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Mar 11, 2013
 |  BioCentury  |  Regulation

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).

According to Pazdur, options for accelerated approval still remain open for drugs that show sufficient benefit over existing treatments for metastatic disease.

Four of six doctors contacted by BioCentury sided with the agency, while the other two said FDA's initial decision harmed patients, and the agency should have at least made the drug available on a limited basis.

Going forward, all the doctors believe the availability of new drugs like Kadcyla and Genentech's Perjeta pertuzumab will make it more difficult for companies to show a benefit in metastatic disease, and that the best opportunity will be to focus on specific subgroups of patients.

Initial disappointment

Genentech markets Herceptin trastuzumab, a humanized mAb against EGFR2 (HER2; ErbB2; neu), to treat HER2-positive breast cancer.

Kadcyla is trastuzumab linked to the DM1 cytotoxic agent using antibody-drug conjugate (ADC) technology from ImmunoGen Inc.

Genentech's original BLA was based on two single-arm Phase II trials in patients with previously treated metastatic HER2-positive disease: the TDM4374g trial in 110 women and TDM4258g in 112 women.

In TDM4374g, Kadcyla had a 33% objective response rate (ORR), with stable disease in 46.4% of patients. In TDM4258g, the ORR was 25.9% with stable disease in 39.3% of patients.

Patients in TDM4374g had a median of seven prior agents for metastatic disease, while patients in TDM4258g had a median of eight prior treatments.

According to Genentech in August 2010, FDA said it refused to file the BLA because "all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population."

However, according to comments Pazdur emailed to BioCentury on Feb. 28 this year, other factors also played a role in the agency's decision. These included the heterogeneity of the patient population, the single-arm design of the trials and the magnitude of benefit.

"The...

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