Avastin For Breast Cancer? No Way: Karuna Explains
12 CommentsBy Ed Silverman // June 27th, 2011 // 8:17 am
An unprecedented, two-day trial begins tomorrow in which Roche and its Genentech unit will fight the FDA over a recent decision to rescind a breast-cancer indication for the best-selling Avastin med, which was inititally authorized as an accelerated approval. The FDA cited study results showing Avastin does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh such risks as hemorrhage and heart attack or heart failure (see this). But the drugmaker forced an appeal which, in recent weeks, prompted feuding over bias and financial disclosures (look here and here). A lot is riding on the outcome - the indication is worth an estimated $1 billion in sales and the veracity of accelerated approval is now under a microscope (read here). Some patient advocates argue accelerated approval is becoming politicized, especially as industry execs and some members of Congress say the FDA is too strict. And some doctors worry cancer drugs will not win accelerated approval if revocation becomes too difficult. But patients are protesting any loss of Avastin (watch the video). We spoke with Karuna Jaggar, the executive director of Breast Cancer Action, which wants the indication revoked…
Pharmalot: Why do you believe the FDA should rescind the breast cancer indication?
Jaggar: We absolutely agree that there need to more and better treatment options for those with metastatic cancer. We don’t want to give false hope. But the current scientific evidence that Avastin works for metastatic breast cancer wasn’t there. Certainly, there was promising evidence that was used to accelerate the FDA approval and given those initial data indicated some possible benefit. But that’s not the case, based on what we subsequently learned. I understand people are disappointed. I feel disappointed, too. But the data that Genentech and Roche presented since 2007 has failed to show a survival benefit and improved quality of life.
Pharmalot: Is there any middle ground here?
Jaggar: The approval should be pulled unless or until Roche and Genentech and show absolute scientific proof that Avastin is improving quality of life. There’s this issue that Roche has gotten sloppy with quality of life data and subbed out progression free survival – that they’re using progression free survival as a surrogate. As I understand it, the quality of life data is incomplete. We would welcome them bringing new data to the table, but the current data we’ve got shows patients don’t live longer and don’t live better.
Pharmalot: The meeting is unusual. What concern does might this raise?
Jaggar: I worry that a large pharma is able to call for a special meeting without presenting the data. What are the grounds for further review if there’s no new data? The science is already really clear. In terms of any accelerated or conditional approval process, it’s only meaningful if you can and do pull the approval. We can’t give a pharmaceutical company a precedent that, once you’ve gotten approval, it’s exceedingly hard to pull it back. We’ve already had an FDA (panel) meeting. The data has been reviewed. The conclusions have been made. In order to go through that exercise again, we need some new data to justify something that has already been resolved.
Pharmalot: What about the women and their families who believe Avastin is a worthy option?
Jaggar: I feel for all the families and women who are grappling with a terrible situation - it’s heart wrenching. The stories are moving. But anecdotes are not science and the fact is that too many patients who were treated with Avastin are not here to tell their stories. There are severe side effects and I don’t think they can be understated. In looking at drug approval, we need to look at science. Avastin carries side effects that are life threatening, including heart failure. You need real science to demonstrate a benefit and to decide whether to take an extremely toxic treatment. That said, we do advocate that Avastin remain available for women who are currently taking it. We want the FDA to pull the approval for women going forward.
Greg Pawelski
Avastin combined with chemotherapy has improved the survival of some lung cancer patients. Avastin plus folfox has improved survival for some colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all cancer patients.
Roche has reported that women with breast cancer who were treated with Avastin in combination with chemotherapy followed by the continued use of single-agent Avastin demonstrated a significant improvement in progression-free survival. It’s unclear if Avastin can help increase the overall survival rate in this indication.
I remember a clinical oncologist involved with real-time studies under real-world conditions of drugs like Avastin, telling me when the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change.
The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some cancer patients are missing out on a treatment that could quite possibly save their lives.
One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another.
The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome.
original industry insider
Quoting Greg above: “Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another”. I agree 100%. But the era of Personalized Cancer Medicine” is to be ushered in scientifically years from now, not presently based on anecdotal reports of success stories and high powered lobbying by Roche and Genentech.
My inside sources tell me that there is a growing chorus rising in the agency against the principle of accelerated approval because of the political pressures surrounding revocation al la Avastin. Accordingly, if the FDA loses this battle and is forced to retain the breast cancer indication for Avastin, this will add significant momentum to those wishing to do away with the accelerated approval process altogether because if the process is retained, as Greg as referenced above, there will undoubtedly be another Avastin-like battle in the near future with yet another oncology drug with irreproducible survival benefits.
dude
you still think this hearing is going to have some affect on accelerated approval program? HAAAAAAA HAAAAAAA… where did that ever come from?
Laura Philben
I agree with both Greg and the Industry Insider. There a probably many people like me who are Stage1V BC (me, since 2006.)
Been on avastin, xeloda since 19-2008 and it HAS improved my quality and duration of life.
None of these drugs can cure Stage 1V. I don’t expect that. Xeloda is loosing its effectiveness after a little less than 3 years.
We will try other options along with Avastin.
I and my family and friends are thankful for this amazing ride with Avastin.
SHAME on YOU FDA. You seem to be a big time whore in bed with the insurance companies.
Observer
LP:
History of cancer in my family makes me believe that HOPE is the most important issue. That said - as Ed posted recently:
In explaining their decision, FDA officials cited the results of four clinical studies and determined the data indicate Avastin does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh significant risks. These include severe high blood pressure; bleeding and hemorrhage; development of perforations in the body, including in the nose, stomach, and intestines; swelling of the brain, and heart attack or heart failure ….
“The limited effects of Avastin combined with the significant risks led us to this difficult decision,” Janet Woodcock, who heads the FDA’s Center for Drug Evaluation and Research, in a statement. “The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”
Last summer, an FDA advisory panel voted 12-t0-1 to withdrawal approval for treating breast cancer. The move came after two recently released studies - which were undertaken as a condition of approval - found that patients given Avastin and chemotherapy didn’t survive longer than those given chemo alone. And patients also suffered serious side effects.
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There are selected groups who will benefit, if we acrually knew who they were - I hope you are part of one of those groups with the right characteristics…. and not part of the majority subject to “the collateral damage,” to put it crudely.
Greg Pawelski
In regards to Avastin side effects, any chemotherapeutic has its range of side effects. With Avastin though (and probably most other agents), it was reported in JCO that emerging evidence shows many of the drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The dose being used for Avastin is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.
There are selected groups who will benefit from Avastin, if they knew who they were. Genentech/Roch (or whatever flavor of the month they are) researchers have been looking for tests to help predict how patients will respond to Avastin. Some have suggested that they should use the cell-based functional profiling platform (AngioRx Assay) to identify a potential targeted population of cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trial among this group.
However, unlike some genetic assays that look whether an individual has a particular mutation or amplification, and therefore tests for “theoretical” candidates for a particular targeted drug, the functional profiling technique may find Avastin not synergistic (cooperative) and finds some other VEGF-targeted (or multiple VEGF-targeted) drug may work better in an individual cancer patient and then put that individual into the clinical trial. I can understand they may not want some other drug tested on their dime.
There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.
This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy. There is really nothing wrong with Avastin. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman. There are not perfect drugs. There are simply drugs that work for certain patients. But that’s not what pharmaceutical companys like to hear. They like to produce drugs that apply to a broad base of patients. To make the most out of a drug, not just some subsets of patients.
original industry insider
Thanks, Greg. It is extremely rare for any malignant tumor to arise from a single gene mutation AND have that single mutant gene persist as the cause of the cancer. Most malignancies don’t arise from single gene mutations, or if they do, ultimately develop new, resistant mutations depending on the biological behavior or the tumor. Thus the whole notion of “targeted therapy” for breast or any other cancer needs to be considered carefully in light of these unfortunate realities of tumor biology.
Beth
Alright, but what about Avastin and lung cancer? There is always talk about breast cancer but it is used for my husband’s stage 4 NSCLC “maintenance”–of course, until they detect disease progression.
Is there an indications as to whether Avastin is not effective for lung cancers, et al as well? I ask this because recently “the news” reported a shortage of Taxol (as well as carboplatin) BUT only mentioned breast cancer neglecting to mention the others: lung, colon, & ovarian cancers. There seems to be a trend here about 1/2 way reporting, or neglecting to reassure non-breast cancer patients that Avastin is still effective. So what’s the story for lung cancers?
Greg Pawelski
Beth
There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.
There is really no lung cancer chemo or breast cancere chemo. There is chemo that is sensitive (effective) or resistant (ineffective) to each and every “individual cancer patient, not populations. There are chemos that share across tumor types. Avastin could be given selectively to patients with VEGF-sensitive tumors with all types of cancer, if it otherwise indicated and if a functional assay is positive for it. It looks at the entire cell to measure the interaction of the entire genome, not just one pathway or a couple of pathways.
Avastin combined with chemotherapy has improved the survival of some lung cancer patients. Must it be Taxol chemo? Of course not.
Roche has reported that women with ovarian cancer who were treated with Avastin in combination with chemotherapy followed by the continued use of single-agent Avastin demonstrated a significant improvement in progression-free survival. It’s unclear if Avastin can help increase the overall survival rate in this indication. Details of the study aren’t scheduled to be published until later in the year.
The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome.
original industry insider
Greg, what percentage of these tumors are positive for the VEGF mutation?
Greg Pawelski
Couldn’t tell you off the top. It would have to be on an individual basis. Some patients express more VEGF than others.
But tumor vasculature does need VEGF to survive. The “key” with Avastin is that it works by blocking VEGF (Avastin “sensitive” tumors). But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc. You need to attack these other targets as well.
Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and/or monoclonal antibodies). Some small molecule drugs like Sutent are multitargeted inhibitors, that act on multiple receptors in the cancerous cells.
All a VEGF mutaton study (genetic testing) can tell us is whether or not cells are potentially susceptible to this mechanism of attack. They don’t tell you if one of these VEGF inhibitors is better or worse than some other that may target this.
VEGF-targeted drugs are poorly-predicted by measuring the ostansible target, but can be well-predicted by measuring the effect of the drug on the “function” of live cells (a functional profiling platform).
original industry insider
Thanks, Greg. Makes it even more amazing how many oncologists swear by the tumor immunohistochemical markers to select \"targeted\" therapy. Has anybody done rigorous sensitivity and specificity testing on these tumor markers as would be done for any standard lab tests? I have a pathology background, I don\’t know that any of these assays would pass muster with CLIA.