinib may be an effective therapy for these cancers, due to its ability to block HER2. Clinical trials are currently underway to test this possibility. Afatinib’s ability to block mutant EGFR proteins that do not respond to gefitinib and erlotinib led investigators to hope that afatinib would be an effective therapy for patients who develop resistance to these drugs. Clinical trials testing afatinb alone for these patients have not been very encouraging. However, a recent trial testing a combination of afatinib with cetuximab (Erbitux) seems more promising. Some squamous cell head and neck cancers respond to therapies that block EGFR activity, so clinical trials are underway to test afatinib’s effectiveness for these patients, as well.


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