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Why a Lung Cancer Drug Works So Well for Some People

By Kate Ruder

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Lung Cancer
Personalized Medicine

The lung cancer drug Iressa has had strikingly positive effects for some of the people who take it. Their tumors shrink by more than 50 percent, and they live months and sometimes years longer than expected.

But only ten percent of the people who take the drug improve, and doctors and researchers have been asking the same question: Why does Iressa work so well for some people and not for others? As two new studies report today, the answer lies with genes.

Two groups of researchers working independently at Harvard hospitals have discovered that people who respond to Iressa have common mutations in their tumors; people without the mutations do not respond to the drug.

Doctors could soon begin screening for these mutations to find patients who are likely to benefit most from Iressa. Researchers from Massachusetts General Hospital have filed a patent on a diagnostic test that is in the early stages of development.

Iressa and drugs such as Gleevac and Tarceva are part of a relatively new class of drugs. Unlike standard chemotherapy drugs, the new class specifically targets a gene in tumors called the epidermal growth factor receptor (EGFR). This receptor helps tumors grow and spread, and these drugs block this receptor.

Itís exciting because the research points to an active therapy and is a window into biology. --Mark Green
“The study shows how important these drugs are,” says Mark Green of the Medical University of South Carolina, who wrote an editorial accompanying the Massachusetts General Hospital study in The New England Journal of Medicine.

“It’s exciting because the research points to an active therapy and is a window into biology,” says Green. “It is also proof of principle for further broad studies looking for specific targeting of targeted drugs.”

Scientists at Mass General conducted the study that appears in The New England Journal of Medicine. Scientists at Dana-Farber Cancer Institute led the study published in Science, which includes other research groups. The journals agreed to publish the papers simultaneously.

The hope now is that once a genetic test is available doctors could screen patients to identify those likely to respond to Iressa. The U.S. Food and Drug Administration approved the drug a year ago for patients with non-small-cell lung cancer.

In addition to the diagnostic test in development at Mass General, researchers at Dana-Farber and AstraZeneca, which manufacturers Iressa, are also working to develop a test.

The drug Iressa blocks receptors (shown here) on the surface of cells that help tumors grow and divide.
Approximately 140,000 people in the United States are diagnosed each year with non-small-cell lung cancer. A genetic test could identify the 10-13 percent of patients likely to respond to Iressa.

If larger studies confirm these two studies, doctors could also start prescribing Iressa early for patients with these mutations in hopes of getting a head start against the progression of disease. In some cases, they might even recommend Iressa as a first-line treatment, rather than standard chemotherapy.

The mutations, which occur in a specific region of the epidermal growth factor receptor gene (EGFR), make the receptor more sensitive to Iressa.

Researchers at Massachusetts General Hospital sequenced the EGFR gene in tumors with patients who responded to Iressa and those who didn’t. Of nine patients who responded to the drug, eight had tumors with mutations in a localized area of the gene, the target of Iressa. Meanwhile, no mutations were found in tumors that didn’t respond to the drug.

Researchers at Dana Farber also sequenced the EGFR gene in tumors from lung cancer patients. Five patients who responded well to Iressa carried similar mutations in the gene, and four patients who did not respond to the drug did not have these mutations.

The team led by Dana Farber also found that mutations occurred in 15 of 58 tumors from Japan and one in 61 tumors from the United States . Previous studies have shown that certain populations of patients—women, non-smokers, and Japanese—are more likely to respond to Iressa.

“The thing we don’t know now is why these mutations happen,” says Bruce Johnson, who led the research at Dana-Farber.

In other news this week, stocks of OSI Pharmaceuticals in Melville, New York, skyrocketed when the company announced that clinical trials of Tarceva extended the life of lung cancer patients compared to a placebo. OSI will announce actual results from the study in June.

Tarceva basically targets the same part of the EGFR gene as Iressa, and scientists are eager to compare data from these two studies to the Tarceva trial, including whether a response to one drug can predict a response to the other.

Learning how to predict how a small percentage of patients will respond to drugs used to treat lung cancer and other cancers such as breast or pancreatic cancer is an important step. Bruce Johnson of Dana-Farber hopes that these small percentages will add up over time.

“My dream is that you could kind of knock off this understanding of small groups of patients one at a time,” he says.

AstraZeneca will pursue further studies of Iressa, including going back and examining the genetics of patients who responded to the drug, but instead of showing dramatic results, had stable disease.

Iressa came from the lab to the clinic before the mechanism of the drug was truly understood because it so dramatically extended some patients’ lives, which is a positive thing.

“These are the first reports, but the studies suggest that the genetic mutation correlates with activity of the drug,” says Roy Herbst, of M.D Anderson Cancer Center in Houston, Texas. He has studied the effects of Iressa for a number of years but was not involved in either study.

“We knew the drug helped patients, but it’s now nice to have a specific mechanism that explains, at least in large part, how it works,” says Herbst.

Paez, J. G. et al. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science (Published online April 29, 2004).
Lynch, T. J. et al. Specific Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine (Published online April 29, 2004).
Green, Mark R. Targeting Targeted Therapy. The New England Journal of Medicine (Published online April 29, 2004).

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