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Erlotinib (Tarceva) 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 erlotinib 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. Erlotinib does just that. 

How is erlotinib currently used in the clinic?
Erlotinib was first approved by the United States Food and Drug Administration (FDA) for use in patients with advanced non-small cell lung cancer who had relapsed after at least one other kind of therapy. In 2005, it was approved for use in combination with another drug, gemcitabine, for advanced pancreatic cancer. In 2010, its use was expanded to include maintenance therapy for patients with advanced non-small cell lung cancer whose disease was stable after four cycles of treatment with a platinum-based drug, such as cisplatin or carboplatin. Patients taking erlotinib usually tolerate the drug quite well. The most common side effects are a skin rash and diarrhea.

In which patients is erlotinib most effective?
Over the past decade, clinicians have gained considerable experience with tyrosine kinase inhibitors, like erlotinib, that block the EGFR. It has become increasingly clear that these drugs work best in patients whose lung cancer 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. Thus, in 2013, erlotinib was approved to be the first treatment for this subgroup of patients, if their cancer could not be cured surgically.

What is erlotinib resistance?
Erlotinib is highly effective in the subset of patients carrying EGFR mutations. However, even these patients will eventually begin to show progression of their cancer after about 12 months of erlotinib therapy. This is due to development of resistance to the drug in the residual cancer cells. In many cases, resistance results from the development of a second mutation in the EGFR protein that prevents erlotinib from attaching to the tyrosine kinase domain. New approaches to treating these patients include a recently developed tyrosine kinase inhibitor afatinib (Gilotrif)​, alone or in combination with cetuximab (Erbitux), which inhibits the EGFR by a different mechanism.


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