FDA Approval for Pertuzumab
Brand name: Perjeta™
- Approved for use in combination with trastuzumab and docetaxel to treat certain patients with HER2-positive metastatic breast cancer
On June 8, 2012, Food and Drug Administration approved pertuzumab injection (Perjeta™, made by 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 more than 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 assigned (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. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent.
All but two patients were female (99.8 percent), and the median age was 54 years. Forty-eight percent of patients were hormone receptor positive, and 47 percent had received prior adjuvant or neoadjuvant chemotherapy. Forty-five percent of hormone receptor-positive patients had received prior adjuvant hormonal therapy. Eleven percent of patients had received prior adjuvant or neoadjuvant trastuzumab.
A statistically significant 6.1-month improvement in median progression-free survival (PFS) was observed in patients in the pertuzumab group compared with patients in the placebo group [HR 0.62 (95 percent CI: 0.51, 0.75), p< 0.0001, log-rank test]. The median PFS was 18.5 months for patients in the pertuzumab group and 12.4 months for patients in the placebo group. At the time of PFS analysis, a planned interim analysis for overall survival (OS) was performed that showed a trend toward better OS in the pertuzumab group [HR 0.64 (95 percent 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 (more than 30 percent) adverse reactions observed in patients who received pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common (more than 2 percent) 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 the 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, 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.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.