FDA Approves First Drug for Neoadjuvant Breast Cancer Use

Nick Mulcahy


October 02, 2013

The US Food and Drug Administration (FDA) today approved pertuzumab (Perjeta, Genentech) to be used in combination with other agents before surgery in women with HER2-positive early-stage breast cancer.

Pertuzumab is the first medicine approved by the FDA for the neoadjuvant treatment of breast cancer. As such, it is a "landmark" approval, said David Steensma, MD, from Harvard Medical School in Boston, Massachusetts, last month, when he and other members of the FDA's Oncologic Drugs Advisory Committee reviewed and recommended the drug.

The targeted therapy was previously approved for use in 2012 in patients with metastatic HER2-positive breast cancer.

The FDA's endorsement of pertuzumab comes under the agency's accelerated approval program. Confirmatory evidence from additional clinical trials will be needed eventually for the approval to be permanent.

Pertuzumab is now specifically indicated for the neoadjuvant treatment of breast cancer, in combination with trastuzumab and docetaxel, for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (>2 cm in diameter) that is high risk, as part of a complete early breast cancer regimen also containing fluorouracil, epirubicin, and cyclophosphamide or carboplatin. As part of this regimen, patients will receive trastuzumab after surgery to complete 1 year of treatment.

"We are seeing a significant shift in the treatment paradigm for early stage breast cancer," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a press statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences.''

Pertuzumab's accelerated approval for neoadjuvant treatment is based on a study designed to measure pathologic complete response (pCR), defined as the absence of invasive cancer in the breast and lymph nodes. In May 2012, the FDA issued a draft guidance on the use of the measure in this setting.

pCR is being used in lieu of the traditional measures of event-free or overall survival. The FDA has admitted that pCR has not been proven to predict either event-free or overall survival. However, an FDA official recently said that this high-risk early breast cancer population "justifies the risk" of considering pertuzumab on the basis of its pCR.

The main study supporting the new application is the Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NEOSPHERE), a randomized trial that compared a number of regimens with and without pertuzumab in women with HER2-positive breast cancer. In that trial, 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel (n = 107) had a pCR compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107).

The most common severe (grade 3 or higher) adverse events for pertuzumab plus trastuzumab and docetaxel were neutropenia (44.9%), febrile neutropenia (8.4%), leukopenia (4.7%), and diarrhea (5.6%).

Other significant adverse effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.

The confirmatory trial is known as Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer (APHINITY) and will provide further data on efficacy, safety, and long-term outcomes. Results are expected in 2016, according to the FDA.


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