Washington Editor

WASHINGTON - Looking to better identify patients for whom Iressa (gefitinib) works, AstraZeneca plc is taking a new tack, according to biomarker study plans reported at an FDA advisory committee hearing on the drug.

Friday's Oncologic Drugs Advisory Committee gathering on Iressa, which two years ago received accelerated approval based on tumor response rate, addressed the drug's failure to demonstrate a broad patient benefit in a post-approval study called Trial 709.

That Phase IV study, which enrolled 1,692 subjects, showed that its use as monotherapy did not produce a survival benefit vs. placebo in a non-small-cell lung cancer patient population. Specifically, AstraZeneca reported primary endpoint data on overall survival showing that Iressa patients had a median survival of 5.6 months compared to 5.1 months among placebo patients, which was not a statistically significant difference.

Promotional activities have been halted since the end of last year, when the company began distributing "Dear Doctor" letters. Since then, total prescriptions are down 49 percent and new prescriptions are 58 percent lower. (See BioWorld Today, Dec. 20, 2004.)

But the London-based company argued that additional findings from Trial 709 showed that Iressa produces a variable outcome, with significant survival increases seen in patients who have never smoked or who are Asian. Other survival benefits were seen in women and adenocarcinoma patients, though neither was statistically significant.

Going forward, AstraZeneca is at work on various biomarker analyses to help further interpret those results and determine the underlying cause of the subgroup benefit seen with use of the drug, a selective epidermal growth factor receptor (EGFR) kinase inhibitor. Per terms of an agreement reported Monday, ViroLogic Inc. also has been enlisted to conduct a cancer biomarker study of Iressa.

"One of the areas they are looking at most closely is EGFR expression for the different subgroups that appeared to be either statistically significant or very close to it in Trial 709, to see if EGFR expression further correlates to that," said Mary Lynn Carver, AstraZeneca's director of communications and external relations.

She noted that the FDA label on a competing lung cancer drug, Tarceva (erlotinib, from Genentech Inc. and OSI Pharmaceuticals Inc.), includes EGFR expression data relative to survival for different subgroups.

"The second piece of it would be the [EGFR] mutation status," Carver told BioWorld Today. Mutations in the EGFR gene, which codes for the protein targeted by Iressa in cancer cells, as well as other genes, can indicate which patients will respond to the drug. But since it appears that more patients respond to Iressa than have the EGFR mutations, some believe that other cellular processes are responsible.

Under its agreement with ViroLogic, which is under way, AstraZeneca is providing more than 100 tumor samples from lung cancer patients treated with Iressa to be tested for specific protein biomarkers identified as indicative of activated signaling pathways in cells, which can drive the accelerated growth of cancer cells. The South San Francisco-based company will use its eTag assays on the samples to evaluate the assays' use in targeting patients who most likely would benefit from the drug. In return, AstraZeneca will pay ViroLogic for its services, though neither company discussed specific financial details.

AstraZeneca expects to complete its analysis by June, after it receives all tissue samples that continue to arrive from the 28 countries in which Trial 709 was conducted.

"If the researchers see huge differences between the tissue samples that come from specific geographic areas in the study," Carver said, "that also could be very interesting as to why there might be a difference here."

Many of Trial 709's patients are from Eastern Europe and Asia, and EGFR mutation appears more prevalent in Asian populations. In a statement released after the panel meeting, AstraZeneca said it supports "updated labeling for Iressa when the complete data set is available."

The company also responded to Public Citizen, a Washington-based patient advocacy group that has called for Iressa's market withdrawal. The group has charged that the drug increases the chances of interstitial lung disease (ILD).

"It is important to remember that ILD is associated with all lung cancer therapies and lung cancer itself," AstraZeneca's statement said, "and the ILD incidence rate for Iressa was equivalent to placebo [in Trial 709] and consistent with globally reported data." The company noted that the incidence of ILD in Iressa-treated patients is 0.22 percent.

Going forward, AstraZeneca added that it is "committed to the development of Iressa and to continuing its availability for patients."