AstraZeneca announced December 17 that its drug Iressa (gefitinib) failed to show a survival advantage in the confirmatory trials needed to receive full approval from the U.S. Food and Drug Administration. Iressa was the first selective epidermal growth factor receptor (EGFR) inhibitor to receive accelerated approval, which was based not on a survival advantage but on preliminary data from a phase II study and on dramatic patient testimony.
The setback surprised and disappointed many in the research community. Many scientists and patients would like to see the drug succeed, especially in light of research reported in both Science magazine and the New England Journal of Medicine in April 2003 after the confirmatory trial of Iressa beganthat found the precise target for Iressa, a targeted therapy approved to treat advanced nonsmall-cell lung cancer (NSCLC). These studies, by researchers at Harvard University and the Massachusetts Institute of Technology, showed that Iressa worked in an estimated 10% of advanced NSCLC patients who had a specific EGFR mutation. Most of these patients were nonsmoking women, and the rate of these mutations may be as high as one-third in some Asian populations.
With the release of these latest trial results, AstraZeneca advised physicians to consider "other treatment options" than Iressa for their patients with recurrent lung cancer, and on January 4, the company withdrew its application to market Iressa in the European Union, saying the drug would not meet approval requirements. AstraZeneca further said that the status of its sponsored studies of Iressa in lung cancer is being reviewed on a trial-by-trial basis while it discusses the future of the drug with the FDA and with drug regulatory agencies in Japan and around the world.
In a statement after the latest trial results were released, the FDA noted that it has the authority to remove a drug from the market if confirmatory studies fail. Mark Kris, M.D., who led the study upon which Iressa received accelerated approval, said that such an action "just doesn't seem right to me."
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To the extent that he is able to comment on the issue, Richard Padzur, M.D., director of the FDA Division of Oncology Drug Products, agrees that the drug needs to be considered in the context of those who respond best to it, and he said he is working with AstraZeneca to see if survival trends exist within the group that was tested. "We have some flexibility," he said, and describes the Iressa application "as a work in progress. We have not closed the books on the drug."
A Surprising Difference
Tarceva, which had been developed under a Fast Track FDA application, received full regulatory approval in November. When tested against a placebo in a randomized trial of 731 patients with locally advanced or metastatic lung cancer, Tarceva improved overall survival by 2 months compared with placebo (6.7 months versus 4.7 months)a statistically significant differenceand the effect on survival was much greater among the approximately 55% of patients who had high EGFR levels than it was in people whose EGFR levels were low.
But the initial analysis of the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, which randomly assigned either Iressa or a placebo to 1,692 patients with advanced NSCLC who had progressed or could no longer tolerate chemotherapy, found that the drug failed to prolong survival. While there was a statistically significant improvement in tumor shrinkage, overall survival was similar in the two study arms5.6 months in treated patients versus 5.1 months in patients given a placebo.
The results surprised those who had been following the trial, leaving researchers to speculate that the mechanisms of action of Tarceva and Iressa may, in fact, be substantially different, that the drug dosing may also be at fault, or that Iressa failed because of bad lucktoo few patients with an EGFR mutation were enrolled compared to the Tarceva trial, thus diluting an overall beneficial effect.
Janet Dancey, M.D., a senior clinical investigator at the National Cancer Institute who has been following the development of EGFR inhibitors, suspects that the issue is not "only that [Tarceva and Iressa] are slightly different chemicals, but they are given at different doses. Tarceva is given to be maximally tolerated and Iressa is not," she said. "It may be that they do not have equal biological effects on the target."
"The million-dollar question, or, for industry, the billion-dollar question, is why Tarceva showed an advantage while Iressa didn't," said Lawrence Einhorn, M.D., an Indiana University School of Medicine oncologist who has chaired panel sessions on Iressa. "We all assumed they were the same drugs because they have the same mechanism of action."
But the newest research is indicating that this is not the case. "For us as investigators, at this point, there are at least 20 different mutations in the EGF receptors in human lung cancers, and we don't know if the same drug works as well for every mutation," said Bruce Johnson, M.D., a researcher at Boston's Dana-Farber Cancer Institute who coauthored the Science report. "It may be that the type of mutation will dictate the treatment, which is why we want as many EGFR inhibitor drugs available as possible for testing."
FDA Doing Its Job
In this new era of targeted therapies, many look upon Iressa's troubles as necessary growing pains for the FDA, drug developers, and researchers. Few seem to blame the FDA for granting the drug its 2002 accelerated approval, which allows the agency to approve drugs based on surrogate endpoints for survival, thus bringing the drugs to market much quicker than if phase III trials had to have been completed. "I hope this setback does not spell the end of accelerated approval because, to me, the process worked like it should," said Kris.
But the situation also suggests to some that the development and approval process for targeted drugs could be strengthened.
"AstraZeneca and the FDA helped a lot of people," said Roy Herbst, M.D., who has tested the drug in lung cancer patients at M. D. Anderson Cancer Center in Houston. "Still, it is necessary to step back, be cautious, and remember that survival is the ultimate endpoint." (Herbst has received research support from and served as a consultant to both AstraZeneca, makers of Iressa, and Genentech, makers of Tarceva.)
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Johnson said that the point being made by the Iressa trial is that "you have to be careful about giving targeted treatments. You need to know the target and how the drug is working against it, so that you can pick appropriate patients." At Harvard-associated hospitals, patients are now being tested for the EGFR mutation before being given Iressa or Tarceva.
Pazdur agrees. "If we had lessons to learn from this situation, it would be to understand the targets as the drug is being developed clinically, to make that part of the drug's development up front."
And like others, Pazdur suggests that surrogate endpoints such as response rate may not be the best measure in evaluating targeted therapies.
"Both Tarceva and Iressa have very similar response rates; however, one drug had a survival improvement and the other did not," he said. "Certain decisions are made on a response rate whether or not response correlates with EGFR receptorpositive status, or whether giving a higher dose of the drug may be more beneficial than a lower dose. Yet that response rate may not well correlate with overall survival."
The FDA's Oncologic Drugs Advisory Committee plans to discuss these issues at its March 4 meeting.
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