Pertuzumab

Uses

Pertuzumab is a HER2/neu receptor antagonist used 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 (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.
• Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence

Pertuzumab is also used to associated treatment for these conditions: Early Breast Cancer, Inflammatory Breast Cancer (IBC), Locally Advanced Breast Cancer (LABC), Metastatic Breast Cancer

How Pertuzumab works

Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor that plays an integral role in cell proliferation, differentiation, and survival. HER2 becomes active following dimerization with another HER2 receptor, another member of the HER protein family (e.g. HER3), or with a ligand - this dimer then phosphorylates and activates numerous intracellular signaling proteins, initiating signal transduction via pathways that include the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3' kinase (PI3K)/Akt pathway, and then Janus kinases/signal transducer and activator transcription pathway. HER2 is also a known oncogene - it is overexpressed or gene-amplified (i.e. HER2-positive) in approximately 20% of breast cancers and these cancers carry a generally poorer prognosis than HER2-negative breast cancers.

Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2, thereby inhibiting ligand-initiated intracellular signaling via the MAP kinase and PI3K pathways. Inhibition of these pathways results in inhibition of cell growth and the initiation of apoptosis, respectively. Pertuzumab also appears to mediate antibody-dependent cell-mediated cytotoxicity.

Dosage

Pertuzumab dosage

For intravenous infusion only. Do not administer as an intravenous push or bolus.

HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency.

The initial Pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion.

MBC: Administer Pertuzumab, trastuzumab, and docetaxel by intravenous infusion every 3 weeks.

Neoadjuvant: Administer Pertuzumab, trastuzumab, and chemotherapy by intravenous infusion preoperatively every 3 weeks for 3 to 6 cycles.

Adjuvant: Administer Pertuzumab, trastuzumab, and chemotherapy by intravenous infusion postoperatively every 3 weeks for a total of 1 year (up to 18 cycles).

Side Effects

Metastatic Breast Cancer:

• The most common adverse reactions (> 30%) with Pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia,neutropenia, nausea, fatigue, rash, and peripheral neuropathy.

Neoadjuvant Treatment of Breast Cancer:

• The most common adverse reactions (> 30%) with Pertuzumab in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and paclitaxel when given for 4 cycles following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue, constipation and headache.
• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and docetaxel when given for 4 cycles following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia.

Adjuvant Treatment of Breast Cancer:

• The most common adverse reactions (>30%) with Pertuzumab in combination with trastuzumab and chemotherapy were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy and vomiting.

Toxicity

There are no data regarding overdose of pertuzumab. Single doses higher than 25 mg/kg have not been tested. Symptoms of overdose are likely to be consistent with pertuzumab's adverse effect profile, and may therefore involve significant diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and/or peripheral neuropathy. Pertuzumab has been associated with the development of left ventricular dysfunction (i.e. cardiotoxicity) that may be exacerbated in instances of overdose.

Precaution

Infusion-Related Reactions: Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms. If a severe hypersensitivity reaction/anaphylaxis occurs, discontinue the infusion immediately and administer appropriate medical therapies

Interaction

No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel, paclitaxel, or carboplatin.

Food Interaction

Pertuzumab Hypertension interaction

[Moderate] Decreases in left ventricular ejection fraction (LVEF) have been reported with agents that block HER2 activity.

Patients who have received prior anthracyclines, those who received anthracycline after stopping therapy with agents that block HER2 activity, or patients who received prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

Therapy with these agents should be administered cautiously in patients with a previous history of heart conditions.

Evaluate cardiac function before, during, and upon completion of treatment.

Withhold or discontinue therapy with agents that block HER2 activity as appropriate, and for a confirmed clinically significant decrease in left ventricular function, or if the LVEF has not improved or has declined further.

It is recommended to monitor overall cardiac function and LVEF by echocardiogram or MUGA scan as appropriate.

Pertuzumab Disease Interaction

Major: pulmonary toxicityModerate: CHF, peripheral neuropathy, thrombocytopenia, renal dysfunction

Volume of Distribution

The average steady-state volume of distribution following intravenous administration is 3.53 - 7.5 L.

Elimination Route

Intravenously administered pertuzumab, given as a loading dose of 840mg followed by a maintenance dose of 420mg every 3 weeks, reaches steady-state concentration following the first maintenance dose. In its subcutaneous formulation, in combination with [hylauronidase], the absolute bioavailability of pertuzumab is approximately 0.7 and the median T_max is 4 days. This subcutaneous formulation leverages the benefits of co-administration with hyaluronidase - this enzyme breaks down hylauronic acid, thereby decreasing the viscosity of the extracellular matrix (ECM) and allowing for greater bioavailability with subcutaneous administration.

Half Life

The median half-life of pertuzumab was determined to be 18 days based on a population pharmacokinetic analysis.

Clearance

The median clearance of pertuzumab was determined to be 0.24 L/day based on a population pharmacokinetic analysis.

Pregnancy & Breastfeeding use

Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of Pertuzumab. There is no information regarding the presence of pertuzumab in human milk, the effects on the breastfed infant or the effects on milk production.

Contraindication

Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

Storage Condition

Store vials in a refrigerator at 2°C to 8°C until time of use. Keep vial in the outer carton in order to protect from light.

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