What is the mechanism of action of Perjeta (pertuzumab)?

From the Guidelines

Perjeta (pertuzumab) is a HER2-targeted monoclonal antibody that works by binding to a specific region of the HER2 receptor, preventing dimerization with other HER family receptors and blocking subsequent cell signaling pathways that promote cancer cell growth and survival. The mechanism of action of pertuzumab involves binding to the HER2 receptor, which is different from the binding site of trastuzumab (Herceptin) 1. This binding prevents HER2 from dimerizing with other HER family receptors, particularly HER3, thereby blocking subsequent cell signaling pathways that promote cancer cell growth and survival. By inhibiting dimerization, pertuzumab disrupts downstream signaling through the PI3K and MAPK pathways, which are critical for cancer cell proliferation. Pertuzumab is typically administered intravenously at a loading dose of 840 mg followed by 420 mg every three weeks, usually in combination with trastuzumab and chemotherapy for HER2-positive breast cancer 1. The complementary mechanism of pertuzumab and trastuzumab creates a more complete blockade of HER2 signaling, which explains why the combination is more effective than either agent alone. Additionally, pertuzumab has immune-mediated effects, including antibody-dependent cellular cytotoxicity (ADCC), which helps recruit immune cells to attack cancer cells. Some key points to consider when using pertuzumab include:

• The combination of pertuzumab and trastuzumab has been shown to improve overall survival and progression-free survival in patients with HER2-positive metastatic breast cancer 1
• Pertuzumab is active in patients beyond the first-line setting, and the combination of pertuzumab and trastuzumab may be considered for patients with disease progression after treatment with trastuzumab-based therapy without pertuzumab 1
• The NCCN panel recommends pertuzumab plus trastuzumab in combination with a taxane as a preferred option for first-line treatment of patients with HER2-positive metastatic breast cancer 1

From the FDA Drug Label

Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, 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 signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).

The mechanism of action of Perjeta (pertuzumab) is to target the HER2 protein and block its interaction with other HER family members, thereby inhibiting cell signaling pathways that promote cell growth and survival. This can lead to cell growth arrest and apoptosis. Additionally, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC), which helps to eliminate cancer cells 2.

• Key mechanisms:
  • Inhibition of ligand-dependent heterodimerization of HER2 with other HER family members
  • Inhibition of ligand-initiated intracellular signaling through MAP kinase and PI3K pathways
  • Mediation of antibody-dependent cell-mediated cytotoxicity (ADCC) 2

From the Research

Mechanism of Action of Perjeta (Pertuzumab)

• Pertuzumab is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor 3, 4, 5, 6.
• It reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors, such as HER3 and HER4 3, 4, 5.
• The HER2-HER3 heterodimer is a robust activator of phosphoinositide 3-kinase (PI3K) pathway signaling and functions as the most transforming and mitogenic of the receptor complexes formed by the HER family of proteins 4.
• Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival 3.
• Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro 3, 5, 6.

Clinical Efficacy of Perjeta (Pertuzumab)

• The efficacy of intravenous pertuzumab in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial 3, 7.
• Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival, objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel 3, 7.
• The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects 7.