v4n2 - EGFR: Who Will Benefit from New Therapies?

In the early 1950s, Stanley Cohen, MD, began working on nerve growth factors, which are involved in the development of the nervous system. By chance, he identified a growth factor involved in the growth of skin cells. He called this new factor epidermal growth factor (EGF)

Besides skin cells, he found that EGF was involved in the growth of other cells, including those of the liver, lungs and ovaries. In 1980, Dr. Cohen found that EGF binds to a very specific receptor in the cell (EGFR). These receptors, when bound to EGF, are called tyrosine kinase receptors—enzymes that are central to the growth and survival of cells. Usually, EGF binds to the receptor site of a cell and sends a signal inside the cell to replicate. Similar receptors have now been found, including the receptors for vascular endothelial growth factor (VEGF). In 1986, Dr. Cohen was awarded the Nobel Prize for his work involving growth factors.

Researchers have known for 20 years that cancer cells have extra amounts of EGFR compared with normal cells, and blocking EGFR was thought to be a possible way to treat cancer. In 2004, Erbitux™ (cetuximab), an antibody targeting EGFR, was approved for advanced colon cancer, and Tarceva, an oral EGFR inhibitor, was approved for lung cancer. Although each drug represented a breakthrough as targeted agents, they caused tumor shrinkage in only a small percentage of patients.

In 2004, a large study of Iressa, another oral EGFR inhibitor, failed to prolong survival in lung cancer patients. At the American Association of Cancer Research meeting held in April 2005, a detailed analysis of this study reported that Iressa might be appropriate in only a certain subset of lung cancer patients (those who never smoked, adenocarcinoma patients and Asian patients). Based on the recent trial results, the FDA limited use of Iressa as of June 17, no longer allowing the drug to be used in newly diagnosed lung cancer patients. Tarceva, on the other hand, has been found to be effective in all categories of advanced lung cancer patients.

Role of EGFR Mutations and Amplifications

In the summer of 2004, researchers from Harvard University found that many patients with lung cancer had a genetic mutation within the EGFR that often caused the signal to remain “turned on”—a state that causes abnormal replication and survival of lung cancer cells.

The EGFR mutation is found in only about 10 percent of all lung cancer patients and is more common in female patients or patients without a history of smoking. A higher proportion of lung cancer patients from Asian countries have this mutation as well—as many as 40 percent.

Patients whose lung cancer has this mutation respond better to drugs like Tarceva and Iressa. Although less than 10 percent of patients see their tumors shrink to at least half with these drugs, the tumor shrinkage rate in these patients can be as high as 80 percent.

Besides mutations in the EGFR, some patients’ tumors carry extra copies of the EGFR gene (this is called gene amplification). Fred Hirsch, MD, from the University of Colorado, recently showed that patients whose tumors have amplification of the EGFR gene, which can be detected by a technique called fluorescent in situ hybridization, are more likely to respond to drugs like Tarceva.

Resistance to Targeted Agents

Although lung cancer patients with EGFR mutations can have dramatic results with EGFR inhibitors, these drugs are not cures. Recent studies suggest that acquired resistance to Tarceva or Iressa is often caused by a secondary mutation in the EGFR that prevents Iressa or Tarceva from binding to it.

Similar secondary mutations in the tyrosine kinase areas are found in the bcr-abl protein, the mutation that causes Gleevec resistance in patients with chronic myelogenous leukemia (see “Treatment Transition”). But patients with secondary mutations may still respond to monoclonal antibodies like Erbitux and panitumumab (ABX-EGF) that bind to the external portion of EGFR.

The Era of Individualized Medicine

Roman Perez-Soler, MD, says that as oncologists explore specific pathways, they have come to realize that treatment may have to be based on a patient’s specific genetic abnormalities.

“ As we understand more and more the biology of cancer, we understand that not all lung cancers are made equal,” Dr. Perez-Soler says. “While they may look similar under the microscope, they are different biochemically and genetically, and as a result, what may work for one may not work for another. ”

Dr. Perez-Soler says from a patient’s point of view, this development of targeted agents could be good news. “We can develop specific therapies for specific tumors,” Dr. Perez-Soler says. “We are moving to a form of therapy that is more individualized and more based on how the tumor is made genetically. I think the process has started and it’s just going to go more and more in that direction.”