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'Middle Ground' Avastin Proposal Could Maintain Access for Molecularly Defined Breast Cancer Patients

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Originally published Aug. 16.

By Turna Ray

In a last-ditch effort to keep Avastin on the market for breast cancer patients, Roche subsidiary Genentech has requested that the US Food and Drug Administration maintain the drug as an option for patients with aggressive disease and limited treatment options — a subset of patients that could include women with a molecularly distinct, triple-negative form of the disease.

Triple-negative breast cancer patients have hard-to-treat and virulent tumors that do not express the genes for estrogen receptor, progesterone receptor, or HER2. During a public hearing in June to discuss the FDA's decision to withdraw accelerated approval for Avastin as a treatment for HER2-negative metastatic breast cancer, several triple-negative breast cancer patients provided anecdotal evidence of superior response to Avastin (PGx Reporter 6/29/2011).

"Accelerated approval exists to facilitate the availability of additional treatment options in areas of unmet medical need. In first-line HER2-negative MBC, the need for greater treatments is profound," Genentech wrote in a proposal submitted to the Federal Register on Aug. 4. "This is even more true for patients with aggressive disease where few other therapies are considered appropriate, including patients with triple-negative metastatic breast cancer and HER2-negative, hormone receptor-positive disease with characteristics such as visceral metastases, high tumor burden, and rapid disease progression."

Genentech received accelerated approval for Avastin in 2008 as a combination treatment with paclitaxel in patients with HER2-negative metastatic breast cancer who have not yet received chemotherapy for metastatic disease. Last December, upon the recommendation of the agency's Oncologic Drugs Advisory Committee, the FDA announced it would nix the breast cancer indication for Avastin.

In appealing FDA's decision, Genentech has requested that FDA maintain Avastin's approval while the company conducts another confirmatory trial. Similar to the E2100 trial with which Genentech originally received accelerated approval, this new trial would investigate Avastin in combination with paclitaxel compared to paclitaxel alone (PGx Reporter 1/26/2011). The new study would also include a "biomarker strategy" to pick out best responders based on VEGF-A serum levels.

Genentech's most recent proposal reiterated its desire to conduct a confirmatory trial while the FDA keeps the drug available for the most needy breast cancer populations. "This proposal would allow continued use of Avastin with paclitaxel only, with limitations such as labeling directed toward those patients with aggressive disease and the fewest treatment options, while Genentech conducts a confirmatory trial aimed squarely at the required showing CDER has now articulated," the firm states in the 133-page proposal.

The proposed 480-patient study will have two co-primary endpoints: progression-free survival in the overall patient population and PFS in patients with high plasma VEGF-A. Secondary endpoints of the study will be overall survival, one-year survival, and response rates. Three-and-a-half years after the start of the study, Genentech plans to conduct an interim analysis, at which point the company has said it could voluntarily withdraw Avastin from the breast cancer setting if it appears that the trial will not meet its endpoints.

During the June hearing, FDA officials appeared unwilling to maintain access to Avastin over the next few years while Genentech conducts another study, which would require the company to develop a companion diagnostic to pick out best responders. At the meeting, several so-called "super-responder" breast cancer patients spoke of how Avastin had stopped their cancer from progressing, but Genentech was unable to provide any clinical data backing a biomarker-driven hypothesis for predicting which patients are likely to live longer with Avastin treatment (PGx Reporter 06/29/2011).

"In the absence of a clinical trial and control, we're having a hard time identifying those [super-responder] patients from a survival curve, [or] a progression-free survival curve," Patricia Keegan, director of FDA's Division of Biologic Oncology Products at CDER, said during the hearing. "I think the more compelling thing is … in 2,400 patients there doesn't seem to be a group emerging that is behaving differently."

As a contrast to the super-responder breast cancer patients who attended the public hearing in support of keeping Avastin on the market, Keegan recognized there were many women who weren't there because they had succumbed to their disease despite treatment with Avastin and had suffered severe toxicities.

Genentech officials have acknowledged that using biomarkers to identify Avastin best responders will be a challenging task. The company has evaluated more than 100 potential markers in clinical specimens of plasma, tumor, and host DNA across seven tumor types, but most of the leads are preliminary and require confirmation. Researchers haven't been able to confirm certain VEGF polymorphisms that appeared promising in E2100. And although in a study called AVADO Avastin seemed to better stall the progression of cancer in patients with high VEGF-A plasma levels compared to those with low VEGF-A, the marker couldn't predict which patients would live longer while on the drug.

If Genentech were to lose the breast cancer indication for Avastin, it would cut around $1 billion from the $7 billion in sales the drug netted the company last year. Avastin is also approved as a treatment for metastatic colorectal cancer, non-small cell lung cancer, and glioblastoma, indications which wouldn't be impacted by FDA's decision on the breast cancer indication. As such, the drug would remain on the market, and oncologists could potentially prescribe it to breast cancer patients off label. Insurers, however, may be reluctant to pay for off-label Avastin use in this setting, which can cost upwards of $80,000 per year.

For the time being, the Centers for Medicare & Medicaid Services continues to pay for Avastin in the metastatic breast cancer setting. CMS decides to pay for a medical intervention if the agency deems it to be "reasonable and necessary" for the Medicare population. "It would be incorrect to say that a decision has been made on coverage of Avastin," CMS spokesperson Donald McLeod told PGx Reporter in an e-mail in July. "So far, to this point FDA's actions have not affected CMS' payment for Avastin. We are aware of the recent advisory committee vote as part of FDA's ongoing review. As the situation evolves we will continue to evaluate and consider our options."

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In the past, CMS has utilized the "national coverage determination" mechanism to pay for off-label oncologics when they are part of a government-sponsored study. In 2005, after reviewing available evidence and published literature, CMS issued an NCD under which it agreed to pay for off-label uses for oxaliplatin, irinotecan, Erbitux, and Avastin when these drugs are given to patients enrolled in one of nine national trials funded by the National Cancer Institute.

It is possible that payment for off-label use of Avastin could be facilitated through an NCD, although CMS has made no such announcement. Furthermore, CMS' experience in determining whether to issue an NCD for Dendreon's prostate cancer immunotherapy Provenge — during which the agency was accused of drug rationing — may make it less than eager to initiate another evaluation for a costly cancer drug.

Provenge — priced at $93,000 for a three-treatment course — had a troubled regulatory path through the FDA after two Phase III trials failed to meet primary endpoints. The drug was approved last year after a third confirmatory trial showed that Provenge-treated patients experienced a four-month survival advantage compared to those given placebo. Some cancer experts felt that this survival advantage needed further confirmation in another trial.

FDA greenlighted Avastin based on data from the E2100 trial, which showed that patients on Avastin/paclitaxel combination therapy experienced a statistically significant median improvement in progression-free survival of 5.5 months over patients on the paclitaxel arm. However, in this trial, there was no improvement in overall survival for patients given the combination regimen. Genentech hasn't been able to show a survival advantage with Avastin treatment in subsequent Phase III studies, which is the main reason FDA has cited for revoking the drug's approval in breast cancer.

Given the high cost of treatment with Avastin and the negative review from the FDA, private payors will likely conduct their own technological assessments to determine the types of breast cancer patients for whom they are willing to reimburse for the drug. Since private payors often peg their payment policies on professional society guidelines, insurers are closely watching groups, such as the National Comprehensive Cancer Network, to track their stance on Avastin's use in breast cancer.

So far, NCCN has said it supports maintaining Avastin as a breast cancer treatment. In a July vote, 24 members of its Expert Breast Cancer Panel voted in favor of maintaining Avastin as a treatment for breast cancer patients, with one committee member abstaining.

In contrast, an international panel of breast cancer experts at the St. Gallen International Breast Cancer Conference in March opposed treating triple-negative breast cancer patients at this time with anti-angiogenic therapies, such as Avastin. "A slim majority agreed that dose-dense chemotherapy should be considered for [triple-negative breast cancer] patients, and the panel was strongly opposed to the inclusion of anti-angiogenic therapies at this time," members of the St. Gallen panel wrote in an article in the Annals of Oncology discussing the highlights from the meeting.

For triple-negative breast cancer patients with ductal-type disease, St. Gallen's experts recommended against the routine use of cisplatin or carboplatin, but favored treatment with anthracyclines, taxanes, and an alkylating agent. Although insurers and physicians in the US pay attention to recommendations from the St. Gallen group, these recommendations likely hold greater weight with payors and oncologists in Europe, and therefore may impact Avastin's use in the breast cancer setting in overseas markets.

Patrick Terry, head of the pricing, reimbursement, and market access practice at the life sciences consultancy Scientia Advisors, took both health regulators and payors equally to task for not focusing on molecularly defined subpopulations when determining whether to keep Avastin as an option for breast cancer patients and when to pay for the treatment.

"To universally say that based on current evidence evaluation breast cancer patients don’t benefit from this highly effective anti-angiogenesis therapy when they are dying from highly heterogenic metastatic tumor burden is ludicrous," Terry told PGx Reporter. "Equally as nonsensical is that costly combinatorial cancer therapies can be delivered off-label to undifferentiated patient populations without predictive classifiers in this age of personalized medicine diagnostics."


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