Eight months after receiving approval for Erbitux in colorectal cancer, ImClone Systems Inc. and Bristol-Myers Squibb Co. set out on another Phase III program for the drug, this time targeting non-small-cell lung cancer.

While New York-based ImClone and Princeton, N.J.-based Bristol-Myers intend to file a supplemental biologics license application in 2005 for Erbitux to treat head and neck cancer, a filing for the lung cancer indication could follow in 2006 if data prove positive. About 80 percent of the 173,000 Americans diagnosed with lung cancer each year have non-small-cell lung cancer - providing Erbitux with another major market opportunity. The American Cancer Society said about 160,000 of those diagnosed will die from the disease.

"It's obviously one of the deadliest cancers in this country, and one of the most prevalent ones as well," said David Pitts, ImClone's assistant vice president of corporate communications. "So it's a substantial market."

ImClone and Bristol-Myers are initiating the Phase III trial of Erbitux (cetuximab), an IgG1 monoclonal antibody, in 800 patients with second-line non-small-cell lung cancer. The trial was designed based on a special protocol assessment with the FDA and could help Erbitux receive an accelerated approval.

"If it's going to reach the $1 billion-plus level at its peak, which many analysts estimate, non-small-cell lung cancer is going to be a major component of that," said Brian Rye, an analyst with Janney Montgomery Scott LLC in Philadelphia.

The primary endpoint is tumor-response rate, defined as tumor regression of greater than 50 percent. Secondary endpoints include progression-free survival and overall survival. The trial will evaluate chemotherapy alone, either with docetaxel or pemetrexed, or the same chemotherapy in combination with Erbitux.

"We don't know how quickly they're going to be able to enroll patients in this study," Rye told BioWorld Today. "If enrollment proceeds on time, I would hope they would be in the position to have results in 2006 and be able to file the sBLA shortly thereafter."

Pitts declined to give timelines for the trial, but said the company likely would have data from an ongoing Phase III pancreatic cancer study being conducted by the Southwest Oncology Group before it has the lung cancer data. The pancreatic cancer trial began enrolling patients at the beginning of this year.

The Southwest Oncology Group also is enrolling patients in a Phase III lung cancer trial with Erbitux. That trial will evaluate the efficacy of concurrent chemotherapy plus Erbitux and chemotherapy followed by Erbitux in 180 non-small-cell lung cancer patients.

In addition to the trial looking at Erbitux as a second-line treatment, ImClone and Bristol-Myers intend to conduct two supportive first-line randomized clinical studies using chemotherapy regimens more commonly used by physicians, including a taxane with platinum-based chemotherapy and gemcitabine with platinum-based chemotherapy, with or without Erbitux. The primary endpoint of those studies will be tumor-response rate.

ImClone's overseas partner, Darmstadt, Germany-based Merck KGaA, already is enrolling 1,100 patients in a Phase III trial in Europe, Latin America and Asia. That trial will look at a platinum-based chemotherapy and vinorelbine alone or in combination with Erbitux with first-line non-small-cell lung cancer. The primary endpoint is overall survival.

Depending on the results of the U.S. Phase III study and the two supportive studies, the companies could seek an indication in first-line treatment with platinum-based chemotherapy.

"We will all share our clinical data with one another to support our respective regulatory filings," Pitts said.

He declined to say how much the lung cancer indication could expand the sales for Erbitux. Rye, too, said he was hesitant to give a financial outlook for Erbitux in the lung cancer indication because of certain variables.

"Not only is the outlook going to be dependent on how successful the clinical trials are," Rye said, "but it will depend on the competitive environment."

OSI Pharmaceuticals Inc., of Melville, N.Y., and South San Francisco-based Genentech Inc.'s drug Tarceva (erlotinib) is just a few months away from a decision in refractory non-small-cell lung cancer, and Palo Alto, Calif.-based Telik Inc. has its Phase III drug Telcyta in development for ovarian and non-small-cell lung cancers.

Genentech's drug Avastin, which was approved around the same time as a first-line treatment for colorectal cancer, has taken some of Erbitux's sales. Avastin had sales of $183 million in the third quarter.

Nevertheless, Erbitux has done quite well as a second-line therapy in its first year on the market. The drug had sales of $71.4 million in the second quarter. ImClone received $28 million in royalties from those sales. The company will release third-quarter results at the end of this month.

"We are certainly pleased with the launch," Pitts said. "And last quarter, the sales were above the analysts' expectations."

Negative Erbitux results in late 2001 led to troubling times for the company, including insider-trading investigations that resulted in prison for the company's former CEO Samuel Waksal. With the Erbitux approval in February, the company named Daniel Lynch CEO and director. He had previously served the company as senior vice president of finance and chief financial officer.

Rye said that Lynch has "done a very good job in transforming the focus from the scandals" back to the company's drugs, particularly Erbitux.

"The stock's done very well," Rye said. "And the company still has a market cap of over $4 billion, so I think it's fair to say that the investment community has been pleased."

Erbitux binds specifically to epidermal growth factor receptors on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor and other ligands. It is approved for use in combination with irinotecan to treat patients with EGFR-expressing metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and as a single agent in the patients intolerant to irinotecan-based chemotherapy.

ImClone's stock (NASDAQ:IMCL) dropped $1.15 on Friday, to close at $51.30.

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