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Iressa Study Finds Response Markers As Abbott Courts AZ for Dx Alliance

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Iressa, often seen as an example of the kind of treatment best suited to pharmacogenomic approaches, has had its share of progress and setbacks in the past two weeks. Although a US National Cancer Institute-sponsored study was halted due to a lack of survival benefit associated with the drug, a new, albeit small, study reports that responders often have a high EGFR-gene copy number, which may prove to be a more effective marker for response than EGFR mutations.

The gene-copy-number study "had a better outcome based on FISH [fluorescence in situ hybridization] than based on mutation studies," identifying more Iressa responders than the previously most promising method, Fred Hirsch, a professor of medicine and pathology at the University of Colorado Health Sciences Center and co-author of the study, told Pharmacogenomics Reporter this week. No one knows how to precisely identify which non-small cell lung-cancer patients Iressa will help, but two 2004 studies in Science and the New England Journal of Medicine pointed to mutations in the tyrosine-kinase domain of EGFR, a factor that the current paper finds less important than gene-copy number.

AstraZeneca discontinued marketing Iressa in December due to a lack of "statistically significant survival benefit" for NSCLC patients taking the drug, compared to placebo, despite "statistically significant improvement" in tumor shrinkage, the company said in a Dec. 17 statement [see Pharmacogenomics Reporter 12/23/2004]. In mid-April, the Data Monitoring Committee overseeing the recent NCI trial halted its evaluation of the drug's potential as maintenance therapy for the same reason. In neither case was an attempt made to prospectively identify responders.

"It has been a bit naïve for [AstraZeneca] to have [intended] the drug [for] all the patients with non-small-cell lung cancer, instead of going after those few that really benefit," said Giuseppe Giaccone, head of the Department of Medical Oncology at the Free University Medical Center in Amsterdam, the Netherlands. "That has been one of the problems." Giaccone spoke at the April American Association for Cancer Research on "Targeted Therapy in Lung Cancer," and he has written extensively about Iressa.

Giaccone said it was "very likely" that AstraZeneca could have identified responders during Iressa's development. Although AstraZeneca's preclinical data were not pointing toward the drug's use for a specific patient group, "when you deal with a drug with a definite target, I think it would be extremely useful to collect material and look at the material in a timely fashion — look at it in a simple way, but just do it," he said. That had not been done in Iressa's case, he added.

AstraZeneca would likely keep Iressa on the market if a marker for response can be found and validated — and if a diagnostic company would be willing to step in with a test. According to AstraZeneca spokesperson Mary-Lynn Carver, the drug company is actively thinking about building prospective studies to identify Iressa's responders. The Colorado group's study is retrospective, but it "certainly provides another piece to the scientific puzzle," Carver said.

Abbott Laboratories, which manufactured the analyte-specific reagent EGFR FISH test used by Hirsch's group, is considering having a test cleared by the FDA for use in identifying Iressa responders. "It's my personal belief that this is definitely heading in that direction," said Timothy Stenzel, medical director of Abbott Molecular. "A general sort of concept for us is that we will launch something as an ASR until its clinical utility is more well established, and then we have good justification to spend the money to get something cleared, probably as a [pre-market approval]," he said. The company's PathVision test, which uses FISH to identify Herceptin responders, followed a similar route to FDA clearance, he added.

"We are monitoring the situation [with Iressa] very closely," said Stenzel. "In order to come up with an IVD, we would obviously have to work closely with the company — and we are pursuing discussions with AstraZeneca, as you might expect," he said.

"There are certainly diagnostics companies that are interested [in producing an Iressa-related test], but we have not made any agreements with anyone," said Hirsch. He declined to name the diagnostics companies that had shown interest in the group's research, but those companies might have to wait: Hirsch's study featured only 102 patients. "This is very encouraging data, and gives us a very strong hypothesis, but for clinical practice, we need more validation," he said. Plans for follow-up studies call for as many as 600 patients, he added.

The University of Colorado Health Sciences Center's study "is still one of the largest studies of this type," said Giaccone. "This opens up the possibility of having a handle on how to make the drug more effective by giving it only to patients that really benefit, so it's an important paper," he said.

The Colorado group's research, which appears in the current Journal of the National Cancer Institute, reports a statistically significant link between EGFR gene-copy number and response, with a 36 percent response rate for patients with a high copy number, compared to 3 percent for patients with a low copy number. The study also found a 67 percent disease-control rate for high copy number patients, versus 26 percent for low copy-number patients, a 9-month time to progression, compared to 2.5 months for the low copy-number group, and an average survival of 18.7 months for high copy-number patients, compared to 7 months for the low-number group.

The study shows the same associations for patients with a high level of EGFR protein expression through immunohistochemistry, but multivariate analysis identified gene-copy number as the only significant factor. "EGFR mutations were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40 percent of the patients with the mutation had progressive disease," the study said.

A test identifying a group of people with a 36-percent response rate would "probably not" make for a perfect diagnostic, said Giaccone. "But it's at least three times higher than what you expect by not doing it, so it narrows down the number of patients, and it gives you some confidence on how to treat the patients, with what, and at what stage," he said. "If a patient belonged to this group, you would probably try these drugs earlier, rather than later," before second-line chemotherapy, he said.

Herceptin is only active in 20 to 30 percent of FISH-identified patients, although it is much more effective when combined with chemotherapy, Giaccone noted. Stenzel puts the proportion of Herceptin responders between about 20 to 50 percent of those patients identified by FISH as likely responders. "I think that a similar situation will work here with EGFR and FISH," said Stenzel.

Hirsch's group used Abbott Laboratories' LSI EGFR SpectrumOrange/CEP 7 Spectrum Green probe for their FISH analyses, and the anti-EGFR antibody made by Zymed for its immunohistochemistry.

— CW

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