Living Beyond Breast Cancer asked members of our Medical Advisory Board to comment on FDA’s decision to move forward with rescinding the approval of bevacizumab (Avastin) to treat metastatic breast cancer. Comments are listed alphabetically and will be updated as they are received. We also invite other providers and women to comment at email@example.com. We encourage you to read Living Beyond Breast Cancer's statement on Avastin.
Updated December 20, 2010, 10:00 a.m.
Julie R. Gralow, MD, director of breast medical oncology at the University of Washington School of Medicine and Seattle Cancer Care Alliance
“The FDA decision today with respect to Avastin in the treatment of metastatic breast cancer is disappointing.
The pivotal trial (E-2100) that lead to FDA approval had a PFS [progression-free survival] primary endpoint, not Overall Survival [OS]. This was agreed on in advance with FDA. The doubling of PFS from six to almost 12 months is very clinically meaningful. To retroactively insist on an OS benefit is not appropriate.
Two additional studies (AVADO and RIBBON-1), using a variety of different chemotherapy drugs with Avastin, also showed a statistical increase in PFS, although much smaller. For the FDA to state that they did not support the efficacy of the agent is incorrect. It is quite possible that the weekly dosing of Taxol in E2100 is a preferred way to combine with Avastin, and several other small trials with a similar dosing of Taxol with Avastin also showed about a 12-month PFS.
It is clear that some breast cancer patients derive substantial benefit from Avastin. We don't know how to select those tumors or patients yet. It is looking like patient factors, not tumor factors, might be the best way to select those who benefit. To withhold this drug from all patients because some don’t benefit is incorrect. We have lots of cancer agents that are approved for all breast cancer patients that don’t result in 100 percent response rates—we don’t withhold in all because they only work in an as yet unidentified subset.
And lastly, the toxicity of this drug is way overstated in the ODAC [Oncology Drugs Advisory Committee] and FDA releases. We follow the blood pressure regularly and respond to it, significant bleeding is quite low (and not different in breast cancer versus the other cancers in which this drug is approved). Chemotherapy in general causes much more serious and life-threatening side effects.”
Clifford A. Hudis, MD, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and associate professor of medicine at the Weill Medical College of Cornell University
"This is an exceedingly complex issue that remains somewhat unresolved. The key is that there are exciting translational developments in the area of angiogenesis and tremendous potential for new and perhaps even better agents ahead."
“I commend the FDA for making a difficult but necessary decision, acting in accordance with the almost unanimous vote of its advisory committee to remove the breast cancer indication for Avastin. After nearly a decade working in drug development and with FDA as an advocate, I am convinced that we will never make real progress in achieving long-term survival and curing metastatic breast cancer as long we accept and pay for expensive drugs that are unable to demonstrate meaningful benefit in the patients who are treated.
Avastin is the biggest selling drug in all of cancer treatment, making a reported $6 billion a year—$1 billion in breast cancer alone. Genentech says that half of the 29,000 newly diagnosed metastatic breast cancer patients receive it every year—a testimony to an incredibly effective marketing campaign. Since we know that the other half of newly diagnosed metastatic breast cancer patients have tumors that are ER positive and/or PR positive and are typically put on hormonal treatments, this figure means that virtually all newly diagnosed patients on chemo have been getting Avastin added to their regimen.
There were high hopes for anti-angiogenic drugs overall, and Avastin in particular. Yet even researchers involved in their development have recently admitted that they have largely been a disappointment in the clinic.
Does Avastin help patients live longer? We now have five large randomized clinical trials that have shown no overall survival benefit when comparing Avastin with chemotherapy to the same chemotherapy alone—meaning that this drug doesn’t extend life in an unselected population.
Does Avastin help patients live better? We have no evidence that it improves quality of life—quite the contrary, as at least 4 percent suffer serious and life-threatening side effects, and virtually all patients experience some toxicities from Avastin, which may or may not be managed successfully, depending on the quality of care received, since these side effects require careful monitoring.
Does Avastin meaningfully extend the time before the cancer progresses? We have evidence from four out of five trials that Avastin may prolong the time before the cancer progresses—but how much time? Depending upon the clinical trial, this ranged from as little as three weeks to as much as five months. The smaller numbers, according to FDA, may be affected by measurement biases. One trial offered no improvement in time to progression. Given the toxicities, that’s not enough benefit, and too much harm, for a drug that doesn't help most patients, and costs upward of $8,000 per month.
Yet we all know of patients who have responded to Avastin and a few who have gone on to have long-term benefit. Genentech/Roche has known for years that most patients do not respond to this drug, and they claim to have looked for and been unable to find any difference between those who respond and those who do not.
The company has had great success marketing Avastin to the medical community. As an advocate, I question whether Genentech/Roche has devoted the level of effort and resources required to identify and test for the responders. There are academic researchers working on this issue with some promising preliminary results—none of which have been supported by Genentech, to my knowledge. As with other pharmaceutical companies, it appears as if they have a vested interest in holding fast to the assertion that there is no way of determining who will benefit and who will not. It’s the right thing to do, for the sake of patients, but it is not the profitable thing to do.
Doctors and patients want the right to decide for themselves and to have all the choices available. That’s understandable. They’re not really thinking beyond those immediate needs, and why would they? Individual variability being what it is, this patient just might be the one who does well on Avastin—so why not try?
But to me, it’s also important to think about the implications of this lowering of standards happening every day, in tens of thousands of consulting rooms. From what I've learned, when it comes to drug development, what we get is only what we insist upon. No more, and no less. So I stand with the National Breast Cancer Coalition on this issue. If we demand that FDA approve only treatments that have been shown to actually prolong life and add to quality of life, then we’ll be able to make real progress. But if we don’t set high standards for drug approval, we're likely to just keep getting mediocre but expensive drugs that help little if at all in unselected populations—and the pharmaceutical industry will never be challenged to do the hard scientific work to find the real blockbusters that will actually revolutionize cancer care, and give metastatic patients years and decades more life. I still believe this is possible, and well worth fighting for.”