Washington Editor

When AstraZeneca plc's Iressa failed to improve survival in non-small-cell lung cancer patients as a treatment added to first-line standards of care, executives at Genentech Inc. and partners OSI Pharmaceuticals Inc. and Roche Holdings Inc. got some less-than-inspiring insight into the possible future of Tarceva, a candidate the three have been studying in a similar population.

Like London-based AstraZeneca before it, Genentech and its partners ended up with poor top-line results from two Phase III studies designed to evaluate the possible benefit of adding Tarceva (erlotinib HCI) to front-line combination chemotherapy regimens of patients with Stage IIIb and Stage IV non-small-cell lung cancer (NSCLC). The primary endpoint was 25 percent improvement in patient survival.

What else do Iressa and Tarceva have in common? They're both endothelial growth factor receptor inhibitors. Iressa (gefitinib) is FDA approved in advanced NSCLC. (See BioWorld Today, May 6, 2003.)

Speaking Wednesday morning in a conference call, Colin Goddard, CEO of Melville, N.Y.-based OSI, said the message of the day is "no change."

"We anticipated these results and I think we've been very frankly communicating to that effect over the course of last year," Goddard said. "I would love to have been here this morning peeling egg off my face for getting it wrong, but our scientific judgment was valid, well thought through, well reasoned, and as I've said before, just as we viewed the front-line as a high risk, we remain confident of our progression in second/third-line [metastatic NSCLC] and the Tarceva program in general."

As for the failure, clearly Wall Street saw it coming.

"I think OSI felt the pain last summer when Iressa failed," Mike King, managing director of Banc of America Securities in New York, told BioWorld Today. "Everyone has been assuming for the past 12-plus months that these studies would fail as well, so what we have here is no surprise."

On Iressa's news in August 2002, OSI's stock dropped 57.2 percent, or $18.74, to close at $14.05. This time around, things weren't so bad. Wednesday, OSI's stock (NASDAQ:OSIP) fell only 49 cents to close at $32.16. Genentech's stock (NYSE:DNA) dipped 42 cents to close at $79.72.

Colleen Sweeney, spokeswoman for South San Francisco-based Genentech, told BioWorld Today, "We're understanding that all cancers do not react the same and cancers at different stages are different."

Results from the trial do not affect Genentech's previous earning-per-share growth projections for the current or future years, the company said.

Similarly, Goddard told those on the conference call that when AstraZeneca announced its failure, OSI logically concluded that its trials could meet the same fate.

"We took steps to adjust to this news and success in front-line was not modeled into our ongoing business plan," he said.

Tarceva is a small-molecule oral therapy designed to inhibit the tyrosine kinase activity of the HER1/EGFR signaling pathway inside the cell, the companies said. The partners' Phase III studies, referred to as TRIBUTE and TALENT, were multicenter, randomized, controlled trials that evaluated the candidate at 150 mg per day in combination with standard chemotherapy.

TRIBUTE, a U.S.-based trial handled by Genentech, randomized 1,050 patients to receive Tarceva plus standard chemotherapy (carboplatin and paclitaxel) or standard chemotherapy plus placebo. Goddard said one of the secondary endpoints, time to symptomatic progression, did achieve statistical significance, but this did not impact either the time to clinical progression or overall survival.

Meanwhile, the analysis of time to progression has not yet been completed for TALENT, the European study conducted by Roche, of Basel, Switzerland. The trial randomized 1,200 patients to receive either Tarceva in combination with standard chemotherapy (gemcitabine and cisplatin) or standard chemotherapy plus placebo.

With TRIBUTE and TALENT behind them, the partners are awaiting study results from Tarceva in other indications.

King believes Tarceva does have market potential. "I think it's pretty clear, at least in my opinion," he said. "Unless Tarceva shows absolutely nothing in [Phase III] second/third-line lung cancer - then there's a problem. But if they show symptom improvement, like they did in the TRIBUTE study, I think this drug gets on the market."

Sweeney said data from the second/third-line NSCLC Phase III are expected in early 2004. The 700-patient randomized trial is assessing Tarceva as a single agent with survival as the primary endpoint.

In another Phase III trial, the companies are evaluating Tarceva in 450 patients with previously untreated metastatic pancreatic cancer. That study is evaluating Tarceva in combination with gemcitabine. The primary endpoint is patient survival and the data are expected in mid-2004.

Genentech started a Phase II study of Tarceva in glioblastoma (brain cancer) earlier this year. The study is enrolling patients.

The partnership between Genentech and OSI calls for a 50-50 split on U.S. profits for Tarceva in any of the indications. Genentech also would receive a royalty on Roche's sales outside the U.S.

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