Dissecting Kadcyla

How FDA's Kadcyla delay resets landscape for accelerated breast cancer drugs

Two and a half years after FDA refused to file Genentech Inc.'s BLA for accelerated approval of Kadcyla ado-trastuzumab emtansine in metastatic breast cancer, the agency has granted full approval - and outlined its rationale behind the 2010 decision.

Drug companies still hoping to win accelerated approval in breast cancer will want to study FDA's thinking about Kadcyla. While the door is open in metastatic disease for compounds that show a robust benefit over existing treatments, developers may want to target underserved subpopulations of patients, or move upstream into the neoadjuvant setting.

On Feb. 22, based on a randomized Phase III trial that showed a survival benefit, FDA granted full approval of Kadcyla (T-DM1) to treat HER2-positive metastatic breast cancer in patients previously treated with Herceptin trastuzumab and a taxane-based chemotherapy regimen.

The original BLA requested accelerated approval to treat HER2-positive breast cancer previously treated with two HER2-targeted therapies in combination with chemotherapy. When FDA refused to file the application in August 2010, Genentech said it was because patients in its single-arm trials had not exhausted all available therapies.

At the time, two doctors contacted by BioCentury said subjecting patients to the full range of cytotoxic agents wasn't ethical because they knew HER2-positive patients wouldn't respond, which raised the question whether any agent could receive accelerated approval in the indication (see BioCentury, Aug. 30, 2010).

Now, FDA says the refusal to file was as much about the design of the Phase II trials and magnitude of response as it was about the number of previous treatments.

Thus, according to Richard Pazdur, director of FDA's Office of Hematology and Oncology Products, accelerated approval is still possible in metastatic breast cancer, even if patients have not exhausted all treatment options.

"A large, compelling response rate in a patient population that has not received prior all available therapies may warrant accelerated approval," Pazdur told BioCentury in an email (Editor's note: Italics in original).

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