On September 30, 2013, the U. S. Food and Drug Administration granted accelerated approval to pertuzumab injection (PERJETA, Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.
The approval of PERJETA for neoadjuvant treatment of breast cancer is based on a randomized, multicenter, open-label trial in patients with HER2-positive, operable, locally advanced, or inflammatory breast cancer (T2-4d). Breast tumor samples were required to show HER2 overexpression (IHC 3+ or FISH amplification ratio ≥ 2.0 determined by a central laboratory). The trial enrolled 417 patients who were randomly allocated to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel; pertuzumab plus trastuzumab and docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel.
Pertuzumab, trastuzumab, and docetaxel were administered preoperatively by intravenous infusion (IV) every 3 weeks for a total of 4 cycles. Following surgery all patients received 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) IV every 3 weeks and trastuzumab was administered IV every 3 weeks to complete 1 year of therapy. The trial’s primary endpoint was pathological complete response (pCR) rate defined as the absence of invasive cancer in the breast (ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
Demographics were well balanced. Seven percent of patients had inflammatory breast cancer, 32% had locally advanced cancer and 70% had clinically node-positive breast cancer. Forty-seven percent of the patients had hormone receptor-positive disease.
The pCR (ypT0/is ypN0) rates were 39.3% and 21.5% in the pertuzumab plus trastuzumab and docetaxel and the trastuzumab plus docetaxel arms, respectively. This difference of 17.8% was statistically significant (adjusted p-value = 0.0063, Cochran-Mantel-Haenszel test). The pCR rates and magnitude of improvement with the addition of pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.
The most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea and neutropenia. The most common (> 2%) NCI – CTCAE (version 3) grade 3 – 4 adverse reactions were neutropenia, febrile neutropenia, leukopenia and diarrhea. Other significant adverse reactions reported with pertuzumab include left ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.
The approval is supported by an additional randomized phase 2 study conducted in 225 patients with HER2-positive, locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety when FEC or carboplatin is incorporated into the preoperative regimen.
Pertuzumab is approved with a BOXED WARNING regarding cardiomyopathy and embryo-fetal toxicity. The cardiomyopathy warning is based on an increased rate of LVEF decline observed in the neoadjuvant trials. Cardiac function should be evaluated prior to and during treatment with pertuzumab. The embryo-fetal toxicity warning is based on observations of oligohydramnios, delayed renal development and embryo-fetal death in animal studies. Patients should be advised of these risks and need for effective contraception prior to starting pertuzumab.
The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered IV as a 60‑minute infusion followed every 3 weeks by 420 mg administered IV as a 30- to 60-minute infusion. Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:
- Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of FEC;
- Three preoperative cycles of FEC alone followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; or
- Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin and trastuzumab (TCH).
Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.
Pertuzumab, originally approved in June 2012, is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of HER2, and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4.
This accelerated approval is based on demonstration of an improvement in pCR rate. No data are available demonstrating improvement in event-free survival or overall survival. Continued approval for this indication is contingent upon demonstration of improvement in disease-free survival in the confirmatory trial.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm,
by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).