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Will Genentech Embrace PGx in Appeal of FDA Decision to Revoke Approval of Avastin in Breast Cancer?

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Originally published Dec. 17.

By Turna Ray

Genentech said this week that it plans to request a hearing to maintain Avastin as a treatment option for metastatic breast cancer following the US Food and Drug Administration's recommendation to withdraw its approval of the drug for that indication.

The Roche subsidiary has 15 days from Dec. 16 to request the hearing, and noted that if the agency grants the request, "there is no set date for when this would occur."

In the meantime, there is still little indication from the company as to whether it is considering pharmacogenomics strategies as a way to keep Avastin as a treatment option for breast cancer patients most likely to benefit from the drug.

FDA said this week that studies have shown that Avastin lacks efficacy and causes serious adverse reactions in breast cancer patients. While the agency's recommendation does not immediately take the drug off the market for this indication, the agency sent out a letter advising physicians "to use their medical judgment when deciding whether a patient should continue treatment with [Avastin] or consider other therapeutic options."

Genentech markets Avastin in combination with paclitaxel in patients with HER2-negative metastatic breast cancer who have not yet received chemotherapy for metastatic disease. The drug is not approved for people who have received prior anthracyclines and taxanes for their HER2-negative metastatic breast cancer.

After reviewing four independent studies, the agency found that none of the trials "demonstrated that patients receiving Avastin lived longer." Furthermore, the studies showed that Avastin-treated patients "experienced a significant increase in serious side effects, including high blood pressure, bleeding and hemorrhage, as well as the development of perforations in the body."

The decision follows that of the FDA's independent expert panel, the Oncologic Drugs Advisory Committee, which in July voted 12 to 1 in favor of removing Avastin from the market in the breast cancer population.

Despite this recommendation, the agency may still be open to reviewing data that shows certain subpopulations of breast cancer patients do benefit from Avastin. "The results of these studies are disappointing," the FDA said in a statement. "We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug."

If the company has mature PGx data that suggests the drug improves survival and reduces toxicities in breast cancer patients, then it might provide Genentech with an avenue for keeping Avastin on the market for a limited subset of patients. The company, however, declined to comment on its strategy for appealing the FDA's decision. "We are not providing details about a potential hearing at this time, beyond that we plan to request a hearing," a Genentech spokesperson told PGx Reporter.

By losing Avastin's metastatic breast cancer market, Genentech faces a shortfall of approximately $1 billion in annual sales. As such, although Genentech has previously said that it is investigating genomic strategies for personalized Avastin treatment through external and internal studies, the company would likely embrace a strategy that would allow it to keep marketing the drug in the largest possible breast cancer patient population.

A Genentech spokesperson told PGx Reporter previously that the company is "looking at biomarkers for angiogenesis as part of our independent work as well as our work with academic centers." Additionally, the spokesperson noted that Genentech is "continuing to evaluate findings in E2100 and other clinical trials."

E2100 was one of the pivotal studies Genentech submitted to the FDA to garner approval for Avastin in metastatic breast cancer two years ago. That trial showed an improvement in progression-free survival in patients with HER2-negative metastatic breast cancer, but did not show improvements in disease-related symptoms or survival. However, researchers conducted genomic studies within E2100 and identified markers that conferred longer survival and protection against drug-induced hypertension.

Specifically, in E2100, researchers uncovered preliminary PGx data linking VEGF-1154 AA and -2578 AA genotypes to an improvement in median overall survival. Additionally, E2100 showed that patients with VEGF-634 CC and -1498 TT genotypes had protection from grade 3-4 hypertension, a common side effect of Avastin.

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Researchers involved in the E2100 genetic analysis believe that those early PGx data weren't sufficient to change the labeling for Avastin to a genetically-targeted patient subset, but the potential is there. The lead author of the E2100 genetic study, Bryan Schneider of Indiana University, wrote in Clinical Cancer Research last year that the PGx findings, "if validated … could help direct which subgroups of patients should receive [Avastin]" (PGx Reporter 08/25/10).

It is not clear to what extent Genentech has been working on validating the PGx leads found in E2100. The company did not submit PGx data on Avastin during ODAC's review of the drug.

Meanwhile, Schneider has received a $5.8 million grant from the patient advocacy organization Susan G. Komen for the Cure to study the impact of certain gene markers on disease-free and overall survival in women treated with Avastin and standard chemotherapy. An e-mail to Schneider about the status of this study was not answered in time for publication.

Komen for the Cure has been a vocal advocate for biomarker studies that might keep Avastin on the market for patients that will benefit from treatment. In a statement following the FDA's recommendation to remove Avastin from the breast cancer market this week, Komen for the Cure President Elizabeth Thompson expressed concern about the potential impact this will have on women who are benefiting from the drug.

"We want to be sure that women who are using Avastin, and for whom it is working, can continue to have access to it, that their insurers will continue to pay for it, and that the drug's manufacturer, Genentech/Roche, continues making the drug available to women through its patient support programs and considers an expanded access program," Thompson said. "We are also urging Genentech/Roche to continue research on a biomarker for Avastin to determine which women will benefit from the drug."

If Avastin's approval in metastatic breast cancer is revoked by the FDA, doctors will still be able to prescribe the drug off-label in breast cancer patients. However, insurers will not cover the treatment — estimated to cost around $8,000 per month — for a non-FDA approved indication.

Breast cancer is an area where oncologists are becoming increasingly comfortable characterizing patients' tumors via molecular profiling and making treatment decisions based on genomic, proteomic, and clinical features of patients. Other than Avastin, metastatic breast cancer patients may be treated with various chemotherapies, radiation treatment, hormone therapy, such as tamoxifen, or undergo surgery.

Herceptin is another metastatic breast cancer drug marketed by Roche/Genentech, but it is given only to women who are HER 2-positive. Ahead of prescribing Herceptin, women's HER 2 status is confirmed by immunohistochemistry or fluorescence in situ hybridization.

Although Avastin is currently indicated in HER-2 negative patients, Roche is working to expand the drug's indication into other tumor subtypes. According to Roche's pipeline, Avastin is being studied in two Phase III clinical trials for the adjuvant treatment of HER 2-positive and HER 2-negative breast cancer. The company expects to submit a marketing application for the HER 2-positive indication in 2013, and plans to file for the HER 2-negative indication after 2013. Additionally, Roche is investigating Avastin in combination with Herceptin as a first-line combination treatment in metastatic breast cancer. For this indication, the expected filing date is next year.

Avastin is also approved as a treatment for colorectal cancer, lung cancer, kidney cancer, and glioblastoma. The FDA's decision to remove the drug in metastatic breast cancer does not impact the drug's availability in these other markets.


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