PHESGO

Indications

• Adjuvant treatment of HER2-positive early stage breast cancer
• Neoadjuvant treatment of HER2-positive locally advanced breast cancer in combination with trastuzumab and chemotherapy
• Treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer in combination with trastuzumab and docetaxel

Dosage

Children: Refer to the BNF for Children for dosing information.

Adults: Refer to product literature or local protocols for dosing information.

Mechanism of action

Pertuzumab is a monoclonal antibody that binds to the extracellular domain II of the HER2 receptor. This binding prevents HER2 from dimerizing with other members of the HER family, which is crucial for signal transduction pathways that promote cell proliferation and survival. By inhibiting these pathways, pertuzumab effectively reduces the growth and spread of HER2-positive tumors.

Pharmacodynamics

Pertuzumab exhibits dose-dependent inhibition of HER2 signaling pathways, leading to decreased cell proliferation and increased apoptosis in HER2-overexpressing tumor cells. Its efficacy is enhanced when used in combination with trastuzumab, as both agents target HER2 through different mechanisms.

Pharmacokinetics

Pertuzumab is administered via intravenous infusion, with a half-life of approximately 18 days. It demonstrates linear pharmacokinetics within the therapeutic dose range. The drug is primarily eliminated by protein catabolism. Its volume of distribution is about 7.5 L, and it is not significantly metabolized by cytochrome P450 enzymes, making it less prone to drug-drug interactions.

Contra-indications

• History of congestive heart failure
• Impaired left ventricular function
• Recent myocardial infarction
• Severe cardiac arrhythmia
• Uncontrolled hypertension

Adverse effects

• Alopecia
• Anaemia
• Appetite decrease
• Fatigue
• Insomnia
• Left ventricular dysfunction
• Leucopenia
• Mucositis
• Myalgia
• Nail disorder
• Nausea
• Neutropenia
• Oedema
• Pain
• Peripheral neuropathy
• Respiratory disorders
• Skin reactions
• Stomatitis
• Taste alteration
• Vomiting

Interactions

• Monoclonal antibodies may interact with other immunotherapies
• Consult Appendix 1 for detailed interactions

Precautions

• Conditions that could impair left ventricular function
• Caution in patients with a history of anthracycline exposure
• Caution in patients with previous radiotherapy to the chest area

Pregnancy

Avoid use during pregnancy due to potential toxicity and teratogenic effects observed in animal studies.

Breast-feeding

Avoid; no information available on the safety of pertuzumab during breastfeeding.

Storage

Store in a refrigerator (2°C to 8°C). Do not freeze. Protect from light.

Formulations

• Pertuzumab (Perjeta®) 420 mg/14 ml concentrate for solution for infusion vials

Indications

• Metastatic breast cancer in patients with HER2 overexpression who have received at least two prior chemotherapy regimens, including an anthracycline and a taxane.
• Metastatic gastric cancer in patients with HER2-positive tumors who have not received prior treatment for this condition.

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients, as specific doses are not provided in the BNF.

Adults: The recommended dosage for adults is typically 8 mg/kg as a loading dose, followed by 6 mg/kg every three weeks, administered via intravenous infusion or subcutaneous injection.

Mechanism of action

Trastuzumab binds specifically to the extracellular domain of the human epidermal growth factor receptor 2 (HER2), leading to inhibition of HER2-mediated signaling pathways, including the PI3K/AKT and MAPK pathways. This blockade reduces cell proliferation and induces apoptosis in HER2-overexpressing cells. Additionally, trastuzumab enhances antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells.

Pharmacodynamics

Trastuzumab demonstrates a dose-dependent effect on inhibiting the growth of HER2-positive cancer cells. Its clinical efficacy is primarily associated with its ability to target HER2 overexpression, leading to decreased tumor growth and improved survival rates in patients with HER2-positive breast and gastric cancers. Common side effects include infusion-related reactions, gastrointestinal disturbances, and increased risk of infections.

Pharmacokinetics

Trastuzumab has a terminal half-life of approximately 5 to 8 days after the initial intravenous administration. It is distributed widely, with a volume of distribution typically around 2-3 L/kg. Metabolism occurs via proteolytic degradation, primarily in the reticuloendothelial system. The clearance is affected by the patient's body size and HER2 expression levels, and it is excreted mainly through the lymphatic system.

Contra-indications

• Severe dyspnoea at rest
• Symptomatic heart failure
• Uncontrolled arrhythmias

Adverse effects

• Abdominal pain
• Alopecia
• Anaemia
• Appetite decreased
• Arthralgia
• Asthenia
• Constipation
• Cough exacerbated
• Decreased leucocytes
• Diarrhoea
• Dyspnoea
• Electrolyte imbalance
• Fever
• Headache
• Hyperbilirubinaemia
• Hyperhidrosis
• Hypogammaglobulinaemia
• Increased risk of infection
• Infusion related reaction
• Malaise
• Mucositis
• Muscle spasms
• Nasal congestion
• Nausea
• Neutropenia
• Pain
• Paresthesia
• Peripheral oedema
• Sepsis
• Skin reactions
• Taste altered
• Thrombocytopenia
• Vomiting
• Weight decreased

Interactions

• Anthracyclines: Severe (increases risk of cardiotoxicity)
• Anthracyclines + trastuzumab-emtansine: Severe (increases risk of cardiotoxicity)
• Cobicistat + trastuzumab-emtansine: Severe (increases exposure)
• Idelalisib + trastuzumab-emtansine: Severe (increases exposure)
• Clarithromycin + trastuzumab-emtansine: Severe (increases exposure)
• Anthracyclines + trastuzumab-deruxtecan: Unknown (increases risk of cardiotoxicity)

Precautions

• Monitor for cardiac function before each treatment cycle and throughout therapy
• Females of childbearing potential should use effective contraception during treatment and for at least 3 months after last treatment

Pregnancy

Use is not recommended during pregnancy. If exposed, monitor the infant for B-cell depletion.

Breast-feeding

It is not known if trastuzumab is excreted in human milk. Caution should be exercised.