New Hope for a Failed Cancer Drug

AstraZeneca's Iressa took an FDA hit in 2005 as a lung cancer treatment, but a recent study showed its potential in breast cancer patients

There may be a second life for Iressa, AstraZeneca's once-promising cancer drug that came to symbolize the hype surrounding a new generation of targeted cancer treatments. Iressa won U.S. Food & Drug Administration approval for lung cancer in 2003 amid much fanfare, labeled by some as a "miracle drug." Two years later, AstraZeneca (AZN) was forced to stop marketing the drug in the U.S. because it failed in a subsequent clinical trial to help patients live longer.

Doctors continued to experiment with the drug, however, which is how researchers at M.D. Anderson Cancer Center in Houston made the surprising discovery that Iressa can significantly delay the spread of breast cancer when given along with standard hormone therapy. "We were very surprised, pleasantly surprised" by the results, says Dr. Massimo Cristofanilli, co-director of Anderson's inflammatory breast cancer research program and lead researcher of the study.

The study, presented June 1 at the American Society of Clinical Oncology (ASCO) meeting in Chicago, is the first positive results for Iressa in breast cancer. AstraZeneca funded the trial and Cristofanilli says M.D. Anderson is already talking to AstraZeneca about conducting a larger study.

Score One for Targeted Treatments

The breast cancer study holds larger significance. Targeted cancer drugs, meant to zero in on tumor cells without damaging healthy tissue, typically work for only a quarter of the patients that receive them. But as doctors continue to test such targeted drugs as ImClone's (IMCL) Erbitux, Genentech's (DNA) Avastin, and Tarceva, developed jointly by Genentech and OSI Pharmaceuticals (OSIP), they are getting better at figuring out which patients will—and won't—respond.

Much of the news out of this year's ASCO conference came from studies meant to determine more precisely how targeted therapies should be used. Such discoveries could save the health-care system considerable sums because drugs that cost tens of thousands of dollars would no longer be wasted on patients whose tumors don't contain the right receptive cells.

Such studies may also revive failed drugs, as appears to be the case with Iressa. The drug blocks a protein called epidermal growth factor (EGF) that allows tumor cells to grow and spread uncontrollably. The FDA gave Iressa conditional approval in 2003 after it proved able to shrink tumors in about 10% of lung cancer patients. Far from a home run, but given that there are few options for victims of lung cancer, there was tremendous enthusiasm for the drug in the cancer community. The approval was conditioned on AstraZeneca later proving that the drug could not only shrink tumors but extend life. But a large-scale trial found no statistical difference on survival between Iressa and standard treatment. The company agreed to stop selling Iressa in the U.S. to any patients other than those already on the drug. Iressa is still sold in some 38 countries, most of them in Asia.

Better-Than-Expected Results

Intriguingly, however, Iressa proved more effective in certain subgroups of patients—women, smokers, and most of all, Asians. That gave a number of researchers reason to keep experimenting with the drug, in the hopes that they could figure out who might respond.

Cristofanilli's breast cancer study enrolled 93 women at 30 centers across the U.S. and Latin America, all with metastatic breast cancer, and all resistant to standard treatment with Arimidex, a hormone-based therapy also made by AstraZeneca. He had noted in animal studies that hormone resistance was strongly associated with an overabundance of EGF, and hoped Iressa might do some good for women.

The researchers were looking for some slight delay in the spread of the cancer, but were stunned by the actual results. Women who received both Iressa and Arimidex went 14.5 months before their cancer spread, compared with 8.2 months in the Arimidex-only patients, a 45% reduction in risk. Additionally, 47% of the women taking the combination had stable disease for more than 24 weeks, compared with 22% on Arimidex alone.

Identifying Patients Who Could Benefit

The breast cancer study comes just a week after the Journal of Clinical Oncology published research from Massachusetts General Hospital finding that genetic screening of lung cancer patients for certain EGF mutations can help identify the 10% who might benefit from Iressa. The researchers found that 55% of patients with the mutation responded to the drug, and their tumor growth was delayed for nine months, compared with four months for patients on standard chemotherapy.

Dr. Alan Barge, head of clinical oncology for AstraZeneca, says the company has filed for approval of Iressa in Europe based on the new data, and the company is in talks with the FDA. Meanwhile, AstraZeneca is applying the lessons learned from Iressa's failure to its other cancer drugs now in the pipeline. At ASCO the company reported that the amount of another tumor growth factor, called VEGF, circulating in the blood can predict which lung cancer patients will best respond to its experimental drug Zactima. Armed with such a predictive test, it hopes to have a much better outcome with the new drug, by testing it only on patients who might benefit.

The downside of such an approach for the company is that it could greatly limit the market size of a particular drug. However, says Barge, he would rather capture 80% of those patients who will actually respond to a drug, than 20% of a larger patient population who may or may not see their cancer improve.