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Old 07-21-2010, 09:54 AM   #1
Hopeful
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Join Date: Aug 2006
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Avastin's Last Hope For Breast Cancer Claim May Be Subpopulations

Supplementary editorial provided by OncologySTAT

EXPERT COMMENTARY

Lee Schwartzberg, MD, Editor-in-Chief

The stunning reversal of ODAC's previous recommendation against the use of bevacizumab in breast cancer may well signal a sea of change in the way FDA approaches approval for oncology products. Rejecting progression-free survival as a meaningful outcome will have a dramatic impact on many pipeline products. This stand is controversial at best and in breast cancer, ill-advised. The natural history of this disease is one of chronicity with benefit achieved by multiple lines of therapy, diluting the survival effect of any specific line of treatment. When asked, patients vote for therapy that extends time with stable to improved symptoms; which is something that bevacizumab achieves. Overshadowing this decision is the high cost of bevacizumab. One wonders if we are entering an era of approval based on de facto cost-effectiveness without transparency about how economic factors are considered in the equation.

ABSTRACT

Genentech's broad metastatic breast cancer claim for Avastin (bevacizumab) appears to be destined for withdrawal, but the company may have the potential to test its effectiveness in specific subpopulations. Two new clinical trials clearly did not provide enough data for FDA's Oncology Drugs Advisory Committee to support moving the drug to full approval for use with paclitaxel in first-line treatment of metastatic breast cancer, voting 13-0 against it July 20.

Committee members also soundly rejected the data in the AVADO and RIBBON-1 trials, which were conducted as part of the drug's accelerated approval. ODAC members indicated there was no favorable risk-benefit analysis for treating the disease with a combination of Avastin and docetaxel, voting 13-0 against, or Avastin and taxanes, anthracyclines, or capecitabine, voting 12-1 against.

Some members who were receptive towards the drug following the 2007 advisory committee meeting, where it also was voted down, said they could no longer support it.

"I think a couple of years ago ... it looked like the data was not as robust, but after I voted against it, looking at the data and thinking about it, maybe I thought I voted the wrong way," said Aman Buzdar, professor of medicine, department of breast medical oncology, University of Texas, M.D. Anderson Cancer Center.

"If you look at the net gains in control data today, I think the data is less robust and ... the risk-benefit ratio I think is in the wrong direction," he said.
The one vote in favor of Avastin among the three questions, Gary Lyman, professor of medicine and director, comparative effectiveness and outcomes research at Duke University, said he cast the vote in protest because he did not like the question. He also said he saw the beginnings of an advantage in coupling Avastin with capecitabine.

Benefit For Specific Populations?

Avastin combined with paclitaxel chemotherapy gained accelerated approval in 2008. Roche/Genentech submitted two supplemental biologics license applications in November 2009 in an effort to gain a full approval for use of the drug in combination with docetaxel chemotherapy and taxanes, anthracycline or capecitabine chemotherapy.

The data from the E2100 trial showed a median progression-free survival of 11.3 months versus 5.8 months with paclitaxel alone.

After rejecting the confirmatory trial results as not clinically meaningful, the committee voted 12-1 in favor of removing the metastatic breast cancer treatment indication from the Avastin label.

Most members reasoned the lack of clinical or survival benefit among the large number of patients in the trials as well as increased adverse events related to those taking the drug versus placebo kept them for supporting the indication.

Patrick Loehrer, interim director, Melvin and Bren Simon Cancer Center, Indiana University, said there still may be some redeeming benefits for Avastin in metastatic breast cancer, if Genentech is willing to consider subpopulation trials.

"I do think that there's activity for Avastin in breast cancer," Loehrer said. "I think I would look forward, if the company was so inclined to look at baseline symptoms ... and see if there was a clinical benefit response that manifested... or some other surrogate marker that might be helpful."

The company said in an e-mail following the meeting that it will submit two more Phase III trials for Avastin in first-line metastatic breast cancer treatment when they are completed.

The additional trials include AVEREL, which looked at Herceptin plus docetaxel with or without Avastin. Data is expected next year. The second trial is CALGB 40503, which enrolled its first patient in the fourth quarter of 2008. It compared hormone therapy -- tamoxifen or letrozole -- with or without Avastin.

Virginia Mason, the committee's consumer representative, voted against removing the indication. She said since the Avastin label already states there is no demonstrated increase in survival, she was willing to keep the indication and leave the decision to patients and physicians.

"I could live with the fact of having that on the label and (allow the) physician and the patient to make a decision if they want to take the risk of a drug that does have significant side effects but could provide an individual some benefit," said Mason, executive director, Inflammatory Breast Cancer Research Foundation.

Progression-Free Survival Remains An Issue

The committee decisions followed the FDA review, which found while AVADO and RIBBON-1 showed statistically significant improvements in progression-free survival, the magnitude of the improvement was not clinically meaningful.

Genentech faced several questions about PFS as in the previous advisory committee meeting about Avastin because it is a surrogate endpoint. The new trials did not measure the traditional gold standard, overall survival, as a primary endpoint.

The median progression-free survival rate in the AVADO trial was 8.71 months for 7.5 mg/kg Avastin with docetaxel and 8.77 months for 15 mg/kg Avastin with docetaxel. Docetaxel alone showed a median PFS of 7.89 months.

In RIBBON-1, a cohort received either Avastin or placebo combined with taxane or anthracycline. Those receiving Avastin showed a better median PFS, 9.2 months, versus placebo, 8 months. Median PFS also improved in the second cohort when Avastin was combined with capecitabine, 8.6 months, versus placebo, 5.7 months.

Ralph D'Agostino, chair of the mathematics and statistics department at Boston University, said ultimately there was no data indicating PFS would translate to improved overall survival.

"We're putting an awful lot of faith in what we mean by progression-free survival under efficacy," he said.

Genentech said in a written statement it stands by its data and believes Avastin should remain an option for patients. The company expects a final decision on the drug's use in metastatic breast cancer by Sept. 17.

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