Genentech also provided results from the TRYPHAENA phase II study that compared three neoadjuvant treatment regimens before surgery; as well as the CLEOPATRA phase III study, the basis of the 2012 approval of trastuzumab. In TRYPHAENA, 225 women with HER2-positive, locally advanced, operable or inflammatory breast cancer, received one of three neoadjuvant treatment regimens. The pCR rates, a secondary endpoint, ranged from about 55% to 64% when pertuzumab was added to trastuzumab and chemotherapy. CLEOPATRA enrolled 808 women with HER2-positive, locally recurrent, unresectable or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. In that trial, pertuzumab in combination with trastuzumab and docetaxel resulted in significant improvements in progression-free survival and overall survival.
The most common adverse events with the three-drug regimen in the NeoSphere study were neutropenia, diarrhea, nausea, fatigue, mucosal inflammation, and rash, according to the company. No unexpected safety signals were observed with the addition of pertuzumab. The addition of pertuzumab did not appear to increase symptomatic cardiac toxicity when added to trastuzumab-based neoadjuvant or metastatic treatment regimens.
The FDA reviewers noted, however, that the rate of left ventricular dysfunction (mostly asymptomatic) was higher with neoadjuvant pertuzumab treatment. Cardiac toxicity appeared to be reversible, however.
Panel member Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, said that there were “some hints of increased cardiac toxicity.” She encouraged the company to closely evaluate patients on longer-term pertuzumab in trials for cardiac toxicity. Dr. Armstrong voted in favor of the benefit risk profile, but like other panelists, was concerned about the potential for approval “opening the floodgates” to the use of this drug in treating patients for whom it may not yet be appropriate.
Citing the clear potential benefit in the intended population, Dr. Michael Menefee of the division of hematology and oncology at the Mayo Clinic, Jacksonville, Fla., also shared his concerns about the potential for toxicity and overuse of the drug. “My hope is that the FDA is very clear in the ultimate labeling so practitioners have clear guidance as to how to use this drug best and most safely.”
Genentech has completed enrollment in the confirmatory, phase III APHINITY study, which will compare chemotherapy plus trastuzumab with or without pertuzumab before surgery in about 4,800 patients with HER-2 positive early breast cancer. The patients will be followed for 10 years, and the study will evaluate invasive disease-free survival. Results are expected to be first available in 2016.
Panel members have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
Genentech also markets trastuzumab.