When traditional therapies fail in cancer treatment, turning off a chemical switch may offer hope to the hopeless.
Thomas Morrow, MD
Recent anticancer therapies have grabbed the headlines. In this month's Tomorrow's Medicine, I would like to focus on a new class of drug that offers an option where none existed in the past.
Last May, gefitinib, brand name Iressa, received the approving nod of the FDA. Iressa inhibits the intracellular phosphorylation of numerous tyrosine kinases. Tyrosine kinases are proteins that can attach a phosphate group to the amino acid tyrosine. This action serves at least two basic roles: It allows two proteins to bind to one another, and it can serve as a switch that turns a function on or off. Thus, tyrosine kinases act like small keys that can regulate a cascade of events, including cellular division. Tyrosine kinase can be a freestanding enzyme within a process or it can be associated with a receptor that is a trigger for a cascade of processes — aptly named a tyrosine kinase receptor. A receptor is simply a docking point for an outside chemical, much like a docking port for the space shuttle on the space station.
Variety of functions
Some tyrosine kinase receptors are present on the outside of cell walls and have a variety of functions. The one that has grabbed recent attention is a tyrosine kinase associated with a specific transmembrane cell surface receptor. This means it is a receptor that transfers a signal from the outside to the inside of a cell. This tyrosine kinase receptor is named epidermal growth factor receptor (EGFR). Sometimes these receptors are "stuck" in the on position because of a mutation, perhaps due to a damaging chemical component of cigarette smoke or a dose of radiation. In this case, the cells are constantly dividing in an uncontrolled fashion, a condition called cancer. Because phosphorylation by the tyrosine kinase triggers the start of division, an inhibitor of this phosphorylation could potentially turn off the process. This inhibitor action can actually cause cell death.
Tyrosine kinase is expressed in normal cells as well as cancer cells. AstraZeneca, the manufacturer of gefitinib, is careful to point out that there have been no clinical studies that have been performed that demonstrate a correlation between the EGFR expression and response to gefitinib. In fact, the mechanism of action of gefitinib is not understood.
Preventing cellular division
One item of interest to those who read this column is that numerous drugs are now in some way targeting the epidermal or epithelial growth factor receptor as well as other tyrosine kinases. EGF receptors are a key factor in cellular division. It appears that growth-promoting EGF proteins link up with a cell via the EGF receptor, thus setting up a cascade of signals that results in cell proliferation. Some examples of drugs that work on the EGF pathways are trastuzumab (Herceptin) and cetuximab (Erbitux). Both of these tyrosine kinase inhibitors are proteins that block the EGF protein from "docking" with the receptor and prevent cancer cellular proliferation.
Iressa is not a protein, but it uses the EGF receptor site as a portal to enter the cell. Iressa "jams" the cascade of signals along its pathway to prevent cellular proliferation. Herceptin works in those women whose breast cancer expresses the HER2 receptor, a receptor closely related to the EGF receptor. Another relatively new drug, imatinib (Gleevec), targets an intracellular protein that communicates in a way similar to the EGF receptor. This drug has revolutionized the treatment for chronic myeloid leukemia and is undergoing clinical trials in other malignancies.
All of these drugs target one step in what appears to be a rather complicated and circuitous pathway toward cellular division. Some types of cancers are thought to be more dependent upon a single pathway to proliferation than others. Trials are under way to determine which cancers use the single pathway. But cancer cells have the ability to adapt and to evolve to avoid these traps. This is demonstrated clearly in the fact that Gleevec has high initial response rates, but is ineffective in cancer cells that have undergone mutation and use other pathways to divide. This eventually leads to a decreased response to therapy, as those cells that have the mutated pathway survive and become the predominant tumor subtype. This leads oncologists to a conclusion similar to the approach that infectious disease specialists have used for years to treat bacterial and HIV infections: Block sequential pathways to cell proliferation and conquer the disease.
Unlike Herceptin, Iressa (as well as Gleevec and Erbitux) has no laboratory test to identify those patients who might benefit. The response is not predictable in individuals. The response rate was found to be highly variable in subgroups and ranged from 5.1 percent in males to 17.5 percent in females, 29.4 percent in nonsmokers and 4.6 percent in previous or current smokers. The cause of this variability is unknown. The low response rate in smokers is unfortunate as smoking is a major risk factor for the development of lung cancer.
The FDA approved Iressa as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel therapies. It is not indicated in patients who have not attempted the other therapies. Iressa is also not without side effects. It may cause interstitial lung disease and hepatotoxicity. It has also been reported to cause corneal erosions.
Iressa has made a huge difference to some people in reducing the size of their tumor. In fact, the FDA approved Iressa based upon its effect on tumor size. But Iressa has not been proven to improve survival or symptoms, a fact that should not escape managed care. In addition, this drug only improves the size of the tumor in 10 percent of recipients overall. This seems like a minor improvement, but remember that these patients have not responded to traditional therapy.
How should managed care respond? First, the ability to give hope to 10 percent of people with NSCLC who have failed the cytotoxic therapies is a dramatic breakthrough. But this comes at a relatively high price: 9 out of 10 people using this drug will probably have no response.
Initial prior-authorization requirements are needed. Guidelines for continuing the drug should be developed. You will also face numerous requests from oncologists to provide this drug — along with other kinase inhibitors — in off-label use, by well-meaning physicians who are offering the only hope left to their patients.
Finally you also must maintain your vigilance, as many more anticancer medications that utilize tyrosine kinase effects will become available to offer hope to patients; these agents will be the subject of upcoming columns in Tomorrow's Medicine!
Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 19 years of managed care experience at the payer or health plan level.