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FDA Advisory Panel Unanimously Recommends Perjeta Approval in Neoadjuvant Breast Cancer Setting

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Originally published Sept. 17.

A panel of experts last week advised the US Food and Drug Administration to grant accelerated approval to Genentech's personalized breast cancer drug Perjeta (pertuzumab) as a neoadjuvant treatment for HER2-positive breast cancer.

The Oncologic Drugs Advisory Committee voted 13 to 0, with one abstention, supporting the approval of Perjeta in combination with docetaxel and Genentech's older HER2-positive breast cancer therapy Herceptin (trastuzumab) as part of a pre-surgery treatment regimen containing other chemotherapeutics for women with locally advanced, inflammatory, or early-stage HER2-positive breast cancer. If the FDA takes the advice of the committee, which experts believe it likely will, then Perjeta will be the first cancer drug approved as a neoadjuvant treatment, meaning that the treatment can be given to breast cancer patients after diagnosis and before surgery.

FDA approval will "allow physicians to add [the therapy] to trastuzumab in the neoadjuvant setting, which will certainly change practice there," George Sledge, head of the oncology division at Stanford University's School of Medicine and a breast cancer specialist, told PGx Reporter.

Although in clinical practice doctors treat certain cancer patients with various drugs off label in the neoadjuvant setting, the FDA has yet to approve a cancer drug for this specific use. In an effort to mitigate the risks of newly marketed cancer drugs, the agency traditionally first approves breast cancer treatments for metastatic disease, and then okays the agent in the adjuvant setting, or after surgical resection of the cancer, as a measure to thwart the disease from returning.

A year ago, the agency approved Perjeta in combination with Herceptin and chemotherapy as a treatment for HER2-positive metastatic breast cancer (PGx Reporter 6/13/2012). The drug was greenlighted with two companion diagnostics developed by Dako to help doctors gauge which patients have HER2-overexpressing tumors and should receive the drug.

Genentech is also studying Perjeta in the adjuvant setting within the 4,800-patient Phase III APHINITY trial. In that study, researchers are comparing Perjeta, Herceptin, and chemo versus Herceptin and chemo, and tracking which regimen best improves invasive disease-free survival. Data from this study, slated for 2016, will serve as the confirmatory study proving Perjeta's efficacy and safety with the FDA.

If approved for the neoadjuvant indication, breast cancer patients can be treated with Perjeta earlier with the hope that the drug will shrink the tumor to make it operable or allow breast-conserving surgery. Roche subsidiary Genentech filed a supplementary biologics license application with the FDA for neoadjuvant Perjeta a few months ago. The agency has granted the application priority review and a decision is slated for late October (PGx Reporter 7/3/2013).

For the sBLA, Genentech submitted data from two Phase II trials, called NEOSPHERE and TRYPHAENA, involving HER2-positive, early-stage breast cancer patients. The company also submitted long-term safety data from the Phase III CLEOPATRA trial with HER2-positive metastatic breast cancer patients.

In the more than 400-patient NEOSPHERE trial, newly diagnosed, early-stage breast cancer patients with HER2-positive tumors were randomized to four neoadjuvant treatment arms: Herceptin and docetaxel; Perjeta, Herceptin, and docetaxel; Perjeta and Herceptin; and Perjeta and docetaxel. Of these, the Perjeta/Herceptin/docetaxel regimen improved the rate of pathological complete response (pCR) in patients by 58 percent compared to the Herceptin/docetaxel regimen.

In the more than 200-patient TRYPHAENA trial, HER2-positive, early-stage breast cancer patients were randomized to three neoadjuvant treatment arms: Perjeta; Herceptin and anthracycline-based chemotherapy followed by Perjeta, Herceptin, and docetaxel; anthracycline-based chemo followed by Perjeta, Herceptin, and docetaxel; and Perjeta, Herceptin, docetaxel, and carboplatin chemo. This study was not powered to compare the three study arms. The primary endpoint was cardiac safety and secondary endpoints were pCR.

No new cardiac adverse events were observed in any of the study arms, Genentech reported. The third arm – Perjeta, Herceptin, docetaxel, and carboplatin – had the greatest impact on pCR (64 percent). In this arm the most common, severe adverse events were neutropenia (46 percent), febrile neutropenia (17 percent), and anemia (17 percent). Additionally, approximately 12 percent of the patients in this arm experienced diarrhea, leukopenia, anemia, and thrombocytopenia.

The advisory committee used data from NEOSPHERE and TRYPHAENA to make its recommendations to the agency. If the FDA takes the expert panel's recommendation, then Perjeta's approval could provide a path for other sponsors to design the necessary clinical trials and seek approval for other neoadjuvant therapies.

The FDA issued guidance last year on using pathologic complete response as a clinical trial endpoint for accelerated approval of neoadjuvant treatments for high-risk, early-stage breast cancer. In the document, the FDA defines pCR as the absence of any residual invasive cancer in the patient after neoadjuvant therapy based on evaluation of the resected breast tumor sample and lymph node sample.

Sledge commented that to date there hasn't been an FDA-approved adjuvant treatment for cancer because the agency has been focused on using disease-free survival as the primary endpoint in clinical trials investigating drugs for the adjuvant treatment.

"Since short-term response (such as the pCR rate) was not a measure of disease-free survival, but only a surrogate [measure of efficacy], the FDA previously did not allow it," Sledge said. "Disease-free survival correlates with overall survival, whereas the relationship of short-term neoadjuvant response to long-term outcome was less certain."

However, after the Oncology Drugs Advisory Committee's review of the data presented by Genentech on Perjeta, the experts "clearly felt that the balance of the data has shifted towards considering short-term neoadjuvant response as a surrogate for long-term benefit," he added.

Between 15 percent and 20 percent of all breast cancer tumors overexpress the HER2 protein. Approximately 6,000 people in the US die of HER2-positive breast cancer each year.

Typically, a small subset of early-stage breast cancer patients receives neoadjuvant therapy. The indicated patient population for Perjeta is further narrowed by its pharmacogenetic indication for HER2-positive tumors. Pre-surgery treatment "is typically given to patients with larger tumors," Sledge said, estimating that a quarter of early-stage breast cancer patients with HER2-positive tumors would receive such therapy.

Genentech's Herceptin, the first drug approved and marketed for HER2-positive breast cancer, is slated to lose patent exclusivity in 2014 in Europe and in 2018 or 2019 in the US. The drug maker is positioning Perjeta and Kadcyla (trastuzumab/emtansine) to eventually replace Herceptin, which brought in close to $6 billion in worldwide sales last year.

For the three months ended June 30, Roche reported that its products for treating women with HER2-overexpressing breast cancer brought in 3.3 billion Swiss Francs ($2.68 billion), an 11 percent increase from the second quarter a year ago. Although sales of Herceptin were flat at 1.5 billion Swiss Francs from the year-ago quarter, the growth in the HER2 breast cancer franchise was driven by Perjeta and Kadcyla, the company said (PGx Reporter 8/14/2013).

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