The much-hyped cancer drug Iressa is showing worrying signs that it may not live up to its promise: clinical trial results released in December showed the drug does not prolong survival in patients with non-small cell lung cancer. Some scientists say the disappointing results underscore the need for clinical trials designed specifically to test targeted therapies.

In January, Iressa's manufacturer AstraZeneca withdrew the application for its approval in Europe, saying results from the clinical study made it unlikely that it would meet approval requirements. The announcement surprised some oncologists, who say Iressa and similar drugs have a promising future in a small group of patients.

“I'd be disappointed if [AstraZeneca] folds up its tent and goes home,” says David Johnson, president of the American Society of Clinical Oncology. An AstraZeneca spokesperson says the company will continue to sell the drug but will not actively market it. AstraZeneca also plans further analysis on subpopulations from the clinical trial.

I'd be disappointed if [AstraZeneca] folds up its tent and goes home. David Johnson,, American Society of Clinical Oncology

Earlier studies had showed that Iressa can significantly shrink tumors in ten percent of lung cancer patients, many of whom have a mutation in an enzyme targeted by the drug (Science 304, 1497–1500; 2004, N. Engl. J. Med. 350, 2129–2139; 2004). This mutation is most common in women, Asians and in those with adenocarci-nomas, the most common type of lung cancer.

The US Food and Drug Administration (FDA) gave Iressa accelerated approval in May 2003, under a program that allows the agency to revoke the decision if postmarketing clinical trials don't support the initial results. The FDA says it will review details of the December study to see if a change in status is warranted.

The FDA approved a similar drug, Genentech's Tarceva, in November 2004. Both drugs are thought to inhibit epidermal growth factor receptors involved in cancer cell growth. In clinical trials, Tarceva was shown to increase survival in cancer patients by two months.

“Most doctors believe there is no significant difference between the two,” says Jennifer Temel, a clinician at Massachusetts General Hospital. Temel attributes the disparate outcomes to small differences in study design. “We all have a handful of patients who have survived years because of [Iressa],” she says.

Iressa was heralded as key example of the potential of targeted cancer therapies. But its power may have been lost in the recent large-scale trial. The 1,700 participants were part of the general patient population, rather than the subgroup most likely to respond to the drug.

Johnson says clinical trials must be designed to clarify the true potential of the growing number of targeted therapies. He and others are trying to change the way such drugs are evaluated. One solution is to better understand how a drug acts and why some patients respond before beginning large-scale trials.

Bruce E. Johnson, director of thoracic oncology at the Dana-Farber Cancer Institute says that, despite the setbacks, Iressa might prove more effective than chemotherapy in that key group of patients, and hopes similar drugs will continue to be developed. “The more agents we have to test and compare, the more opportunities to tailor-make treatments for specific individuals.”