The final FDA review of AstraZeneca's Iressa NDA is being complicated by reports of interstitial pneumonia possibly associated with use of the non-small cell lung cancer agent.

FDA is understood to have received approximately 120 postmarketing reports from Japanese patients who have been on Iressa therapy since its introduction in July; roughly half the cases are understood to be fatalities. Japanese regulatory authorities are said to be planning to add a black box warning to the label about the reports.

The Japanese reports have prompted FDA to take a closer look at the safety profile of Iressa (gefitinib). The agency is understood to have identified a handful of deaths associated with interstitial pneumonia in the Phase III INTACT trial, and about 50 deaths in the 12,000-patient expanded access program.

One option the agency may be considering is bringing the application back to the Oncologic Drug Products Advisory Committee. In September, the committee agreed that Iressa's 10% response rate in refractory NSCLC patients from two Phase II trials was reasonably likely to predict a clinical benefit (¹ Also see "Iressa Cross-Over Study Could Show Clinical Benefit, AZ Says; ODAC Is Wary" - Pink Sheet, 30 September, 2002., p. 13).

ODAC is tentatively scheduled to meet in December, with one likely topic being a review of Corixa/ GlaxoSmithKline's Bexxar (tositumomab). Another possibility would be to hold a follow-up committee meeting for Iressa in January.

A potentially larger complication for AstraZeneca would be a complete reopening of the question of approvability in light of the INTACT results. The Phase III trials showed no additional benefit when Iressa was used in combination with standard chemotherapy in the front-line setting (² Also see "AstraZeneca Iressa Focus Is Sequential Therapy After INTACT Studies Fail" - Pink Sheet, 26 August, 2002., p. 9).

FDA's user fee deadline for Iressa is in February. AstraZeneca submitted the clinical portions of the application in December 2001, but the chemistry, manufacturing & controls portion was not filed until August.

Draft labeling circulating within FDA is understood to include a black box warning for interstitial pneumonia; statements against concomitant use with chemotherapy; use as third-line therapy only; and statements that use with radiotherapy remains unproven. A description of Iressa as specifically targeting the epidermal growth factor receptor is understood to be absent from the draft label.

AstraZeneca Iressa NDA Review Complicated By Pneumonia Reports

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