Why was Avastin pulled by the FDA for treatment of breast cancer?

I was reading a piece in The Star-Ledger this morning and came across a news piece written by a Washington Post reporter (http://tinyurl.com/washpost-avastin) about the FDA ending the use of Avastin to treat metastatic breast cancer. The reason that the FDA is pulling the drug (according to the above news piece) is “…that the drug was harming women more than it was helping them.” The remainder of the article discussed the price of the drug ($88,000/year/patient) and the outcry from patients and advocates for access to new treatments. It was stated that clinical trials failed to support the drug’s promise to treat breast cancer but at no point does the reporter tell readers the harmful side-effects that prompted the FDA to remove approval of the drug for breast cancer treatment. I think these two pieces of information are quite important to understand the FDA’s decision. However, the use of Avastin to treat colon, lung, kidney, and brain cancers is not in jeopardy.

So let’s start with how Avastin is supposed to work to treat cancers (I’ll post at the bottom of this page the links to where I obtained my information for anyone who wants to learn more). Avastin is also known as bevacizumab. It is an injectable cancer medication that works by blocking a protein that is important for the formation of blood vessels. This is a method for targeting solid tumors since the cells that are in the interior of the tumor need a supply of nutrients, which are brought in via new blood vessels. As tumors get larger, the cancer cells start expressing proteins that will induce cells of the body to generate new blood vessels. In 1971, Dr. Judah Folkman of Harvard Medical School first proposed that large tumors need these blood vessels to grow and metastasize, which he called angiogenesis. He also proposed that inhibiting angiogenesis may be one way to treat cancer – besides inhibiting cellular replication. His research and the work of others over the years led to the discovery of several proteins that cause angiogenesis. One of these proteins is VEGF (vascular endothelial growth factor) which is the target for the drug Avastin. Patients whose breast tumors express VEGF in high quantities have a poor prognosis, so VEGF should be a very good drug target. Avastin binds to all forms of VEGF in the blood which prevents VEGF from binding to its receptors and functioning to induce blood vessel formation. However, this drug has little effect on its own in treating breast cancer but does help to increase the efficacy of other drugs that inhibit cell growth such as paclitaxel. But more importantly, the combination only extended overall survival by less than one year! An increase of survival of less than one year does not seem like much of an improvement; and this would be especially true if there are any serious side effects associated with use of the drug.

So what are the side effects, how often are they observed in patients, and how significant are these side effects? Side effects observed included kidney damage, development of holes in parts of the body (for example, nose, stomach, intestines), massive bleeding requiring blood transfusions, and various cardiovascular problems (for example, heart attack, stroke, clotting in arteries, chest pain, and reduced blood flow to the brain). These are pretty serious side-effects that can cause death or brain damage. The rate of severe or life-threatening side effects was 14-20% higher in patients who were on Avastin plus chemotherapy as compared to patients on chemotherapy alone. Additionally, there was an increase risk of treatment related deaths in patients receiving Avastin with chemotherapy as compared to chemotherapy alone.

So because there was very little benefit and significant risk to patients taking Avastin, the FDA rightly pulled the approval of using this drug to treat metastatic breast cancer. These results are also a good example of why accelerated approval of drugs is not necessarily a good thing. Accelerated approval allows earlier approval of drugs to treat serious diseases, and that fill an unmet medical need. Generally clinical trials results are based on clinical outcomes (ie. prolonged survival or years disease-free) and obtaining these types of results can take a very long time. Accelerated approval of drugs started when AIDS activists pushed to have anti-retroviral drugs approved at a faster rate for treating AIDS. At the time, there were no treatment options for HIV infected patients except to treat the opportunistic infections that these individuals would get due to their suppressed immune system. So we have the balance the good (getting new and better drugs to patients at a faster rate) and the bad (may not observe some of the severe side-effects or treatment-associated deaths during shortened clinical trials) when deciding whether accelerated approval of a drug should occur.

Additional information:

FDA site for post-market safety information for Avastin: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm193900.htm

Encyclopedia Britannica article on angiogenesis: http://www.britannica.com/nobelprize/article-224720

Paper by L.S. Rosen, H.L. Ashurst, and L. Chap discussing treatments for metastatic breast cancer: http://theoncologist.alphamedpress.org/content/15/3/216.long

Letter from the FDA regarding pulling Avastin: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM237286.pdf

Genentech’s (manufacturer of Avastin) website for Avastin: http://www.avastin.com/avastin/patient/gbm/sideeffects/index.html

Accelerated approval at the FDA: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/ucm128291.htm#accelerated