(Recasts, adds Genentech document, paragraph 7, other details)
By Kim Dixon
WASHINGTON, Dec 3 (Reuters) - Toxic side effects of Avastin in treating breast cancer can in some cases be fatal and must be weighed against the benefits of the drug sold by Roche Holding AG ROG.VX and Genentech Inc DNA.N, U.S. regulatory staffers said in documents released on Monday.
The U.S. Food and Drug Administration staff review comes ahead of a Wednesday advisory panel meeting on a bid by Roche and U.S. partner Genentech to extend use of the drug, which is already approved to treat lung and colon cancer, to patients with breast cancer.
The FDA panel will consider broadening Avastin’s use to a first-line treatment for breast-cancer patients whose disease has spread. About 41,000 women died of breast cancer in 2004, the last year cited by the U.S. Centers for Disease Control and Prevention, making it among the top 10 killers of women.
The key issue for the panel, whose advice the FDA usually follows, will be whether an improvement in progression-free survival is enough to prove that the benefits outweigh risks.
The drug failed to extend overall survival in a major study, although it did meet its primary goal of extending progression-free survival — the probability that a patient will remain alive, without the disease getting worse.
A median 5-1/2-month improvement in progression-free survival “must be weighted against the increased toxicity, including deaths associated” with the drug, FDA staffers wrote in an executive summary, posted on the FDA’s Web site.
Genentech, in documents posted ahead of the panel, said there is precedence for the FDA to use the progression metric in approving other drugs that treat metastatic, or spreading, breast cancer. The drug’s safety profile is similar to earlier trials on which the FDA based Avastin’s approval in other cancers, it said.
Avastin already reaps blockbuster sales — $2.65 billion in the first nine months of this year. Shares of Roche would be expected to take a significant hit if FDA advisers went against the conventional wisdom, which predicts approval.
“The risk-reward for this short period of time is against Roche,” said Denise Anderson, an analyst at Landsbanki Kepler. “I think everybody does expect the drug will be recommended for approval in the indication; so if it’s not, obviously that would be quite a disappointment.”
U.S. sponsor Genentech is majority-owned by Swiss drugmaker Roche.
Doctors are already prescribing the drug for breast cancer, a practice known as off-label use, but a broader label indication in the world’s biggest market would help reimbursement. Avastin is already cleared for breast cancer in Europe.
The drug works by choking off the blood supply that tumors need to grow.
Patients in the study were given either a commonly used treatment called paclitaxel, or paclitaxel combined with Avastin, known generically as bevacizumab.
Among 722 total patients, those in the Avastin group had a 20 percent increase in serious toxicity, including hypertension, blood clots, and heart attacks, among other side effects, the FDA staff said.
Death attributed to the drug by the FDA was about 1.7 percent of the Avastin group, versus zero in the control group.
The FDA staff disagreed with Genentech about the likely causes of death in some of the patients studied.
“Most importantly,” staffers wrote, in the Avastin group “five out of 12 deaths were found to be possibly/definitely related to” treatment.
In September of last year, the FDA delayed the approval process, citing incomplete data. The FDA also asked for an independent radiological review of events, given the subjective nature of judging progression-free survival as a primary study goal.
“The FDA does not love (progression-free survival) as a primary endpoint,” Friedman Billings Ramsey analysts wrote in an investor note, adding: “There’s still the issue of whether tumor shrinkage equates with prolonged survival.”
Still, the firm agrees with the consensus predicting approval.
Roche participation certificates, its most widely traded form of equity, were 3 percent lower at 209 Swiss francs. Shares of Genentech closed down 3.6 percent at $73.50 on the New York Stock Exchange.
The briefing documents for the advisory meeting can be found at: here ndex.htm. (Additional reporting by Sam Cage in Zurich, editing by Gary Hill)