SILVER SPRING, MD. – Pertuzumab is likely to be approved for the neoadjuvant treatment of breast cancer in the preoperative setting, based on the recommendation of a Food and Drug Administration advisory panel.
At a meeting on Sept. 12, the FDA’s Oncologic Drugs Advisory Committee panel voted 13-0, with 1 abstention, that treatment with pertuzumab, a human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody, had a favorable benefit-to-risk profile as a neoadjuvant treatment in combination with trastuzumab and docetaxel before surgery in patients with locally-advanced, inflammatory, or early-stage breast cancers greater than 2 cm in diameter. The neoadjuvant approach would be part of a complete early breast cancer treatment regimen containing fluorouracil, epirubicin, and cyclophosphamide or carboplatin.
The drug is being reviewed under the accelerated approval process, a mechanism that makes drugs available to fill an unmet medical need in patients with serious diseases. Historically, the usual sequence of the FDA approvals for breast cancer agents starts with approval for metastatic disease, followed by approval for early-stage disease years later after the results of large studies with long follow-up periods are available. Pertuzumab, marketed as Perjeta by Genentech, was just approved in 2012 as a first-line treatment for metastatic HER2-positive breast cancer in women who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Accelerated approvals are based on a surrogate endpoint that is considered “reasonably likely” to predict clinical benefit. In this instance, pathologic complete response rate (pCR) was used in the phase II NeoSphere study. For this trial, pertuzumab was added to trastuzumab (Herceptin) – another HER2 receptor antagonist – and docetaxel, and was given before surgery to women with HER-2-positive, locally advanced, inflammatory or early-stage breast cancer. The comparator group was patients treated preoperatively with trastuzumab and docetaxel.
The women who received the three-drug neoadjuvant regimen had an 18% improvement in pCR as compared to women given trastuzumab and docetaxel only.
In addition to the NeoSphere study, the panel also considered the body of data on pertuzumab in metastatic breast cancer, the known biology of the pertuzumab, and the activity of HER-2 targeted therapies in breast cancer.
Should pertuzumab receive the accelerated approval, its full approval will be contingent on the final results of APHINITY, a confirmatory study. If the APHINITY results do not confirm the NeoSphere results, the FDA can withdraw the approval for this indication.
The vote to support the first approval of a drug for the neoadjuvant treatment of breast cancer is “a historic moment,” said the panel chair, Dr. Mikkael A. Sekeres of the Cleveland Clinic. “In so doing, we are supporting the rapid movement of a highly active drug for metastatic breast cancer to the first-line setting with the hope that women with earlier stages of breast cancer will live longer and better.”
However, he added, “all eyes will be on the confirmatory APHINITY trial” and on Genentech, to “verify this initial signal of efficacy and to confirm the bandwidth of safety we have seen so far.” If the results are negative, he and other panelists urged the company to voluntarily remove the drug for this indication, and avoid what happened with another Genentech drug, bevacizumab (Avastin), which was granted an accelerated approval as a first-line treatment in combination with paclitaxel for metastatic breast cancer in 2008. The FDA decided to withdraw approval of this indication after studies failed to confirm the benefit. The company appealed the decision, however, delaying the FDA’s withdrawal of the approval until 2011.
NeoSphere, a randomized study conducted outside of the United States, compared four treatment regimens in 417 women newly diagnosed with locally advanced, inflammatory or operable HER2-positive early breast cancer, with tumors greater than 2 cm, treated for four cycles before surgery. The median tumor size was about 5 cm, and two-thirds were node positive.
Based on the pCR definition used by Genentech (the absence of invasive cancer in the breast), almost 46% of those on the combination of pertuzumab, trastuzumab, and docetaxel reached the primary endpoint, compared with 29% of those on trastuzumab and docetaxel – a statistically significant difference of nearly 17%. Based on the FDA-preferred definition of pCR definition (the absence of invasive cancer in the breast and lymph nodes), the pCR rate was almost 18% higher with the three-drug regimen (39.3% vs. 21.5%).
The FDA considers pCR as “reasonably likely” to predict outcomes in HER2-positive breast cancer.
The treatment has the potential to cure more patients in this high risk population, said Dr. Suparna Wedam, a medical officer in FDA’s Office of Hematology and Oncology Products. Yet, still to be determined are whether the regimen has long-term safety and results in improvements in overall survival, progression-free survival, and other improvements in long-term outcomes.