What is pertuzumab (Perjeta)?

From the Guidelines

Pertuzumab is a highly effective treatment for HER2-positive breast cancer, and its use in combination with trastuzumab and a taxane is recommended as a first-line treatment for patients with metastatic disease, based on the strongest evidence from the CLEOPATRA trial 1.

Key Points

• Pertuzumab works by binding to the HER2 receptor on cancer cells, preventing them from receiving growth signals.
• The standard dosing regimen begins with an initial loading dose of 840 mg, followed by 420 mg every three weeks for subsequent treatments.
• Common side effects include diarrhea, hair loss, nausea, fatigue, rash, and potential cardiac dysfunction.
• Patients receiving pertuzumab should have regular heart function monitoring through echocardiograms or MUGA scans, as it can reduce left ventricular ejection fraction.
• The combination of pertuzumab, trastuzumab, and a taxane has been shown to improve progression-free survival and overall survival in patients with HER2-positive metastatic breast cancer, with a 34% reduction in the risk of death 1.

Treatment Recommendations

• 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.
• Pertuzumab plus trastuzumab in combination with docetaxel is an NCCN category 1 recommendation, and in combination with paclitaxel is an NCCN category 2A recommendation 1.
• For patients with disease progression after treatment with trastuzumab-based therapy without pertuzumab, a line of therapy containing both trastuzumab plus pertuzumab with or without a cytotoxic agent may be considered 1.

Evidence Summary

• The CLEOPATRA trial demonstrated a 6.1-month improvement in median progression-free survival with the addition of pertuzumab to trastuzumab and docetaxel, and a 34% reduction in the risk of death 1.
• The PERUSE study showed that median PFS was comparable between docetaxel, paclitaxel, and nab-paclitaxel when used in combination with pertuzumab and trastuzumab 1.
• The MARIANNE trial demonstrated that T-DM1 and T-DM1 with pertuzumab were noninferior to trastuzumab plus taxane, with better QOL and possibly better tolerability for some patients 1.

From the FDA Drug Label

Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) PERJETA is a HER2/neu receptor antagonist indicated for: Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence

Pertuzumab is a HER2/neu receptor antagonist used in combination with other therapies for the treatment of HER2-positive breast cancer. The main indications for pertuzumab are:

• Metastatic breast cancer: in combination with trastuzumab and docetaxel for patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
• Neoadjuvant treatment: in combination with trastuzumab and chemotherapy for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer.
• Adjuvant treatment: for patients with HER2-positive early breast cancer at high risk of recurrence. 2 2 2

From the Research

Mechanism of Action

• Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of HER2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4 3.
• 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; thus, blockade of HER2-HER3 likely represents the most relevant action of pertuzumab 3.
• Pertuzumab reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors, resulting in a reduction of tumour cell proliferation, invasiveness and survival 4.

Clinical Use

• Pertuzumab has been approved by the U.S. Food and Drug Administration for use in combination with trastuzumab and docetaxel for the first-line treatment of patients with advanced HER2-positive (HER2(+)) breast cancer 3.
• The addition of pertuzumab to trastuzumab and docetaxel significantly prolonged progression-free survival with an increase of 6.1 months (12.4 vs. 18.5 months, respectively) 3.
• Pertuzumab conferred a 34% reduction in the risk of mortality in a subsequent analysis with 30 months of median follow-up 3.
• Pertuzumab is also used as a standard of care for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer 5.

Efficacy and Safety

• 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 4.
• 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 4.
• Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial 4.
• The most common adverse reactions with pertuzumab-trastuzumab-docetaxel were alopecia, diarrhea, nausea, and neutropenia 5.