Pertuzumab (DB06366): A Comprehensive Monograph on a First-in-Class HER2 Dimerization Inhibitor

Executive Summary

Pertuzumab, marketed under the brand names Perjeta and as a component of Phesgo, is a first-in-class, recombinant humanized IgG1 monoclonal antibody that represents a significant milestone in the targeted therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Developed by Genentech, Pertuzumab functions as a HER2 dimerization inhibitor, a novel mechanism of action that complements the activity of the foundational anti-HER2 agent, trastuzumab. By specifically binding to the extracellular dimerization domain (Subdomain II) of the HER2 receptor, Pertuzumab sterically inhibits the formation of ligand-activated heterodimers with other HER family members, most notably the highly potent HER2/HER3 signaling complex. This action blocks critical downstream cell survival and proliferation pathways, such as the PI3K and MAPK pathways, and induces antibody-dependent cell-mediated cytotoxicity (ADCC).

The clinical development of Pertuzumab has been defined by a series of landmark trials that have reshaped the standard of care across the spectrum of HER2-positive breast cancer. The Phase III CLEOPATRA trial in the metastatic setting demonstrated an unprecedented median overall survival benefit of nearly 16 months when Pertuzumab was added to trastuzumab and docetaxel. In the adjuvant setting, the Phase III APHINITY trial established a significant long-term survival benefit for a Pertuzumab-based regimen in patients with high-risk, lymph node-positive early breast cancer, providing critical evidence for risk-stratified treatment. Furthermore, neoadjuvant trials like NEOSPHERE validated the use of pathological complete response (pCR) as a surrogate endpoint for accelerated approval, showing significantly higher pCR rates with the addition of Pertuzumab.