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The FDA and Avastin: Breast Cancer Patients Are Thrown Another Curve In An Ongoing Saga

by Dr. Len July 20, 2010

The news this afternoon that an FDA advisory panel recommended removing approval for bevacizumab (Avastin®) as a treatment for advanced breast cancer is certainly going to be difficult for patients, their families, supporters and doctors alike.

 

The unfortunate reality is that despite earlier reports that this targeted therapy (which has been successful in treating a number of other cancers and works by inhibiting the growth of new blood vessels that feed cancer tumors) was successful in treating advanced breast cancer didn't hold up when studied in further clinical trials.

 

Bevacizumab in the treatment of breast cancer has followed a long, somewhat tortuous course beginning as early as 2005 with an announcement by the National Cancer Institute that the drug was successful in a clinical trial where women with advanced breast cancer were treated with the drug.

 

Following that announcement, it took an additional almost 3 years until the FDA approved bevacizumab as a treatment for breast cancer.  However, that approval was not a "slam dunk", after another FDA advisory panel had recommended against approval on a close vote.  The FDA overrode the panel's recommendation, and gave the drug a conditional approval while further clinical trials were underway.

 

It was the results of those clinical trials that were presented to the FDA's cancer drug advisory panel today, resulting in an overwhelming (12-1) vote to remove approval of bevacizumab as an effective treatment for advanced breast cancer.

 

The trials in question used standard chemotherapy with or without bevacizumab, and looked to see how long the treatment(s) delayed the progression of breast cancer (what we call "progression free survival", or PFS) as well as how long the women lived after they received their treatment ("overall survival" or OS).

 

The reports from a couple of years ago showed the addition of bevacizumab almost doubled progression free survival from 5.8 months to 11.3 months.  However, the data at that time did not show that bevacizumab increased survival, which up to this point in time has been the "gold standard" for approving almost all cancer treatment drugs.  That is one of the reasons the FDA asked for more information.

 

For some of us, the core question at that time was whether or not women had a better quality of life during that period of extended progression free survival, even if the drug did not increase the length of their days.  The thinking was that even if total survival wasn't improved, at least if they had better function and less pain, it would still be worthy to consider the drug effective.  Unfortunately, the studies were not designed to give an answer to that question.

 

Now come the two new studies, and the news wasn't particularly impressive that bevacizumab made a real difference in the treatment of the women in the trials.

 

According to an FDA report, although the drug was effective in increasing the progression free survival, the duration of that effect was around 0.82 to 0.88 months in one study and 1.2 months in the other. When looking at survival, there was no real difference in women who received bevacizumab compared to those who did not.  In fact, if anything, the data suggested (but did not prove) that women who did not get bevacizumab lived longer than those who did.

 

The safety review of the drug also showed many more severe adverse side effects when bevacizumab was added to the treatment regimens. 

 

So where does this leave us?

 

Although there were suggestions that bevacizumab had some effect in increasing response rates in breast cancer treatment, that did not translate into particularly long increases in how long it took breast cancer to progress.  It clearly did not increase the survival for these women.  In fact, the overall survival appeared to be shorter in women who took the drug.  The reasons for that are not clear, and the possibility remains that some known or unknown side effect of the drug could have contributed to this outcome.

 

The panel was overwhelming in its decision, but that does not mean the FDA will withdraw the drug for this particular treatment indication.  The panel voted previously in December of 2007 not to approve the drug, but the vote then was much closer (5-4) and the FDA eventually overrode that recommendation and provided the conditional approval.  So one should not draw conclusions based on today's reports alone as to what the FDA will do in this particular situation.

 

There are clearly women out there who have had significant responses to bevacizumab when used either alone (during clinical trials) or with other chemotherapy.  And for them and their families today's reports are going to be difficult to accept.  But the information is what it is, and given the FDA's published concerns about the earlier clinical trials, it may be that today's evidence is a bit more solid than that presented previously.

 

There are several real issues that patients and their physicians will have to address immediately, such as what do you do if you are currently receiving bevacizumab as part of a treatment program?  And, especially, what if you are a woman with advanced breast cancer and have had a response to your chemotherapy regimen which contains bevacizumab? 

 

For women currently on the drug, it is vital that you have an open and honest conversation with your oncologist who knows you best.  The FDA has not withdrawn approval of the drug, and no one should take any drastic action (such as insurance companies stopping payment for this treatment) based on today's committee vote. 

 

For women with advanced breast and their doctors who may be contemplating treatment options, situation has become a bit more complex, and there is no easy answer.  I suspect there will be a lot of experts who will be offering their thoughts in various media and other reports from respected medical organizations which might give some guidance to oncologists as to what their next steps should be.

 

And-and this is a very important "and"-this recommendation does not apply to other cancers such as colon cancer and lung cancer where bevacizumab has shown to be effective.  Nothing about today's recommendation has anything to do with the approved use of bevacizumab in the treatment of other cancers.

 

Ultimately, this committee vote reflects some of the difficulties we have in determining which drugs are truly effective in treatment which cancers.  With all of the new targeted therapies on the horizon, the situation is becoming even more complicated.  Think back to Iressa®-another targeted therapy that was conditionally approved for lung cancer and then withdrawn-and the recent events surrounding the approval of Provenge® for advanced prostate cancer, and you have a sense of what I mean.

 

In the meantime, it is critical that we make our best efforts to design clinical trials in such a way that interpretation of the results leaves little to chance.  We can't go through too many of these events before we begin to question why we got into this situation in the first place.  When it comes to bevacizumab and breast cancer, we have had reports of success, followed by tempering of those reports, followed by a limited success resulting in a conditional approval, to today's decision to recommend withdrawing approval for treatment in advanced breast cancer be removed.

 

During the swing and sway of all of these decisions and recommendations over the past 5 years there have been patients, families and their doctors looking for some hope that a new drug was effective in treating a deadly disease.  Too much back and forth that never should have happened.  Too many lives have been caught in the crossfire of indecision that has enveloped this drug in the treatment of this disease.

 

I suspect the FDA won't take a long time to make its final decision, but no one knows for sure.  In the meantime too many women and their families are left hanging, wondering whether the cost in human and financial terms is worth it for a drug that may or may not work.

 

We need to do better.

Comments

7/20/2010 6:24:52 PM #

Ronald W. Gumbs

We need to study the effect of diet on risk of breast cancer and to increase the funding of the National Center for Complementary and Alternative Medicine. This branch of the NIH system could then conduct more clinical studies to evaluate and determine if food can be used to prevent cancers of the breast and prostate. The American Cancer Society should support this proposition, instead of relying on Big Pharma to lead this war against cancer.

Ronald W. Gumbs

7/21/2010 11:33:35 PM #

Gregory D. Pawelski

Actual results in patients count and theory doesn’t matter as much as the evidence that it does what we want it to do. It would be more advantegeous to sort out what’s the best profile in terms of which patients benefit from this drug.

Some scientists are not sure whether Avastin or any other anti-angiogenic agents are working primarily by pruning new blood vessels, increasing the delivery of another anti-cancer therapy, or potentially another mechanism.

Clinical oncologists involved with functional tumor cell profiling analysis, can actually examine this. They have a method for testing anti-angiogenic/anti-microvascular agents, such as Avastin and testing for synergy between different anti-microvascular agents on an individual patient, individual tumor basis. Avastin appears to better deliver the effects of other classes of drugs.

Avastin facilitates vascular access of cytotoxics to tumors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it’s the most promising thing on the near term therapeutic horizon.

As for Avastin’s side effects. Evidence in the Journal of Clinical Oncology shows that many of the highly expensive targeted drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. Avastin is one example. The dose being used is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.

Gregory D. Pawelski

7/31/2010 2:49:13 PM #

Donald L Parrish

As a spouse of a breast cancer patient/survivor, the news of the FDA advisory panel was very disturbing to me as well as my wife.  First diagnosed in 1992 with successful treatment and a first recurrence in 2005 with two more recurrences between 2005 and 2008 the treatment process has been arduous to say the least.  In the fall of 2008 she was placed on a chemotherapy/avastin tx regimen.  That regimen continued for six three weeks of once per week treatments and a week off.  In the spring of 2009 the cancer that had spread from the breast to both lungs and bone in the pelvis were no longer detected on a pet scan.  Avastin has been the treatment for the past year and a pet scan in March of 2010 continued to indicate the cancer was still not detected on the pet procedure.  Side effects have been to say the least since chemo has been stopped have been negligible.
Our oncologist whom we feel is a world class practitioner and who we have total confidence in has explained the mutation to treatment for cancer and that the goal is to treat it as a chronic disease that cannot be cured.  He explained his colleagues throughout the country have found avastin to be effective for up to 2.5 years with the women with which it works.
We read daily of scores of research efforts, of which one solid conclusion is constant.  Each cancer is different which means that each responds differently to different drugs.  As a care giver, my fear is dollars and cents as well as an attempt to reinstitute a one size fits all treatment is going to send us backwards in the care of cancers.  The ACS itself has not been listened to in this process nor have the politicians who tout health care improvement, except Sen. Witter of La, expressed any concern.  
I realize I am far from a cancer expert but I do live and understand what works for us and what this type of engagement does to people.

Donald L Parrish

8/3/2010 5:00:30 PM #

PATRICK MORGAN

www.thepetitionsite.com/.../...atic-breast-cancer. Everyone needs to go to this web site and read the astonishing positive comments that the FDA and American Cancer Society seem to ignore. I say ACS because they do not want to recommend keeping this amazing drug available to keep our wifes, daughters and friends alive. At minimum they should be saying more research needed and while doing so leave it on the market. It works and I always thought the ACS stood for research and ultimately life. We know the FDA is a precursor to Obama Care and perhaps what Pallin was alluding to when she made the "death squad" comments.........weeding out the low percentage patient, even with effective treatment.
My wife who is approaching two years on Avastin had a treatment this morning and her circulating tumor cell count remains at zero, thus prolonging her life with hope and clarity........she goes back to work.  The decision for use of this drug should be between the patient and her doctor, not by politicians and panels. What all these analytical types don't seem to understand is that life with side effects is better than death and if you read the comments on the web site above there seems to be little side effects. To continue this drug if removed would cost American women 50k to 90k which only politicians and doctors could afford. I am so ashamed of America for letting politics and profit decide our lives. And especially the ACS for sitting on the sidelines. I expected them to stand up for womens rights and cancer treatment advances.............but I now believe they are just another bureaucratic extension. Donald Parrish, the commenter above has more tact than I even want to provide I am so upset. Read his comments closely. Sue Myrick R-NC send a touchy feely letter to the FDA, but it was so sweet it probably was not taken seriously. The local chapter in Charlotte told me that the ACS was going to take no action on this life saving drug. If these decision makers had cancer rather than study it, I bet they would speak out the other side of the mouth.

Comments from my wifes oncologist:

It is still too early to draw conclusions about  Avastin regarding breast cancer death, as we are still awaiting the women on the trials to die from breast cancer, it may take another 5 years to know the answer.  The panel has reviewed only responsive data not survival data.  

EXCERPT FROM THE ESTEEMED PANEL:

Since PFS (progression free survival) is the endpoint being studied,” said Dr. Wyndham Wilson, the ODAC chair, “what we are here to judge is whether or not there is a clinically meaningful—from a patient’s point of view—[difference in] quality of life between the patients who received Avastin and those who didn’t.”

The committee found any such difference impossible to ascertain, since the trials had not collected patient-reported quality-of-life data that could show an improvement in symptoms or psychological state in tandem with PFS. The AVADO trial collected a set of quality-of-life data, but only to show that the addition of bevacizumab (Avastin) did not decrease patients’ quality of life. Sponsors of future trials evaluating PFS should take this issue to heart, stated Dr. Pazdur. “Sponsors really need to pay very close attention to [measuring quality of life], build it carefully into their protocols, and approach it with the same degree of caution and resources…as one would with a primary endpoint,” he said.  This panel seems to be covering the butts over decisions made two years ago. But every month a survivor lives, some new treatment may be discovered.



PATRICK MORGAN

8/4/2010 8:09:48 AM #

PATRICK MORGAN

My wifes CTC markers remain at zero per oncology visit this morning.  She had her scheduled Avastin and went to work................This drug works and I cannot imagine anyone even considering its removal. Let this be between the patient and her oncologist Please honor petition to keep this drug available to all women with metastatic cancer. Note the positive comments. Please.....................................and pass along

Thanks, Pat

www.thepetitionsite.com/.../...atic-breast-cancer.

PATRICK MORGAN

8/4/2010 10:44:24 AM #

Donald L Parrish

Pat
Thank you for the information on you and your wife's experiences and the comments on the need for rational thought on the benefits.  Two years ago I truly thought I would not be enjoying this summer with my wife.  Avastin has made it happen!
The petition is signed and passed along.  Our best wishes to you and to your wife in the year's ahead.  Our oncologist takes the approach at this stage it is a chronic disease like many others which he will manage.  
Our best
Donald

Donald L Parrish

8/11/2010 3:45:53 PM #

Shirley Patterson

I have been on Avastin for several months now with absolutely no side effects. My scans are stable with no growth and my numbers are within the normal range. Why on earth would someone consider removal Avastin for the treatment of metastatic breast cancer is beyond my understanding.

Shirley Patterson

8/12/2010 8:58:39 PM #

Donald L Parrish

Shirley
There is no understanding.  It is cost.  It is Obamacare.  He appointed a czar of medicare who openly states we can learn and model from the UK system. They twice denied coverage for avastin, not for effectiveness but for cost.  Please see Pat Morgan's comments above which are pretty succint regarding the priorities.  You can also access the comments of The Honorable David Vitter on the archives of the the Natchez Democrat who earlier this week affirmed his information that it is indeed cost here as well.  The senator and the Honorable Susan Myrick of NC are the only political beings that are known to stand up for the breast cancer patients who are alive for the grace of avastin.
I live in Iowa and NH and Sen Grassley ignored my request to join Sen Vitter and Sen Shaheen of NH sent me a tutorial that stated the purpose of the FDA!  Do we really think she cares?  I have written Oprah who is silent on the cause.  I have tried the other side meaning Fox News and they are silent.  Perhaps it will make better news after the FDA does the outrageus thing to pull the approval and women die as a result.  Thanks America!
We have a population of a quarter billion people and society is so self absorbed or politicians are so self important to ignore this crisis and life saver.  All in the name of money!
My wife survives today after being stage 4 because of avastin.  Today no scan reveals cancer in her body.  Still there which will come back when avastin is stopped.  She told me tonight she will not go back on chemo or use our finances to pay for avastin when the govt follows through with its course of death panel action.
Thank you Barack Obama for creating change.  Only it is not the change we understood!  Please read the comments of survivors on Patricks site for the petition and see the women who have survived years because of avastin and nothing else!
Donald

Donald L Parrish

8/19/2010 4:46:25 PM #

drlen

Does anyone have the link to the NPR show referenced above?  I went to the NPR site but the only recent broadcast I could find was regarding the use of Avastin in macular degeneration.

Thanks

drlen

8/26/2010 12:52:36 AM #

VB

The link you seek is:

thedianerehmshow.org/.../fda-drug-approval-process-rebroadcast

I am a stage 4 breast cancer survivor with NED (no evidence of disease).  I was diagnosed in December, 2005 and was treated with Avastin, Taxol, and Carboplatin for approximately 6 months, followed by two chemoembolisations, three months apart.  I had a single lesion in the liver, which was reduced during treatment, but based on my understanding, the significant point is that there was no further metastatsis to other parts of my body, most likely thanks to the Avastin. In January, 2007, I was able to have a liver resection to remove the remainder of the tumor, and have had clean PET scans every 6 months since. However, shortly before my surgery, I was discovered to have necrotizing fasciitis from the tumor site with perforation of the stomach which was beginning to work through the abdominal wall. My surgery was expedited because of this, and thanks to the extraordinary skill of Dr. Lynt Johnson of Georgetown University Hospital, I am alive and well today. This adverse effect was likely caused by the Avastin, so what saved me may have almost killed me.  I am thankful, nevertheless, to be alive, and am grateful to have been able to realize the benefits of this drug.  If there is a study to try to identify those who would benefit from the drug, I would be more than willing to be analyzed, as I do believe I benefited, despite my adverse experience.

VB

8/28/2010 2:10:17 PM #

Gregory D. Pawelski

An article appearing in the Journal of Internal Medicine reported that until the Microvascular Viability Assay (MVA) test, there have been the lack of a relevant and practical system for testing anti-microvascular drugs against human tumors in which to discover synergistic anti-microvascular drug combinations.

According to Dr. Larry Weisenthal, MD, PhD., developer of the test, it works by measuring drug effects upon endothelial cells which make up blood vessels. The MVA test is both relevant and practical for use in discovering synergistic drug combinations and identifying which patients are most likely to benefit from which drug combinations.

Dr. Weisenthal says he would like to see the test become available to patients worldwide through service agreements with larger laboratory companies or with a biotechnology company which might develop a testing kit for sale to hospitals and laboratories. He also would like to license the test to pharmaceutical companies for use in new drug development.

It has been suggested perhaps Genentech/Roche should use assays like MVA to identify a potential target population of breast cancer patients that it thinks will benefit from the drug Avastin and then conduct a randomized clinical trial among this group. I couldn't agree more!

Source: J Intern Med 264:275-287, September 2008

Gregory D. Pawelski

8/28/2010 2:23:31 PM #

Gregory D. Pawelski

An article appearing in the Journal of Internal Medicine reported that until the Microvascular Viability Assay (MVA) test, there have been the lack of a relevant and practical system for testing anti-microvascular drugs against human tumors in which to discover synergistic anti-microvascular drug combinations.

According to Dr. Larry Weisenthal, MD, PhD., developer of the test, it works by measuring drug effects upon endothelial cells which make up blood vessels. The MVA test is both relevant and practical for use in discovering synergistic drug combinations and identifying which patients are most likely to benefit from which drug combinations.

Dr. Weisenthal says he would like to see the test become available to patients worldwide through service agreements with larger laboratory companies or with a biotechnology company which might develop a testing kit for sale to hospitals and laboratories. He also would like to license the test to pharmaceutical companies for use in new drug development.

It has been suggested perhaps Genentech/Roche should use assays like MVA to identify a potential target population of breast cancer patients that it thinks will benefit from the drug Avastin and then conduct a randomized clinical trial among this group. I couldn't agree more!

Source: J Intern Med 264:275-287, September 2008

Gregory D. Pawelski

9/7/2010 11:43:08 AM #

Eleanor

I cannot find this article that you speak of. Can you send me a link to the paper?

Eleanor

9/14/2010 3:36:50 PM #

Donald

My wife Rachel received word this afternoon from her oncologist at Dartmouth Medical Center that her cancer screening scan done yesterday once again has excellent results.  No sign of cancer activity for the third scan in a row, thanks to the effectiveness of avastin with her cancer.  He said it would be a huge mistake should the FDA withdraw approval for use as tx of met bc!!

Donald

11/4/2010 10:44:02 PM #

Gregory D. Pawelski

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood

http://www.ncbi.nlm.nih.gov/pubmed/18793333

onlinelibrary.wiley.com/.../full

Gregory D. Pawelski

12/19/2010 11:56:17 AM #

Donald Parrish

With FDA action this past week which is devastating to say the least to the thousands of women receiving life from avastin, there is a temporary respite with the FDA giving genentech time to ask for an appeal.  None is however promised.  There are many things that can be done to let the voices be heard:
- The Susan Komen foundation is continuing to serve as an arduous advocate as there can be for the breast cancer victims being put into this predicament. The American Cancer Society continues to however shirk any advocacy for an unknown reason.
- The FDA has opened a public docket for comments at www.regulation.gov.  FDA-2010-N-0621  Make yourselves heard.
- Many politicians - most republicans - especially Sen Vitter, Congressman Steve King and many others have written and written supportive comments and stayed with us who depend on avastin.  People need to write their elected officials and demand the govt stop its efforts to save us from the side effects from our drug that saved cancer victims untold numbers of their lives with a quality of life opportunity.  Our doctors do not need to have the govt looking over their shoulder.  They and their patients can decide for themselves the options and risks. The govt has not even perfected the evaluation processes that could determine a responder vs a non responder to a drug such as this.  Instead the lives of those depending on the drug are at risk either from the govt or insurance companies!  I find that to be disgusting to say the least!
Thank you
Donald Parrish

Donald Parrish

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About Dr. Len

Dr. Len

J. Leonard Lichtenfeld, MD, MACP - Dr. Lichtenfeld is Deputy Chief Medical Officer for the national office of the American Cancer Society.

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