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Perjeta Poised to Blaze a New Trail in Neoadjuvant Breast Cancer Therapy

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By Catherine Shaffer
Staff Writer

The FDA’s Oncologic Drugs Advisory Committee voted 13 - 1 Thursday to support approval of Genentech Inc.’s supplemental biologics license application for Perjeta (pertuzumab) in neoadjuvant (preoperative) treatment of breast cancer. The application is the first for a neoadjuvant indication.

Historically, new agents for breast cancer have been approved first in metastatic cancer, with early stage use following years later, based on large randomized trials with prolonged follow-up. Neoadjuvant trials assess therapy delivered before surgery, and could expedite development and approval of treatments for early breast cancer. Genentech’s application is expected to be the first of many, as the FDA is planning to open a regulatory pathway for agents in neoadjuvant breast cancer.

The FDA asked the committee to discuss questions regarding the application, including whether the advantages of neoadjuvant accelerated approval outweighs concerns of exposing patients with curable disease to unknown rare and late toxicities, the appropriateness of pathological complete response (pCR) as a surrogate endpoint and other questions related to the conduct and results of the trials supporting Perjeta in neoadjuvant breast cancer.

South San Francisco-based Genentech, a unit of the Roche Group, supported its application with three studies, NEOSPHERE, TRYPHAENA and CLEOPATRA. NEOSPHERE is the main study supporting efficacy of Perjeta in the neoadjuvant setting. It was a randomized trial evaluating four neoadjuvant regimens in 417 patients with operable, locally advanced or inflammatory HER2-positive breast cancer. Patients were randomized to Herceptin (trastuzumab) plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab or pertuzumab plus docetaxel vs. pertuzumab plus trastuzumab and docetaxel. The primary endpoint of the study was pathologic complete response defined as absence of invasive cancer in the breast.

That trial showed statistically significant improvements in pCR in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. The subgroup of patients with hormone receptor-positive tumors showed less improvement compared to those with hormone receptor-negative tumors. Total pCR was improved by 17.8 percent compared to Herceptin and docetaxel alone, and the most common adverse events for the Perjeta regimen were neutropenia, febrile neutropenia and diarrhea.

TRYPHAENA was a randomized Phase II study in 225 patients with HER2-positive, locally advanced, operable or inflammatory breast cancer. Patients received one of three regimens before surgery. The primary endpoint of the study was cardiac safety, and secondary endpoints included pCR, progression-free survival (PFS) and overall survival (OS).

Results of TRYPHAENA showed higher pCR rates in the pertuzumab treatment arms compared to the NEOSPHERE study, possibly because of the inclusion of an anthracycline preoperative regimen.

CLEOPATRA was a randomized, double-blind, placebo-controlled trial in 808 patients with HER2-positive metastatic breast cancer receiving pertuzumab in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel.

Perjeta initially was approved based on a clinically significant 6. 1-month improvement in PFS compared to placebo. The trial also achieved superiority of pertuzumab in OS.

A good part of the discussion was dedicated to the use of pCR as a surrogate endpoint for clinical benefit in terms of disease-free survival (DFS), event-free survival (EFS) and OS. There has been an association of pCR with EFS and OS in the CTNeoBC meta-analysis, which enrolled 11,955 patients. That association is greater among patients with aggressive tumors, including HER2-positive and triple-negative tumors, compared to less aggressive types of tumors. However, the meta-analysis also found that while pCR has a prognostic value for individual patients, the association could not be confirmed at the level of a clinical trial.

Accelerated approval comes with a postmarket study requirement to confirm clinical benefit. The benefit of a surrogate endpoint in a case like the use of Perjeta in neoadjuvant breast cancer is that the surrogate endpoint can be assessed earlier than EFS or OS, leading to earlier approval of a drug to meet an unmet medical need. However, there is also a risk that the agent ultimately will not show clinical benefit, and patients would have been exposed to the risks of therapy in the meantime.

The committee acknowledged that trade-off and generally agreed it was worthwhile. Genentech has plans to submit efficacy and safety data from an ongoing, almost fully accrued Phase III study APHINITY that is evaluating pertuzumab in the adjuvant setting, with the primary outcome measure of invasive disease. That study could confirm clinical benefit of pertuzumab in the neoadjuvant setting to support conversion of accelerated approval to regular approval. Genentech said, however, that APHINITY just finished accruing, so it would be some time before that data was available.

The committee overwhelmingly supported the application. James Liebmann, a Medical Oncologist for the University of Massachusetts, explained his yes vote, “I felt the potential for providing meaningful clinical benefit exceeded the potential harms.” He cautioned that the company should look closely at the results of its ongoing APHINITY trial and modify or remove the indication if the data don’t support it.

The FDA is due to make an approval decision by Oct. 31.