Changing End Points in Breast-Cancer Drug Approval — The Avastin Story

[Hopeful]

http://healthpolicyandreform.nejm.org/?p=14796&query=OF

Hopeful

[gdpawel]

In regards to changing endpoints, a summary of clinical trial data presented at the ASCO 2010 Kamofsky Memorial Lecture was presentated at a industry supported symposium at the SGO 2011 meeting on survival benefit associated with biomarker-directed therapy in advanced disease. Participants were to learn about the addition of an ovarian-specific profile testing platform following the publication of the original data in the JCO in October, 2010.

If this was any indication of their previous presentation on breast cancer, they invented another endpoint. A 30% increase in time to progression (TTP) over the most recent prior therapy. If Dr So and So gave the patient XYZ therapy and it provided a 3 day response, then the genetic guided therapy needed only provide a 4 day response to show statistical significance. In the previous data set, the 106 patient accrued had a whopping response rate of 5.6% by intent to treat with an objective response rate in the group of fully tested and treated patients of 10%.

The rather new "accelerated approval" program is based on a surrogate endpoint study rather than the gold standard of overall survival, bona fide clinical efficacy, or quality of life improvement. Surrogate endpoint trials are generally faster than traditional efficacy trials that are required for full drug approval because the surrogate endpoints are typically laboratory readouts that are available before direct measure of effectiveness.

Progression-free survival does not address the patient's quality of life during those additional months of some serious side effects a number of women experience, and it hasn't been shown to correlate with overall survival. 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?

The problem with Avastin is that doctors don't know which patients will respond favorably in terms of overall survival. Pharmacogenomics should be used to identify the best candidate patient population and a subsequent studies should then be undertaken to determine biomarkers that have clinical utility in measuring the efficacy of Avastin in those patients.

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) level. Because what may benefit one individual cancer patient may not benefit another.

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.

[gdpawel]

[Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.]

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

[gdpawel]

Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. However, the anti-angiogenic effects of dose-dense therapy may be masked and marginalized by the way it is usually administered. The main targets of high-dose chemotherapy are presumed to be proliferating tumor cells. The main targets of low-dose chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics are used as anti-angiogenic agents.

The process of angiogenesis is controlled by two distinct types of proteins, referred to as "angiogenic growth factors" and "angiogenesis inhibitors." Medical researchers have identified 19 angiogenic growth factors in the human body and 31 angiogenesis inhibitors. In a healthy body, a perfect balance of factors that promote and prevent angiogenesis is maintained. After cells become cancerous, the regulation of this balance is disturbed, stimulating the production of new blood vessels.

Targeted therapies, such as Avastin, were originally designed with the goal of replacing chemotherapy, to reduce the serious morbidities associated with standard high-dose chemotherapy. Although targeted therapies may be somewhat less toxic, most of them have been found to have very modest efficacy, at least when used as single agents in treating patients with advanced disease. They have therefore mainly been used in combination with standard chemotherapy or radiation protocols.

It is becoming more apparent to administer drugs to patients with certain types of cancer on a weekly schedule. The advantage of low-dose chemotherapy is the possibility of combining it with anti-angiogenic drugs as well as other types of targeted therapies, such as those that target specific signal-transduction molecules or with antitumor vaccines.

Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply. When administering both anti-tumor and anti-angiogenesis drugs, the endothelial cells (involved iin angiogenesis) are the first in the tumor to undergo cell death (apoptosis).

Adding Avastin, which only goes after VEGF-sensitive cancer cells, you need to go after other pro-angiogenic factors which can substitute for VEGF: FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc. And with Taxol promoting an increase of IL-8, how effective is it with Avastin? With the low-dose protocol having an anti-angiogenic effect, you really wouldn't need to add a drug like Avastin into the mix.

Source: Cell Function Analysis

[gdpawel]

According to Merriall Goozner (who occasionaly writes for the Journal of the National Cancer Institute), two clinical trials showed no improvement in mortality among women with metastatic breast cancer. Those trials didn’t even replicate the delay in progression of disease that had been shown in the original trial that led to accelerated approval in 2007. Now comes the firestorm from patient advocacy groups, who will use anecdotal stories to claim the drug works for some women.

Here’s the truth of those matters: Anecdotes are not science. Those who insist their use of the drug is the reason why they are remaining alive longer than average will still have access to the drug since most insurance companies and Medicare will continue to follow the National Comprehensive Cancer Network guidelines.

NCCN’s guideline writing committee, a third of whom have financial ties to Roche/Genentech, has said it will not withdraw Avastin’s use in metastatic patients. A few years ago, CMS passed a rule that said it would reimburse any use of a cancer drug, even if the FDA had not approved it for that use, if it was included in the NCCN guidelines and accompanying formulary.

http://www.fda.gov/NewsEvents/Newsroom/UCM279485

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.

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials.

[gdpawel]

Ed Silverman
Pharmalot.com

After more than a year of controversy and anticipation, the FDA has decided to formally yank the breast cancer indication for Avastin after deciding the widely used medication is not safe and effective for that purpose. However, the drug - which is sold by Genentech - will remain on the market to treat cancers that affect the colon, lung, kidney and brain.

The decision marks a trying stretch for the agency as debate broke out over the wisdom of using progression free survival as a surrogate - instead of quality of life - for conferring approval, while breast cancer patients and their families lobbied hard to maintain the status quo. The episode also highlighted ongoing concerns about the FDA accelerated approval - or fast track - program that first greenlighted Avastin for treating breast cancer.

“This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” FDA commish Margaret Hamburg says in a statement.

“After reviewing the available studies it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”

The move comes nearly a year after the FDA initially announced plans to revoke the indication, citing 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 severe high blood pressure; hemorrhage; swelling of the brain, and heart attack or heart failure. The agency had reviewed two additional studies that Genentech submitted in hopes of maintaining the indication.

After the agency gave its initial thumbs down, Genentech appealed, setting up an unusual two-day meeting last summer to review trial data, where the panelists voted 6-to-0 nothing to pull the breast cancer indication. The drugmaker recently offered a compromise that would have modified the Avastin usage and labeling.

The decision to revoke the breast cancer indication was seen as an important test for Hamburg, who has emphasized drug safety as a hallmark of her tenure, which began in the lingering aftermath of the corrosive Vioxx scandal. And for the past several months, Avastin has come to symbolize a willingness to brook extensive pressure to allow a drug to remain on the market amid safety issues.

“This decision sets an important precedent: accumulated science has trumped politicized argument,” says Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA.’ “The agency faced enormous political pressure from the company and from organized interest groups, and yet rendered a strong decision based upon a searching reading of the available evidence.

Whether this move will put to rest some of the issues raised during the Avastin episode is unclear. In particular, critics say more data should be required before accelerated approval is employed. The FDA has also been criticized for not forcing drugmakers to provide required follow-up data more quickly. Last year, Pfizer withdrew a drug used to treat acute myeloid leukemia after a study found a lack of clinical benefit and an unexpected number of deaths, but the study began four years after approval.

“In an ironic way, this decision actually allows the FDA to expand the accelerated approval program, as there is now a strong, visible and clear precedent for withdrawing an approval when postmarket experiments for an approved drug produce disconfirming efficacy evidence and perhaps problematic new safety signals,” Carpenter says. “This is not an anti-innovation decision and could, in fact, assist pharmaceutical innovation in the years ahead…I predict its longer-term impact will be to help rebuild the agency’s reputation for science-based decisionmaking and for independence from emotionally charged lobbying.”

Some patient advocates hailed the FDA move, having argued that the FDA moved too quickly to endorse the breast cancer indication in the first place. “If we are to continue to speed up the rate at which treatments reach patients we must be able to take back approval when the evidence shows that a drug doesn’t work. Although some individual women believe that Avastin worked for them, there are many women who are not here to tell their story about how Avastin didn’t work. We all want better treatment for women with this disease. Unfortunately, Avastin is not that treatment,” Karuna Jaggar, who is executive director of Breast Cancer Action, writes us.

As for Genentech, the drugmaker now stands to lose an estimated $1 billion in sales. “We are disappointed with this outcome,” the Roche unit says in a statement. “Despite today’s action, we will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin.”

Indeed, Genentech does have an option to resubmit an application to the FDA for a breast cancer indication for Avastin if additional studies prove successful. The drugmaker also has the option of a legal challenge to the agency decision to yank the indication.

The decision is certain to have significant implications for patients, doctors and payers. A recent survey found doctors were largely split over whether they would continue to use Avastin to treat breast cancer. Nearly 45 percent would use Avastin in a first-line setting and nearly 52 percent would use the drug in combination with paclitaxel, otherwise known as Taxol, regardless of an FDA decision.

Meanwhile, the National Comprehensive Cancer Network, an organization of major cancer hospitals, reaffirmed last summer that Avastin was “an appropriate therapeutic option for metastatic breast cancer.” This decision is significant because the NCCN panel of oncologists carries great weight with other specialists and its guidelines are widely used as a reference by the Centers for Medicare & Medicaid Services and insurers for making coverage decisions.

In fact, CMS earlier this year indicated it would continue to provide coverage, even if treatment amounts to off-label use. But one big insurer recently eliminated coverage. Blue Cross of California last month decided to no longer pay for Avastin to treat breast cancer. Whether other insurers follow suit will become a closely watched sport.

For the record, the formal indication that the FDA is now revoking involves Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative.

[gdpawel]

Some industry-insiders have suggested the Compassionate Use Program could work for Roche, with Avastin. Now that the FDA has rejected Avastin for breast cancer, breast cancer now becomes a non-approved indication and therefore any investigator wishing to do a compassionate use trial would have to do so under a Treatment IND.

In 1987, the FDA enacted regulations that provided increased access to experimental drugs for patients with life-threatening or seriously-debilitating diseases when no alternative treatment exists. These guideline, commonly called Treatment IND (Investigational New Drug), provide for rapid review of new therapies even when clinical trial results proving efficacy have not been established.

Typically Treatment IND applications are made for drugs that are in Phase III trials; however in rare cases the FDA approves a Treatment IND for a drug that has not yet progressed beyond Phase II. In order to stay compliant with the protocol, the drug developer must continue to collect safety and efficacy data on test subjects in order to better establish a drug's therapeutic benefit to patients.

Additionally, it must continue to make a good faith effort to win final approval from the FDA; if the drug developer stops working on the product, the Treatment IND can be rescinded and patients may lose access to the drug.

The company would have to write the protocol with prettly strict inclusion/exclusion criteria and thus Roche has to ask the question as to whether it's worth it since they can't sell it for this purpose.