PERTUZUMAB APPROVED BY FDA FOR NEOADJUVANT TREATMENT OF HER2+ BREAST CANCER

The US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 13 to 0 in support of pertuzumab (Perjeta, Genentech/Roche), in combination with other agents, to be used before surgery in women with HER2-positive early-stage breast cancer.

The favorable vote sets the stage for pertuzumab to be the first medicine approved for the neoadjuvant treatment of breast cancer. The FDA often, but not always, follows its advisory committees' recommendations.

The ultimate FDA decision represents "a potentially landmark approval," said committee member David Steensma, MD, from Harvard Medical School in Boston.

Pertuzumab is already approved for use, in combination with other agents, in patients with metastatic HER2-positive breast cancer. Pertuzumab is a "very effective drug" in the metastatic setting, said committee chairperson Mikkael Sekeres, MD, from the Cleveland Clinic Taussig Cancer Institute.

If approved for this expanded use, pertuzumab would be 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), as part of a complete early breast cancer regimen containing fluorouracil, epirubicin, and cyclophosphamide (FEC) or carboplatin.

The committee's supportive vote was a "historic moment," according to a number of committee members.

The ODAC review of pertuzumab was not without controversy.

At this point, no data demonstrate that pertuzumab improves either event-free or overall survival in the neoadjuvant setting in women with early HER2-positive breast cancer.

As a result, the FDA is reviewing pertuzumab in the neoadjuvant early breast cancer setting as a potential accelerated approval. In lieu of event-free or overall survival, pathologic complete response (pCR) is the efficacy measure.

The FDA admitted that pCR has not been proven to predict either event-free or overall survival. However, an FDA official said that the 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 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).

"It's well worth the risk," said committee member Frank Balis, MD, from the University of Pennsylvania School of Medicine in Philadelphia, about approving pertuzumab in this setting based on an outcome — pCR — that is not a proven surrogate for survival. The totality of the evidence of pertuzumab's efficacy, including that from the metastatic setting, compensates for the NEOSPHERE data, he suggested.

The accelerated approval process requires that companies return to the FDA with further evidence of a drug's efficacy. The specter of bevacizumab (Avastin, Genentech/Roche), which received accelerated approval for use in breast cancer on the basis of progression-free survival data but was never found to improve overall survival, was present at the ODAC meeting. "We don't want another situation like [bevacizumab]," said Dr. Sekeres at one point.

A number of committee members requested that Genentech ultimately withdraw its current application if a confirmatory trial does not eventually find that pertuzumab improves survival in this new setting.

The various comments were a reference to the torturous process that ultimately resulted in the FDA withdrawing the bevacizumab indication for metastatic breast cancer.

News reports earlier this week positioned the eventual FDA approval of pertuzumab in this setting as a done deal. But an FDA official cast a bit of doubt on that. "By no means have we made a decision on this application," said Richard Pazdur, MD, from the Office of Hematology and Oncology Products at the FDA.