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Taking a step to expand Avastin's label, Genentech Inc. submitted a supplemental biologics license application to the FDA for use of the VEGF inhibitor in patients with second-line metastatic colorectal cancer.

"Genentech has been very clear about its intentions for the use of Avastin across multiple solid tumors," said Jason Kantor, a San Francisco-based analyst for RBC Capital Markets. Its "very detailed filing strategy," he said, includes the sBLA, as well as two more expected next year for first-line breast and lung cancer treatment, which will be "of much higher importance from a commercial perspective."

Avastin (bevacizumab), which already is approved as a first-line metastatic colorectal cancer treatment in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy, generated $325.2 million in U.S. sales during the company's most recently reported quarter. That represented a 78 percent increase of the previous year's third quarter, and its worldwide sales for the nine-month period ended Sept. 30 totaled about $851 million. Kantor, who said the label addition would have a modest financial impact for the product, nonetheless noted that the filing "is a necessary thing in terms of growing the business in colorectal cancer."

He also told BioWorld Today that the sBLA fulfills management's stated timelines and "underscores their ability to get these filings done on time and on plan." Genentech, of South San Francisco, said there are 180,000 metastatic colorectal cancer patients of all stages in the U.S.

"We look forward to the day when Avastin is a foundational therapy for patients with colorectal cancer, no matter what their stage," Krysta Pellegrino, Genentech's manager of product communications, told BioWorld Today.

The submission is supported by data from a Phase III trial that enrolled 829 patients whose disease progressed following previous treatment with 5-FU and irinotecan-based chemotherapy. Findings showed that those who received Avastin and the 5-FU-based chemotherapy regimen called FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 percent reduction in the risk of death, the primary endpoint, which is equivalent to a 33 percent improvement in overall survival, compared to patients who received FOLFOX4 alone (hazard ratio of 0.75).

The patients had been randomized to receive FOLFOX4 treatment with or without Avastin, which acts by interfering with the vascular endothelial growth factor protein to disrupt blood supply to a tumor. The trial initially included a third arm, which evaluated single-agent Avastin, but that was closed in March 2003 on the recommendation of a data monitoring committee that determined that overall survival among those patients appeared to be inferior to that of the other two arms.

"When you're already approved for first-line, obviously the second-line indication is a little bit less important," Kantor said. "But it gives them the ability to more aggressively market the drug to that specific portion of the marketplace, and if there's anybody out there who isn't reimbursing Avastin in this setting, it would certainly pressure them to provide reimbursement."

The study began before those on which the drug's initial approval was based. It was sponsored by the National Cancer Institute, part of the National Institutes of Health in Bethesda, Md., and conducted by a network of researchers led by the Eastern Cooperative Oncology Group. Genentech provided supplies of Avastin under a cooperative research and development agreement with the NCI for its clinical development, as well as financial support for data management.

Genentech is investigating the drug in a range of clinical trials in more than 20 cancer types, including adjuvant and metastatic colorectal, renal cell, breast, pancreatic, non-small-cell lung, prostate and ovarian. It also is the subject of earlier-stage trials in a variety of solid tumor cancers and hematologic malignancies.

The number of regulatory filings on Genentech's plate is "somewhat unprecedented," Kantor said, noting the recent submission to expand the lymphoma drug Rituxan (rituximab) into rheumatoid arthritis and the latest application. There are plans for more Avastin filings in breast and lung cancers "that will really expand the market," as well as Lucentis (ranibizumab) for age-related macular degeneration, he said.

On Monday, the stock (NYSE:DNA) lost $2.59 to close at $89.76.

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