Washington Editor

SILVER SPRING, Md. - An FDA advisory panel provided late-stage lung cancer patients with a ray of hope Tuesday when it leaned toward recommending approval of Iressa, an epidermal growth factor receptor tyrosine kinase inhibitor.

The panel did not specifically vote on whether to recommend approval or not. Instead, the Oncologic Drugs Advisory Committee voted 11-to-3 that a 10 percent response rate from a 216-patient Phase II trial (Trial 39) submitted by London-based AstraZeneca plc for Iressa was "reasonable to predict clinical benefit in non-small-cell lung cancer." The application, filed under accelerated approval guidelines, seeks marketing clearance for patients with locally advanced or metastatic NSCLC who previously have received platinum-based chemotherapy.

The FDA now will consider the new drug application.

Following the meeting, Gerard Kennealey, vice president, clinical research oncology for AstraZeneca in Wilmington, Del., told reporters that the favorable vote did not surprise him. "This is great news for cancer patients and the panel confirmed our clinical trials."

Iressa (gefitinib or ZD 1839), a fast-track once-daily oral tablet, is the first in a new class of anticancer drugs known as selective epidermal growth factor receptor (EGFR) inhibitors that target and block, within the cell, signaling pathways that are implicated in the growth and survival of cancer cells. These pathways appear to play a major role in the growth of many solid tumors, according to information provided by the company.

In recent months, Iressa gained much attention among investors and within the industry when AstraZeneca released poor results of two Phase III trials (INTACT 1 and INTACT 2) using the drug as a first-line therapy when added to standard platinum-based chemotherapy vs. chemotherapy alone in advanced non-small-cell lung cancer. The trial did not demonstrate improvement in survival. (See BioWorld Today, Aug. 21, 2002.)

The bad news was of particular interest for biotechnology companies that are working in the EGFR inhibitor arena, including Abgenix Inc., via a partnership with Amgen Inc.; ImClone Systems Inc. and its partner, Bristol-Myers Squibb Co.; and the partners OSI Pharmaceuticals Inc., Genentech Inc. and F. Hoffmann-La Roche Ltd.

Abgenix is developing ABX-EGF, a humanized monoclonal antibody, in monotherapy and combination therapy studies in NSCLC, colorectal, kidney and prostate cancer. OSI's Tarceva is a small-molecule inhibitor, and ImClone's Erbitux is a chimeric monoclonal antibody.

On release of the poor data back in August, whispering within the drug research community hinted that other EGFR inhibitors could produce the same result.

Not everyone agreed with that.

While Kennealey would not discuss other EGFR inhibitors, he said the outcome of the meeting indicates a "proof of concept for the class of drugs." He added that each drug would have to be approved on its own merits and "I wouldn't want to speculate on other drugs."

John Carpenter, a panel member and professor of medicine at the University of Alabama at Birmingham, said the failed Phase III trials just proved that AstraZeneca and the clinicians running the trials didn't know how to study the drug. In fact, Carpenter said the 10 percent response rate in the Phase II was "hard data."

In his presentation for the FDA, Grant Williams, deputy director of the agency's division of oncology drug products, cautioned, "We must weigh the significance of these negative findings on this accelerated approval application."

The agency had expected INTACT 1 and 2 to be submitted as complementary studies to the new drug application.

But George Blackledge, AstraZeneca's clinical vice president of oncology, told the panel that results from the Phase III trials are not applicable to the third-line NSCLC trials submitted as part of the application, which included two Phase II trials, known as IDEAL 1 and IDEAL 2.

In its analysis of why INTACT 1 and 2 failed, Blackledge quoted a colleague who said, "We've said that these new therapies are dramatically unlike chemotherapy, but we've tried to develop them as if they were. Now we know they're not and Iressa has to be used following different paradigms."

When pressed by Richard Pazdur, director of the FDA's division of oncology drug products, as to why INTACT 1 and 2 failed, Blackledge said he couldn't provide a reason at this time. Pazdur said if they hadn't failed, Iressa probably would have been easily approved.

AstraZeneca's application presented Tuesday focused on data from two Phase II trials of approximately 400 patients in which the response rate was 10 percent.

Trial 39, or IDEAL 2, was a randomized, double-blind, parallel, multicenter study in patients with advanced NSCLC who have previously received at least two chemotherapy regimens that contained platinum and docetaxel given concurrently or as separate treatment regimens. The other was Trial 16, or IDEAL 1, a supporting trial, also a randomized, double-blind, parallel, multicenter study in patients with advanced NSCLC who have failed one or two previous chemotherapy regimens, at least one having contained platinum as a primary second-line treatment. In Trial 16, the response rate for Caucasian patients was 10.8 percent and for Japanese patients 27.5 percent.

The primary objectives were tumor response rate and symptom improvement rate at 250 mg and 500 mg. But Martin Cohen, an FDA medical reviewer, said symptom improvement was difficult to assess because there was no control arm and patients were on other medications. And, "telling a patient his or her tumor is shrinking is of great benefit," he said.

Indeed, during the first hour of the panel hearing, at least 20 NSCLC patients - many choked up with tears - thanked AstraZeneca representatives for Iressa and implored the panel to approve it.

Adriane Riddle, a San Bernardino, Calif., college student, was 18 years old when she was diagnosed with Stage IV NSCLC. "This drug has given me a chance to turn 20," she said.

Others said Iressa works fast and produces only minor side effects, such as ache, skin rash or diarrhea.

But in a 9-to-5 vote, the panel agreed that symptom improvement data could not be adequately evaluated without a randomized, blinded study with an adequate control arm.

Iressa has been approved for advanced NSCLC in Japan, and filings in other countries are planned. The drug is in Phase II trials for other solid tumors, including head and neck, colorectal and breast cancers.

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