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FDA Rejects Avastin as Breast Cancer Drug; Genentech to Conduct New Trial to ID Best Responders

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Originally published Nov. 18.

By Turna Ray

Genentech has failed to sway the US Food and Drug Administration to keep its oncologic Avastin on the market as a breast cancer treatment, but is planning a clinical trial that will evaluate whether a potential biomarker can determine best responders to the drug.

The FDA this week revoked Avastin's breast cancer indication "after concluding that the drug has not been shown to be safe and effective for that use."

The decision follows a nearly year-long evaluation period, during which the Roche subsidiary has urged the agency to keep Avastin on the market for breast cancer patients who were responding to the drug so the company would have more time to conduct a biomarker-driven clinical trial to identify so called "super-responders."

Though it stood by its intent to revoke the breast cancer indication for Avastin, the FDA this week said that Genentech is free to conduct its proposed study exploring a personalized medicine strategy for Avastin in breast cancer, and the data for such a trial could form the basis of a new approval. Genentech had said it would conduct a trial focusing on whether patients with high levels of plasma VEGF-A have a superior response to Avastin compared to those with low VEGF-A levels (PGx Reporter 1/26/2011).

"If such a therapeutic relationship could be demonstrated, that might represent a basis for Avastin to be approved for use by certain patients," FDA Commissioner Margaret Hamburg explained in a 69-page explanation of the agency's decision.

Genentech told PGx Reporter that the company will conduct a new trial evaluating whether Avastin plus paclitaxel improves breast cancer patients' outcomes compared to treatment with just paclitaxel, and will include an analysis of a patients' response to treatments based on VEGF-A levels.

"Despite [the FDA'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," Hal Barron, Genentech's chief medical officer, said in a statement.

As a result of the FDA's decision, the breast cancer indication "must now be removed from Avastin's product labeling," the agency said. Avastin will still remain on the market as a treatment for colon, lung, kidney, and brain cancers.

According to Hamburg, oncologists will still be able to prescribe Avastin off label to breast cancer patients. "FDA does not regulate the practice of medicine, and it is part of the practice of medicine for a physician to be able to prescribe a drug that is approved for one use … for another, unapproved use," Hamburg wrote.

However, revoking FDA approval for Avastin may impact whether certain private insurers continue to pay for the drug for breast cancer patients. Although different insurers may have divergent payment policies regarding Avastin's use in this setting, private payors "may continue to reimburse for the use of Avastin for the breast cancer indication (use with paclitaxel), as many apparently now reimburse for use of Avastin with anti-cancer drugs other than paclitaxel even though use in combination with other drugs has never been approved by FDA," Hamburg explained.

The Centers for Medicare & Medicaid Services said a few months ago that it would continue to reimburse Avastin for the Medicare population for the time being, but is continuing to evaluate the drug and the agency's options (PGx Reporter 8/17/2011).

From Accelerated Approval to Removal

The FDA initially okayed the metastatic breast cancer indication for Avastin in 2008, through its accelerated approval scheme. Accelerated approval provides early access to potentially life-saving medications based on data from incomplete or early-stage studies that "reasonably" suggest that the drug will be beneficial for patients. However, following accelerated approval of a product, sponsors are required to submit data from post-marketing studies confirming the safety and efficacy of the drug in the "intent to treat" patient population.

The FDA granted accelerated approval based on the results of the E2100 trial, which enrolled previously untreated metastatic breast cancer patients and treated them with either Avastin plus paclitaxel or just paclitaxel. In this study, patients in the combination arm experienced progression-free survival for 5.5 months longer than those in the chemo-only arm.

For its post-marketing study commitments, Genentech submitted data from two confirmatory studies, AVADO and RIBBON1. After reviewing data from these trials, the FDA notified Genentech in December of its intent to revoke Avastin's approval in metastatic breast cancer because the drug/chemo combination did not improve overall survival over standard chemotherapy regimens, marginally improved progression-free survival, and caused serious adverse reactions in breast cancer patients (PGx Reporter 12/22/2010).

After a contentious public hearing in June — and subsequently reviewing "thousands of pages" of data and public comments — the FDA was still not swayed that Avastin treatment would benefit breast cancer patients more than it would harm them (PGx Reporter 6/29/2011).

At the June hearing, many patients, particularly those with triple-negative breast cancer — a hard-to-treat and virulent form of the disease where tumors do not express estrogen receptor, progesterone receptor, or HER2 — said they had experienced robust responses to Avastin treatment and pleaded with the agency to keep the drug on the market. However, the FDA's analysis of the available data on Avastin's efficacy and safety in breast cancer patients did not agree with Genentech's analysis of the same data.

Furthermore, FDA officials pointed out that although some patients may have benefited from the drug, the available data showed that far more patients did not respond to the drug and also experienced treatment-related adverse reactions. The agency was also not convinced that Genentech's biomarker data on predicting best responders to Avastin was mature enough to justify keeping the drug on the market while the company conducted a new trial that would take more than three years to complete.

After the June hearing, the FDA's Oncologic Drugs Advisory Committee voted six to zero in favor of withdrawing approval of Avastin's breast cancer indication. In an earlier meeting, the same committee had voted 12-1 in favor of removing Avastin from the market for this purpose.

"FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval," Hamburg said in a statement this week. "I encourage Genentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug."


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