Pertuzumab, sold under the brand name Perjeta among others, is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer. Side effects in more than half the people taking it include diarrhea, hair loss, and loss of neutrophils; more than 10% experience loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, nail disease, and muscle pain. Women who are pregnant or planning on getting pregnant should not take it, it was not studied in people with certain heart conditions and should be used in caution in such people, and it should not be used with an anthracycline. It is unknown if pertuzumab interacts with doxorubicin. It is the first-in-class of a kind of medication called a "epidermal growth factor receptor (HER) dimerization inhibitor" — it inhibits the dimerization of HER2 with other HER receptors, which prevents them from signalling in ways that promote cell growth and proliferation. It was discovered and developed by Genentech and was first approved in 2012.
Medical uses Pertuzumab, along with trastuzumab (Herceptin), docetaxel (Taxotere), and carboplatin, is given as intravenous (IV) infusions for the treatment of early stage, HER-positive breast cancer. Pertuzumab, in combination with trastuzumab and docetaxel, are given as a first line treatment for HER2-positive metastatic breast cancer. Women of child-bearing age should use contraception while taking pertuzumab; it may damage the fetus in pregnant women, and it may be secreted in breast milk.
Adverse effects In clinical trials of the three-agent combination therapy in metastatic breast cancer, adverse effects occurring in more than half the people taking it included diarrhea, hair loss, and loss of neutrophils; more than 10% of people experienced loss of neutrophils with fever, and loss of leukocytes. After docetaxel was dropped in some people, the most common adverse effects were diarrhea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), swelling of nasal passages and throat (often due to catching the common cold) (17.0%), weakness (13.4%), itchiness (13.7%), joint pain (11.4%), nausea (12.7%), pain in an extremity (13.4%), back pain (12.1%) and cough (12.1%). In clinical trials of the neoadjuvant use of the combination, more than 50% of people had hair loss and loss of neutrophils. In both uses, more than 10% of people additionally experienced: loss of red blood cells, hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, nail disease, and muscle pain.
Pharmacology The metabolism of pertuzumab has not been directly studied; in general antibodies are cleared principally by catabolism. The median clearance of pertuzumab was 0.235 liters/day and the median half-life was 18 days.
Mechanism of action HER2 is an extracellular receptor—a receptor tyrosine kinase - that when activated, sets off signal transduction through several pathways that stimulate cell proliferation and cell growth; if overexpressed it can cause uncontrollable growth. HER2 positive breast cancer is caused by ERBB2 gene amplification that results in overexpression of HER2 in approximately 15-30% of breast cancer tumors. HER2 normally combines another protein in order to function (a process called dimerization); it can bind with a second HER2 receptor (acting as a homodimer) and it can heterodimerize with a different receptor of the HER family. The most potent dimer for activating signalling pathways is HER2/HER3. The epitope for pertuzumab is the domain of HER2 where it binds to HER3, and pertuzumab prevents the HER2/HER3 dimer from forming, which blocks signalling by the dimer. Trastuzumab is another monoclonal antibody against HER2; its epitope is the domain where HER2 binds to another HER2 protein. The two mAbs together prevent HER2 from functioning.
Chemistry and manufacturing Pertuzumab is an immunoglobulin G1 with a variable region against the human HER2 protein, a human-mouse monoclonal 2C4 heavy chain, disulfide bound with a human-mouse monoclonal 2C4 κ-chain. It is manufactured recombinantly in CHO cells.
History The monoclonal antibody 2C4 appears to have first been published in 1990 by scientists from Genentech, the same year that F. Hoffmann-La Roche AG acquired a majority stake in Genentech. By 2003, Genentech understood that 2C4 prevented HER2 dimerizing with other HER receptors and had begun Phase I trials, aiming for a broad range of cancers, not just ones overexpressing HER2. It was the first known HER dimerization inhibitor. In 2005, Genentech presented poor results of Phase II trials of pertuzumab as a single agent in prostate, breast, and ovarian cancers, and said that it intended to continue developing it in combination with other drugs for ovarian cancer. In 2007, Genentech dropped the trade name Omnitarg. In March 2009, Roche acquired Genentech. In 2012, the results were published of the CLEOPATRA trial, a randomized placebo-controlled Phase III trial of pertuzumab in combination with trastuzumab and docetaxel in HER2-positive metastatic breast cancer. Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer later that year. Results of a Phase II trial in the neoadjuvant setting, NeoSphere, published in 2012, and results of a Phase II cardiac safety study in the same population, Tryphaena, published in 2013. The FDA approved the neoadjuvant indication in 2013. Pertuzumab was approved for medical use in the European Union in 2013.
Clinical Trials
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