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FDA Panel Set to Vote on Milestone Neoadjuvant Pertuzumab Combo

Ben Leach
Published: Wednesday, Sep 11, 2013

Dr Dietmar Berger

Dietmar Berger, MD

Most targeted therapies in cancer care are initially approved for the treatment of patients with metastatic disease. The hope is that these drugs will eventually be used in patients with earlier stage disease as well. For the breast cancer drug pertuzumab (Perjeta), that hope is being put to the test this Thursday.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) is convening tomorrow to discuss whether pertuzumab—which is now approved in combination with trastuzumab (Herceptin) and docetaxel as first-line therapy in HER2-positive breast cancer—can be moved up in the treatment spectrum and given to patients prior to surgery in the neoadjuvant setting. If approved in this indication, it would be the first neoadjuvant regimen formally approved by the FDA for the treatment of cancer.

While other drugs and regimens might already be used in the neoadjuvant setting, it’s important to note that this is a regimen that has been formally explored in large, international clinical trials and has demonstrated activity warranting its approval in this earlier setting.

“With the addition of Perjeta, we’re improving neoadjuvant therapy, and we’re improving outcomes,” said Dietmar Berger, MD, vice president of Clinical Oncology at Genentech, the company that manufactures pertuzumab.

Pertuzumab, like trastuzumab, is a monoclonal antibody that targets HER2 receptors. However, each drug binds to HER2 receptors at different sites, allowing the combination of the two drugs to create a dual blockade strategy. Pertuzumab works by preventing the receptor from linking to the HER3 protein and creating a dimer—a combination of two similar proteins or molecules—that signals tumor growth. The drug is able to induce antibody-dependent, cell-mediated toxicity when it binds to the protein.

Dr Brian Leyland-Jones

Brian Leyland-Jones, MB BS, PhD

“The most potent heterodimer pair signaling in the HER2 pathway is the HER2-HER3 heterodimer, which this drug blocks,” said Brian Leyland-Jones, MB BS, PhD, director of Edith Sanford Breast Cancer Research, Sioux Falls, South Dakota. “This makes pertuzumab a remarkable drug.”

The FDA will not make its official approval decision on the neoadjuvant pertuzumab regimen this week. Instead, ODAC will vote on recommending whether or not the FDA should approve the drug. Specifically, ODAC will be voting on the question of whether pertuzumab has demonstrated “a favorable benefit to risk evaluation for the neoadjuvant treatment of early breast cancer,” according to a draft guidance made publicly available by the FDA.

Though the FDA is not required to follow ODAC’s decision, the government agency usually adheres to the panel’s recommendations. The pertuzumab filing was granted Priority Review by the FDA, and a decision regarding the drug’s approval for the neoadjuvant setting is expected to take place on or before October 31, 2013.

Two Pivotal Trials Support Submission

Genentech’s regulatory filing for the neoadjuvant indication was based on the results of two pivotal trials: NEOSPHERE and TRYPHAENA.

In the NEOSPHERE trial, a multicenter, open-label, phase II study, treatment-naïve patients with HER2-positive breast cancer were randomly assigned in a 1:1:1:1 ratio and stratified by operable, locally advanced, and inflammatory breast cancer as well as hormone receptor expression.1 These patients received four neoadjuvant cycles of either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2, escalating, if tolerated, to 100 mg/m2 every 3 weeks; n = 107; group A); pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) in combination with the group A trastuzumab and docetaxel regimen (n = 107; group B); the pertuzumab and trastuzumab regimens without docetaxel (n = 107; group C); and pertuzumab plus docetaxel (n = 96; group D). The primary endpoint of the study was pathological complete response (pCR).

Patients who received the combination of pertuzumab, trastuzumab, and docetaxel had a pCR rate of 45.8% (95% CI, 36.1-55.7), a significant improvement over patients who received trastuzumab and docetaxel without pertuzumab, who had a pCR rate of 29.0% (95% CI, 20.6 -38.5; P = .014). The PCR rates for the remaining two groups were 24.0% in those who received pertuzumab and docetaxel without trastuzumab (95% CI, 15.8-33.7), and 16.8% in patients who received pertuzumab and trastuzumab (95% CI, 10.3-25.3).

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