In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On September 30, 2013, pertuzumab injection (Perjeta) was granted accelerated approval for use in combination with trastuzumab (Herceptin) and docetaxel for neoadjuvant treatment of patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (either > 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer.1 The accelerated approval is based on demonstration of an improvement in pathologic complete response rate. No data are yet available showing improved event-free survival or overall survival. Continued approval for this indication is contingent upon demonstration of improvement in disease-free survival in a confirmatory trial.
The approval is based on a randomized, multicenter, open-label phase II trial in patients with HER2-positive operable, locally advanced, or inflammatory breast cancer (T2-4d).2,3 Breast tumor samples were required to show HER2 overexpression (immunohistochemistry [IHC] 3+ or fluorescence in situ hybridization [FISH] amplification ratio ≥ 2.0). A total of 417 patients were randomly assigned to receive one of four neoadjuvant regimens: trastuzumab plus docetaxel (n = 107), pertuzumab plus trastuzumab and docetaxel (n = 107), pertuzumab plus trastuzumab (n = 107), or pertuzumab plus docetaxel (n = 96).
Pertuzumab (initial dose of 840 mg, followed by 420 mg), trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg), and docetaxel (75 mg/m2, escalated to 100 mg/m2 at investigator discretion) were administered preoperatively by intravenous infusion every 3 weeks for a total of four cycles. Following surgery, all patients received three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) intravenously every 3 weeks, and trastuzumab was administered intravenously every 3 weeks to complete 1 year of therapy.
The primary endpoint was pathologic complete response rate, defined as the absence of invasive cancer in the breast (ypT0/is). The FDA-preferred definition of pathologic complete response is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
Demographics were well balanced among treatment groups. Median ages were 49 to 50 years, 71% of patients were Caucasian, 7% had inflammatory breast cancer, 32% had locally advanced cancer, 61% had operable cancer, 70% had clinically node-positive cancer, and 47% had hormone receptor (HR)-positive disease.
Statistically significant improvements in pathologic complete response rates by both the study definition and the FDA-preferred definition (39.3% vs 21.5%, difference of 17.8%, adjusted P = .0063) were observed in patients receiving pertuzumab plus trastuzumab/docetaxel vs patients receiving trastuzumab/docetaxel. The pathologic complete response rates and magnitude of improvement with pertuzumab were lower in the subgroup of patients with HR-positive tumors (22.0% vs 12.0%) compared with patients with HR-negative tumors (54.4% vs 29.8%).
How It Works
Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of HER2 and thus blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major pathways, mitogen-activated protein kinase, and phosphoinositide 3-kinase. Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity.
How It Is Given
The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered intravenously as a 60-minute infusion followed every 3 weeks by 420 mg administered intravenously as a 30- to 60-minute infusion.
Pertuzumab should be administered every 3 weeks for three to six cycles as part of one of the following treatment regimens for early breast cancer: four preoperative cycles of pertuzumab in combination with trastuzumab/docetaxel followed by three postoperative cycles of FEC; three preoperative cycles of FEC alone followed by three preoperative cycles of pertuzumab in combination with docetaxel/trastuzumab; or six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab.
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 six 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.
In the primary trial supporting approval, the most common adverse events (> 30%) with pertuzumab in combination with trastuzumab/docetaxel were alopecia (65% vs 66% with trastuzumab/docetaxel), neutropenia (50.5% vs 64%), diarrhea (46% vs 34%), and nausea (39% vs 36%). The most common grade 3 or 4 adverse events (>2%) were neutropenia (45% vs 59%), febrile neutropenia (8.4% vs 6.5%), leukopenia (4.7% vs 11.2%), and diarrhea (5.6% vs 3.7%). Other significant adverse events reported with pertuzumab included left-ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.
The approval is supported by an additional randomized phase II 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 carries a boxed warning for cardiomyopathy and embryo-fetal toxicity. The cardiomyopathy warning is based on an increased rate of left-ventricular ejection fraction decline observed in 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.
Pertuzumab also has warnings/precautions f or embryo-fetal toxicity, left-ventricular dysfunction, infusion-related reactions, hypersensitivity reactions/anaphylaxis, and HER2 testing. HER2 testing should be performed using FDA-approved tests by laboratories with demonstrated proficiency. ■
1. U.S. Food and Drug Administration: Pertuzumab injection. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm370449.htm.
2. PERJETA® (pertuzumab) injection prescribing information, Genentech, Inc, October 2013. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125409s051lbl.pdf.
3. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or 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), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).