Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Abstract

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.

Keywords:

• CLEOPATRA
• docetaxel
• double blockade
• HER2
• metastatic breast cancer
• pertuzumab
• target therapy
• trastuzumab

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Pertuzumab binds to extracellular domain II of the HER2 receptor and prevents HER2 from forming dimers with other HER receptors, especially the HER3 receptor, blocking this essential step in the activation of ligand-dependent HER2 intracellular signaling.

• In patients with HER2-positive metastatic breast cancer who had experienced progression during prior trastuzumab-based therapy, combination therapy with pertuzumab and trastuzumab was more effective than pertuzumab alone. Because they have slightly different mechanisms of action, administration of the two agents together provides a more comprehensive blockade of HER2 signaling, resulting in greater antitumor activity than either agent alone.

• The CLEOPATRA trial is an international, randomized, double-blind, placebo-controlled, Phase III trial. Adults with HER2-positive adenocarcinoma of the breast with locally recurrent or metastatic disease will be randomized (1:1) to receive docetaxel, trastuzumab and pertuzumab (pertuzumab group) or docetaxel, trastuzumab and placebo (control group).

• The CLEOPATRA trial demonstrates the benefit of adding pertuzumab to trastuzumab and docetaxel, and the adverse event profile during the treatment period was generally similar between both groups. Consequently, the combination of pertuzumab, trastuzumab and docetaxel has been the standard first-line therapy for patients with HER2-positive metastatic breast cancer.

• Some ongoing trials are evaluating the efficacy and safety of pertuzumab combined with other cytotoxic agents for patients with HER2-positive metastatic breast cancer.