FDA Panel Says No to Avastin for Advanced Breast Cancer

[gpawelski]

(HealthDay News) -- A U.S. Food and Drug Administration advisory panel recommended that the cancer drug Avastin should not be used to treat women with advanced breast cancer.

In a close vote, 5-4, the advisers decided the drug's ability to slow down the growth of tumors did not outweigh the increased risk of blood clots and other cardiovascular troubles among users, the Associated Press reported. In rare cases, patients taking Avastin with standard chemotherapy have died.

Avastin was approved to treat colon cancer in 2004, and lung cancer in 2000. It works by cutting off the tumor's blood supply.

"Everybody wants to offer metastic breast cancer patients hope, but we shouldn't offer them false hope," panel member Natalie Compagni-Portis, a patient representative with Breast Cancer Action in San Francisco, said during the meeting, according to the AP. "We have to raise the bar in terms of safety."

"These patients are terminal, and it's our job to make their lives better, not to say that it's OK to have a stroke or that it's manageable," Maha Hussain, an oncologist at the University of Michigan and the advisory panel's chairwoman, said during the meeting. "You didn't show that patients are living better or that they're living longer."

In trial results submitted to the FDA by the drug's U.S. maker, Genentech Inc., use of Avastin (bevacizumab) did boost the progression-free survival of women with advanced breast cancer by an average of 5.5 months, when combined with the chemotherapy drug pa****axel. Progression-free survival refers to survival without any advancement of the malignancy.

However, the same Genentech study of 722 patients showed that patients reaped no gain in terms of their overall survival after taking Avastin.

Another company-funded trial, this time including 462 patients with advanced breast cancer, showed similar results, with Avastin having no effect on overall survival.

At the same time, the FDA said, the drug has "major safety issues," including hypertension, clotting events, left ventricular heart dysfunction, heart attack, gastrointestinal perforation and proteinuria (excess protein in urine). A special FDA staff review of the data found that rates of grades 3 to 5 toxicities rose by more than 20 percent when cancer patients received Avastin on top of regular chemotherapy.

Furthermore, in the Avastin-pa****axel trial, the rate of patient deaths linked to Avastin use was 1.7 percent (six out of 363 users) compared to no deaths among the 348 participants who did not receive the drug, the FDA noted.

In its approval submission statement to the FDA, Genentech contended that, "Analysis of the safety and efficacy data in total demonstrates a highly favorable risk-benefit profile for bevacizumab in combination with pa****axel that supports full approval of bevacizumab for the treatment of locally recurrent and metastatic breast cancer."

The FDA is not obligated to follow the recommendations of its advisory panels, but usually does. A decision is expected by Feb. 23, the AP reported.

Avastin is not traditional chemotherapy, but instead is a monoclonal antibody that robs tumors of their blood supply. It has been found to boost the survival of patients with metastatic colorectal cancer and non-small-cell lung cancer when added to chemotherapy and used as a first-line treatment.

But the drug has its downside. In an analysis of pooled data from five randomized controlled trials involving more than 1,700 patients with metastatic colon, breast or lung cancers, Genetech researchers found that 3.8 percent of patients experienced blood clots while on the drug, compared to 1.7 percent of those who took standard chemotherapy alone.

Patients who were 65 or older appeared to be at special risk for clots while taking Avastin, according to the study, which was published in August in the Journal of the National Cancer Institute.

The exact link between Avastin and cardiovascular risk remains unclear, although the Genentech team speculated that a vascular endothelial growth factor (VEGF), a natural compound that boosts blood vessel growth, may play a role.

More information

Find out more about breast cancer and its treatment at the American Cancer Society. http://www.cancer.org/docroot/CRI/CRI_2x.asp?sitearea=&dt=5

[gpawelski]

ASCO has become a trade group masquerading as a scientific body. $1 million annually in lobbying. >40% of funding from industry. I’m surprised it isn’t more. Could anyone think Genentech and Roche (which owns most of Genentech) don’t have the juice necessary to get an abstract published or, as in this case, to create a special oral session for it? No surprises.

http://blogs.wsj.com/health/2007/12/11/avastin-for-breast-cancer-the-pre-history/

Avastin (bevacizumab) is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside which are protected from the drug. The cells may pass small molecules back and forth.

Vatalanib (PTK/ZK) is a "small" molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug potently inhibits the formation of new blood vessels (angiogenesis).

However, do the drugs even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.

A major modification of the DISC (cell-death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as bevacizumab (Avastin) and vatalanib. The microvascularity viability assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect.

Each of these new targeted drugs are not for everybody. According to the National Cancer Institute, those who benefit substantially from "targeted" drugs is approximately 10% to 20%. What if you are one of those few? This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first.

[gpawelski]

Breast Cancer Action (BCA) strongly disagrees with the Food and Drug Administration's decision giving accelerated approval to biotech company Genentech's application to market its drug Avastin as a treatment for metastatic breast cancer at this time.

"The FDA has lowered the bar on the approval of breast cancer therapies. At a time when many questions are being raised about how the FDA approves drugs for market, the decision is a victory for drug companies, but not for patients," BCA Executive Director Barbara A. Brenner said.

BCA has long opposed Genentech's application, arguing that no evidence has been presented that shows Avastin improves overall survival or quality of life.

In its application to the FDA, Genentech said that a clinical trial indicated that Avastin prolongs progression-free survival. However, BCA argued that that endpoint is meaningless because it does not address the patient's quality of life during those additional months, a very real question because of some of the serious side effects a number of the women experienced, and it has not been shown to correlate with overall survival.

Breast Cancer Action is a national watchdog and advocacy organization that carries the voices of people affected by breast cancer to inspire and compel the changes necessary to end the breast cancer epidemic.

Since 1998, BCA has refused to accept funds from corporations that may create a real or apparent conflict of interest for BCA. Corporations covered by this policy include pharmaceutical companies.

I think the Breast Cancer Action's comment about the FDA lowering the bar on the approval of breast cancer therapies is very valid.

The FDA rejected the recommendation of its advisory panel because the benefit in slowing tumor growth wasn't believed to be worth the added risk of serious side effects, including high blood pressure and death. Avastin killed more patients than the control arm.

This mirrors the statin debacle. Drug companies didn't have to prove that lowering cholesterol did anything positive for patients, just that it lowered cholesterol.

So we're back to square one again. Instead of showing a drug can increase survial, all they have to do is show that it can shrink a tumor. Didn't we just come from that neanderthal moment?

Avastin is already approved for advanced colon and lung cancer and was already Genentech's best-selling drug last year. However, an additional indication of Avastin for advanced breast cancer would drive new revenue for the company.

The introduction of targeted drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of these drugs. There should be an immediate recognition that matchmaking between cancer and cancer treatment is one area in cancer research and treatment which is deserving of much greater attention and utilization.

There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function/cell culture) level. Because what may benefit one individual cancer patient may not benefit another.