National Editor

Almost eight months after a positive FDA panel review, AstraZeneca plc won accelerated approval Monday for Iressa (gefitinib), its epidermal growth factor receptor tyrosine kinase inhibitor pill for advanced non-small-cell lung cancer.

Whatever else skeptics might say about EGFR therapies - and plenty has been said - the small-molecule Iressa represents "the first time anything other than surgery, chemotherapy or radiation has ever been approved to treat lung cancer," noted Mary Lynn Carver, director of oncology public affairs for London-based AstraZeneca.

Iressa will be available in pharmacies in two weeks, she said, at a wholesale cost of $1,560 per month and an expected retail cost of $1,900 per month.

AstraZeneca's shares (NYSE:AZN) closed Monday at $43.05, up $1.54.

Approval didn't seem as likely last summer, when Iressa failed to offer a survival advantage as a therapy added to the first-line standards of care - news that sent AstraZeneca's stock into a tailspin, along with shares of other companies with EGFR projects in the works. (See BioWorld Today, Aug. 21, 2002.)

"The current theory is that instead of using it as an added therapy, it may have been redundant, and what we have to look at is sequential use," Carver told BioWorld Today, adding that a trial is ongoing to test Iressa when used after chemotherapy, much as the hormonal drug tamoxifen is used in breast cancer.

In any case, AstraZeneca redeemed the negative situation a month later, providing data from a 216-patient Phase II study that convinced the FDA's Oncologic Drugs Advisory Committee the response rate of 10 percent was "reasonable to predict clinical benefit in non-small-cell lung cancer." (See BioWorld Today, Sept. 25, 2002.)

Accordingly, the FDA has granted marketing clearance for Iressa against advanced or metastatic NSCLC in cases where platinum-based and docetaxel chemotherapies don't work.

AstraZeneca noted the drug's efficacy is based solely on objective response rates, with no controlled trials that show a clinical benefit.

"We're doing survival trials" as part of the accelerated approval agreement with the FDA, Carver said. "We don't have them mapped out as far as when results are going to be available," she added, but the likely timeline is 2005.

Meanwhile, others are pursuing drugs in the EGFR arena, and each has its own problems. OSI Pharmaceuticals Inc., of Melville, N.Y., is developing Tarceva (erlotinib HCl), also a small molecule, with Genentech Inc., of South San Francisco, and Basel, Switzerland-based Roche Holding Ltd. The companies are exploring the drug in Phase III trials in non-small-cell lung cancer and pancreatic cancer.

Last month, Genentech disclosed that a data safety monitoring board said the drug should be stopped for patients after the disease progresses in a Phase III trial with Tarceva as a front-line therapy. Neither Genentech nor OSI could offer details. (See BioWorld Today, April 11, 2003.)

OSI is expected to have Phase I data for Tarceva against glioblastoma at the end of this month; final data from a pair of Phase III studies in combination with paclitaxel and carboplatin against NSCLC as a front-line therapy in July; and data from another pivotal study as a monotherapy against refractory NSCLC late this year or early next.

With Iressa already having failed in the front-line setting, some investor hopes for OSI and Tarceva have turned to the third-line approach and glioblastoma.

Carver wouldn't comment on any other company's efforts, but noted that Iressa's label includes "important" information about Iressa - that it does not show more efficacy at higher levels, even though the drug is "nowhere near" its dose-limiting toxicity mark. Differing indications may require differing doses of various EGFR drugs, she added, and more trials will reveal more about the class in general.

OSI's shares (NASDAQ:OSIP) closed Monday at $20.72, down 47 cents. Genentech's stock (NYSE:DNA) ended the day at $38.55, down 4 cents.

ImClone Systems Inc., of New York, is developing another, even more troubled EGFR therapy, the monoclonal antibody Erbitux (cetuximab), with Bristol-Myers Squibb Co., also of New York. In a case ridden with scandal, the FDA has refused to accept ImClone's marketing application for the drug because of missing or faulty trial data.

Monday's closing price for ImClone (NASDAQ:IMCLE) was $21.17, up 17 cents. Bristol-Myers (NYSE:BMS) ended at $45.83, down 32 cents.

Iressa won approval despite worries by some that more than 200 fatalities in Japan linked with use of the drug would have an affect on the FDA's deliberations, especially since the September advisory panel did not vote directly on whether to recommend the marketing go-ahead.

Carver acknowledged the problems in Japan with interstitial lung disease (ILD), which includes certain types of pneumonia and other lung inflammation.

"They have been reporting rates much higher than we've seen anywhere else in the world, including all the clinical controlled studies," she said. "There's been a lot of uproar about it in Japan," although last week Japan's regulatory agency reiterated its faith in Iressa, which had been cleared for sale in a second country - Australia - earlier this month.

ILD is "pretty much a known [risk] in lung cancer, whatever the treatment," Carver said, and pointed to "a lot of confounding factors" in Japan, including cultural differences and fewer oncologists.

As EGFR research by various companies goes on, Iressa at least can help some lung cancer patients, she said.

"The reality is that the majority of patients diagnosed with lung cancer die in a year," Carver said. In EGFR experiments, "the ups and downs have to do with [the question], How do you fit any sort of targeted therapy into an old paradigm?'" she added. "We're just the first ones out of the gate."