Usage
Pertuzumab + Trastuzumab is prescribed for the treatment of HER2-positive breast cancer. This includes:
- Early breast cancer: As neoadjuvant therapy (before surgery) for locally advanced, inflammatory, or early-stage breast cancer at high risk of recurrence. It is also used as adjuvant therapy (after surgery) for patients at high risk of recurrence.
- Metastatic breast cancer: In patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Pharmacological Classification: Monoclonal antibody, targeted therapy, antineoplastic agent.
Mechanism of Action: Pertuzumab and Trastuzumab are both monoclonal antibodies targeting the human epidermal growth factor receptor 2 (HER2) protein, but they bind to different regions (epitopes). This dual blockade prevents HER2 dimerization (pairing) and subsequent cell signaling, inhibiting cancer cell growth and proliferation. They also enhance antibody-dependent cell-mediated cytotoxicity (ADCC), a process where immune cells destroy targeted cancer cells.
Alternate Names
A combination product of pertuzumab and trastuzumab for subcutaneous injection is marketed under the brand name Phesgo.
How It Works
Pharmacodynamics: Pertuzumab and Trastuzumab exert their anti-tumor effects by inhibiting HER2 signaling pathways, which are involved in cell growth and survival. Dual blockade leads to enhanced suppression of these pathways compared to either drug alone.
Pharmacokinetics:
- Absorption: When administered intravenously, both drugs reach peak plasma concentration at the end of the infusion. Phesgo, the subcutaneous formulation, achieves peak concentrations later, followed by a decline.
- Metabolism: As monoclonal antibodies, their metabolism is expected to follow general protein degradation pathways. No significant drug-drug interaction between Pertuzumab and Trastuzumab has been observed.
- Elimination: Both drugs are eliminated via multiple routes, including intracellular catabolism and renal/hepatic elimination.
Mode of Action: Both drugs bind to specific epitopes on the HER2 receptor. Pertuzumab binds to domain II, preventing receptor dimerization with other HER receptors. Trastuzumab binds to domain IV, inhibiting downstream signaling pathways. This combination results in enhanced anti-tumor activity.
Receptor Binding, Enzyme Inhibition or Neurotransmitter Modulation: Pertuzumab + Trastuzumab works by binding to the HER2 receptor, which is a transmembrane receptor tyrosine kinase. By blocking this receptor, the drugs inhibit its signaling cascade, thus impeding cancer cell growth.
Elimination Pathways: The exact mechanisms are not fully elucidated but involve pathways typical for monoclonal antibodies. These pathways may include:
- Renal/hepatic excretion, possibly after protein catabolism
- Metabolism by CYP enzymes
Dosage
Standard Dosage
Adults:
- Intravenous Administration (Pertuzumab + Trastuzumab): Pertuzumab: initial dose of 840 mg followed by 420 mg every 3 weeks. Trastuzumab: initial loading dose of 8mg/kg followed by 6mg/kg every 3 weeks.
- Subcutaneous Administration (Phesgo): Initial loading dose of 1200 mg Pertuzumab / 600 mg Trastuzumab, followed by a maintenance dose of 600 mg Pertuzumab / 600 mg Trastuzumab every 3 weeks.
Children: No established dosing guidelines for children.
Special Cases:
- Elderly Patients: No specific dose adjustment recommended, but increased monitoring for side effects, especially diarrhea, is advised.
- Patients with Renal Impairment: No specific dose adjustment is needed.
- Patients with Hepatic Dysfunction: No specific dose adjustment is needed.
- Patients with Comorbid Conditions: Monitor patients with cardiovascular disease closely for left ventricular dysfunction.
Clinical Use Cases
The usage of Pertuzumab + Trastuzumab is specific to HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings. It’s not typically used in conditions like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of its oncology indications.
Dosage Adjustments
Dose adjustments are not typically recommended for Pertuzumab or Trastuzumab. Treatment is generally held or discontinued for cardiac dysfunction, severe infusion reactions, or other significant adverse events.
Side Effects
Common Side Effects
Diarrhea, nausea, fatigue, alopecia, rash, peripheral neuropathy, neutropenia, mucosal inflammation, infections, and nail changes.
Rare but Serious Side Effects
Left ventricular dysfunction (decreased heart function), hypersensitivity reactions (including anaphylaxis), embryo-fetal toxicity (birth defects), and severe infusion reactions.
Long-Term Effects
Long-term effects can include persistent cardiac dysfunction.
Adverse Drug Reactions (ADR)
Severe hypersensitivity reactions (anaphylaxis), severe infusion reactions, and symptomatic left ventricular dysfunction require immediate intervention.
Contraindications
- Known hypersensitivity to Pertuzumab, Trastuzumab, or any components of the formulations.
Drug Interactions
No significant drug-drug interaction between Pertuzumab and Trastuzumab. Anthracyclines should not be given concurrently with Pertuzumab/Trastuzumab. Exercise caution with other cardiotoxic agents.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Data not available.
Fetal Risks, Teratogenicity, and Developmental Concerns: Pertuzumab + Trastuzumab can cause embryo-fetal harm, including birth defects and death. Contraception is crucial during treatment and for 7 months after the last dose.
Drug Excretion in Breast Milk and Potential Neonatal Side Effects: The amount of drug excreted in breast milk is likely low, but it is generally recommended to discontinue breastfeeding during treatment and for 7 months after the last dose due to potential infant harm.
Drug Profile Summary
- Mechanism of Action: Dual HER2 blockade, inhibits cell growth and enhances ADCC.
- Side Effects: Diarrhea, nausea, fatigue, alopecia, cardiotoxicity, infusion reactions.
- Contraindications: Hypersensitivity to drug components.
- Drug Interactions: Anthracyclines and other cardiotoxic agents.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: See dosage section above.
- Monitoring Parameters: LVEF (left ventricular ejection fraction), complete blood counts, liver function tests.
Popular Combinations
- Pertuzumab + Trastuzumab + Docetaxel for metastatic and neoadjuvant treatment of breast cancer. The combination provides enhanced efficacy compared to Trastuzumab + Docetaxel alone.
- Pertuzumab + Trastuzumab + chemotherapy (other than Docetaxel) for neoadjuvant and adjuvant treatment of early breast cancer.
Precautions
- General Precautions: Evaluate LVEF before and during treatment. Monitor for hypersensitivity and infusion reactions. Ensure adequate hydration and manage diarrhea promptly, especially in elderly patients.
- Specific Populations: See dosage adjustments section above.
- Lifestyle Considerations: No specific lifestyle restrictions besides general health recommendations, but counseling about alcohol, smoking, and balanced diet is always beneficial.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pertuzumab + Trastuzumab?
A: See detailed dosage guidelines above, as the dosage depends on the route of administration (intravenous or subcutaneous), specific regimen, and whether it’s the loading or maintenance dose.
Q2: What are the most common side effects?
A: The most common side effects include diarrhea, nausea, fatigue, alopecia, rash, peripheral neuropathy, neutropenia, and nail changes.
Q3: What are the serious side effects to be aware of?
A: Serious side effects can include left ventricular dysfunction (heart problems), hypersensitivity reactions (including anaphylaxis), and embryo-fetal toxicity.
Q4: Can Pertuzumab + Trastuzumab be used during pregnancy?
A: No, Pertuzumab + Trastuzumab is contraindicated during pregnancy due to the risk of fetal harm.
Q5: What is the mechanism of action of Pertuzumab + Trastuzumab?
A: Both drugs target the HER2 receptor, but at different binding sites. This dual blockade prevents receptor dimerization and activation, inhibiting cancer cell growth and promoting destruction by immune cells.
Q6: How is Pertuzumab + Trastuzumab administered?
A: Pertuzumab + Trastuzumab can be administered intravenously or subcutaneously (Phesgo).
Q7: What monitoring is required during treatment?
A: Patients should have their cardiac function (LVEF) monitored before and during treatment. Regular blood counts and liver function tests are also recommended.
Q8: Are there any drug interactions I should be aware of?
A: Concurrent use of anthracyclines is contraindicated. Caution should be exercised when using with other cardiotoxic agents.
Q9: What is the difference between neoadjuvant and adjuvant therapy?
A: Neoadjuvant therapy is given before surgery to shrink the tumor, while adjuvant therapy is given after surgery to eliminate any remaining cancer cells and reduce the risk of recurrence.
Q10: How long does treatment with Pertuzumab + Trastuzumab typically last?
A: The duration depends on the stage of breast cancer and the patient’s response to treatment. In the adjuvant setting, it’s typically given for one year. In the metastatic setting, it’s continued until disease progression or unacceptable toxicity.
