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PERJETATM(pertuzumab)注射剂，为静脉使用 美国初次批准：2012 适应证和用途 剂量和给药方法 剂型和规格 禁忌证 警告和注意事项 不良反应 在特殊人群中使用 患者咨询资料
The FDA has approved pertuzumab for patients with HER2-positive metastatic breast cancer as part of a dual inhibition strategy that researchers expect to bring about significant changes in the way the subtype of the disease is treated. Genentech will market the drug under the trade name Perjeta. The approval states that pertuzumab should be combined with trastuzumab (Herceptin) and the chemotherapy drug docetaxel in patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. The decision, released Friday night, came on Genentech’s application for priority review just six months after pivotal trial findings were presented at the San Antonio Breast Cancer Symposium in December. “This is likely to become the new standard of therapy for this patient population,” lead investigator José Baselga, MD, PhD, chief of the Division of Hematology/Oncology and associate director of the Massachusetts General Hospital (MGH) Cancer Center in Boston, said in an interview earlier this year. Both pertuzumab and trastuzumab are monoclonal antibodies that target HER2 receptors. The drugs bind to HER2 at different sites, creating a dual blockade of the HER2 growth factor. Specifically, pertuzumab prevents the receptor for linking to the HER3 protein and creating a “dimer”—a combination of two similar proteins or molecules—that signals tumor growth. When bound to the protein, pertuzumab induces antibody-dependent cell-mediated toxicity. “Since trastuzumab was first approved more than a decade ago, continued research has allowed us to better understand the role HER2 plays in breast cancer,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “This research provided the background to combine two targeted drugs–trastuzumab and Perjeta with docetaxel to slow disease progression in breast cancer.” The agency approved pertuzumab based on the results of the CLEOPATRA trial in which 808 patients with HER2-positive metastatic breast cancer were randomized to receive pertuzumab and trastuzumab plus docetaxel versus trastuzumab plus docetaxel and a placebo as first-line treatment. PFS was the primary endpoint. The study found that the median PFS in the pertuzumab group was 18.5 months compared with 12.4 months in the control group (HR=0.62; 95% CI, 0.51-0.75, P < .001). The data for overall survival (OS) were not yet available at the time of the analysis, but the authors wrote in The New England Journal of Medicine in December that the initial results favored the pertuzumab arm. In addition to the positive results regarding PFS, the authors noted that the drug appeared to be well tolerated. The incidence of left ventricular systolic dysfunction–a cardiac condition associated with the use trastuzumab–did not increase when compared to the control group. However, grade 3 or above febrile neutropenia and diarrhea were higher in the pertuzumab group than in the control group. “Initially, there were some concerns about the potential toxicity of giving these two drugs together. But, at the end, this is one of the safest combinations that we have in oncology today,” said Baselga in the interview. At the same time, pertuzumab has been approved with a “boxed warning” stating that the drug poses a potential risk of death or severe effects to a fetus and that pregnancy status must be verified prior to the start of treatment. The positive CLEOPATRA results came after earlier clinical trials in which pertuzumab as a single agent did not perform as well as expected. However, two subsequent trials, the BO17929 trial and the NEOSPHERE, showed that pertuzumab had better results when given in combination with trastuzumab. “Based on what we were seeing in these studies, we began to understand that these drugs were having a synergistic effect with one another,” said Paula Klein, MD, chief of Breast Medical Oncology at Continuum Cancer Centers and associate professor of medicine at Beth Israel Medical Center Comprehensive Cancer Center in New York City, and one of the researchers on CLEOPATRA. Klein said that better tests are needed to determine which HER2-positive metastatic breast cancer patients could potentially have the best results when given this combination therapy. Additionally, the current approval is only for metastatic breast cancer patients who have not received any prior lines of chemotherapy or anti-HER2 therapy. Klein said that more clinical trials are under way to test pertuzumab’s efficacy in additional settings, including the APHINITY trial, which is investigating the use of the combination of pertuzumab with chemotherapy and trastuzumab as adjuvant therapy in patients in operable HER2-positive breast cancer. The pool of patients who could potentially be candidates for pertuzumab therapy is large. In 2012, 226,870 women are expected to be diagnosed with breast cancer; about 20% of breast tumors overexpress HER2, according to the FDA. The FDA decided to approve the drug so that patients could start receiving it rather than delay approval while “production issues relating to future supply” are resolved, the agency said in a press release. Genentech said it expects to meet demand for Perjeta and that the drug would be available in the United States within two weeks. The company said it has agreed to “postmarketing commitments related to the manufacturing process for Perjeta,” including FDA review of data from the next several productions. “We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, PhD, head of Pharma Global Technical Operations for Genentech, in a statement. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it.” |
