FDA Approves Pertuzumab Injection
Friday, June 08, 2012
The U.S. Food and Drug Administration approved pertuzumab injection (PERJETA™, Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Pertuzumab 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.
The approval is based on a randomized, double-blind, placebo-controlled, multicenter trial in patients with HER2-positive metastatic breast cancer. Breast tumor specimens were required to show HER2 overexpression defined as 3+ IHC or FISH amplification ratio ³ 2.0 using FDA-approved tests at a central laboratory. Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment.
The trial enrolled 808 patients who were randomly allocated (1:1) to receive pertuzumab in combination with trastuzumab and docetaxel (n=402) or placebo in combination with trastuzumab and docetaxel (n=406). Pertuzumab was given by intravenous (IV) infusion at an initial dose of 840 mg, followed by 420 mg every three weeks thereafter. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal.
All but two patients were female (99.8%), and the median age was 54 years. Forty-eight percent of patients were hormone receptor positive, and 47% received prior adjuvant or neoadjuvant chemotherapy. Forty-five percent of hormone receptor positive patients received prior adjuvant hormonal therapy. Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab.
A statistically significant 6.1 month improvement in median progression-free survival (PFS) was observed in patients receiving pertuzumab compared to those receiving placebo [HR 0.62 (95% CI: 0.51, 0.75), p< 0.0001, log-rank test]. The median PFS was 18.5 and 12.4 months for patients on the pertuzumab and placebo arms, respectively. At the time of PFS analysis, a planned interim analysis for overall survival (OS) was performed [HR 0.64 (95% CI: 0.47, 0.88), p=0.0053]. However, the HR and p-value for the interim analysis of OS did not meet the pre-defined stopping boundary (HR ≤ 0.603, p ≤ 0.0012).
The most common (> 30%) adverse reactions observed in patients receiving pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common (> 2%) NCI–CTCAE (version 3) Grade 3–4 adverse reactions were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. Other significant adverse reactions reported with pertuzumab include left ventricular dysfunction, infusion-associated reactions, hypersensitivity reactions, and anaphylaxis. Pertuzumab in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with trastuzumab and docetaxel.
Pertuzumab is being approved with a BOXED WARNING regarding embryo-fetal toxicity and birth defects, 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 as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30 to 60 minute IV infusion. When administered with pertuzumab the recommended initial trastuzumab dose is 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When administered with pertuzumab, the recommended initial docetaxel dose is 75 mg/m2 administered as an IV infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.
Full prescribing information, including Boxed Warning for embryo-fetal toxicity, clinical trial information, safety, dosing, and use in specific populations is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125409lbl.pdf
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).