Effective last-resort cancer medications are few and far between. When preliminary evidence indicated that the medication Iressaalso known as ZD1839 or gefitinibmight be a substantial advance in the treatment of late-stage lung cancers, at least for some patients, pharmaceutical manufacturer AstraZeneca pushed for accelerated approval from the U.S. Food and Drug Administration. Last September, during an Oncologic Drugs Advisory Committee (ODAC) meeting, panelists agreed, voting 11-3 to recommend that Iressa be approved by the FDA for use by patients who had not responded to at least two chemotherapy agents, and thus would have no further treatment option (see News, Nov. 6, Vol. 94, No. 21, p. 1596).
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In early January, the FDA notified AstraZeneca that the agency would delay its fast-track decision until May 5. The FDA has not publicly spoken of the matter since, and declined to comment for this article.
Nevertheless, by the beginning of the year the drug had been administered to more than 10,000 Japanese patients with advanced, non-small-cell lung cancer. In the aggregate, side effects appeared minimal, with most recipients reporting some alleviation of symptoms. The toxicity rate was statistically modest when compared with other treatments. Given the severity of patients late-stage illnesses and the salutary effects many reportand who otherwise would face further accelerated deterioration of their conditionIressa remained a viable treatment option. In addition, the occurrence of ILD, traditionally and commonly observed in clinical trials with both chemotherapy and radiotherapy, was not unexpected, at least by practitioners.
Put Into a Context
"The reported deaths have to be put into a context: 170-plus deaths versus 10,000 recipients. The actual rate of Iressa-induced toxicity is very low," said Janet Dancey, M.D., senior investigator in the Investigational Drug Branch at the National Cancer Institute. "Patients are dying of progressive abnormalities in the lung. Theyre prone to a worsening cancer that can be confused with pneumonia, or they can develop pneumonia in spite of treatment. They can also hemorrhage in the lung. All these conditions are difficult to diagnose on X-rays."
Iressa is in a class of oral medications known as selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) that target and block growth signals within cancerous cells. Taken daily, a single Iressa pill is intended to shrink malignant tumors without causing the nausea and other physically debilitating effects brought on by repeated rounds of infusional chemotherapy.
Because it has thus far been studied as a treatment of last resort, Iressas effectiveness as a frontline or stand-alone medication remains unknown. Although the drug primarily has been evaluated for lung cancer, it also appears to have potential benefit in cancers of the breast, prostate, colon, and gastrointestinal tract. Its efficacy does not, however, improve when administered concurrently with other chemotherapeutic agents. AstraZeneca claims that, worldwide, the drug has so far been given to some 62,500 patients, with toxic effects experienced by 0.3% to 0.4% of recipients.
Tumor Response
"Iressa works dramatically in a small number of patients, producing a major, objective response rate in about 10% to 15% of patients," said Ronald Natale, M.D., an oncologist and director of the National Lung Cancer Research Program for Salick Health Care in Los Angeles. "It stabilizes symptoms in an additional 20% to 30%. Weve so far studied it in late-stage lung cancers. It may also have a role to play in early-onset cancer."
For roughly half those receiving Iressa, there seem to be substantial improvements in quality of life. Patients report that the medication can relieve coughing and chest discomfort, decrease pain and reduce or eliminate the need for a bronchial dialator. For the 10% of responders who see their symptoms improve, Iressa causes tumors to shrink dramatically or disappear altogether, according to information compiled by AstraZeneca.
"These are patients who have gone through everything medical science can offer," said Mary Lynn Carver, AstraZenecas director of oncology public affairs. "Theyre still progressing. They take Iressa and, in 4 to 6 weeks and sometimes sooner, their tumors have shrunk by 50% or more. Some have tumors that disappear completely."
A recent editorial in the Wall Street Journal supported fast-track approval and chided the FDA for "dithering." "Cancer patients are dying as Iressa remains bottled up. New FDA Commissioner Mark McClellan has a lot to do, but the doctors who treat dying patients will tell him that approving Iressa deserves to be a priority," the editorial stated.
The FDA traditionally has opted for prudence over speed during the drug approval process, even when a new medication appears to be medically effective. Given that researchers are still trying to determine the precise metabolic mechanisms engaged by agents such as Iressa, the drugs long-term effectiveness has yet to be determined.
"The FDA is responding appropriately," said NCIs Dancey. "Theyre evaluating all the evidence so that we will all have a good gauge of what the risk really is. Should this drug end up on the market, patients and physicians should be aware of what the risk is and how to mitigate it."
More Studies
More than 100 studies of Iressa are either ongoing or beginning, including trials in the adjuvant setting for lung cancer after chemotherapy. Iressa is also in phase II trials for a variety of other solid tumors, including head and neck, colorectal, breast, and prostate cancers; AstraZeneca contended that initial data in those studies are encouraging. Company spokesperson Carver said that independent evaluations of Iressa-induced ILD are ongoing in Japan, with physicians recruited from leading research institutes to conduct studies and report on results without any outside interference.
"Pulmonary toxicity has slowed things down, but I think thats getting sorted out," said John Carpenter, M.D., an ODAC panel member and oncologist and professor of medicine at the University of Alabama at Birmingham. "The FDA is struggling with how good does Iressa have to be to approve it. Im not sure it will until theres more substantiated evidence of what [Iressa] does."
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