Trastuzumab (Herceptin) - Uses, Dose, Side effects, MOA, Brands

Trastuzumab, also known by its brand name Herceptin, is a medication used in the treatment of breast cancer and stomach cancer. It belongs to a class of drugs called monoclonal antibodies. Trastuzumab specifically targets and binds to a protein known as human epidermal growth factor receptor 2 (HER2) that is overexpressed in certain types of cancer cells, particularly breast cancer.

Trastuzumab Uses:

  • Breast cancer, adjuvant treatment:
    • It is used as an adjunctive treatment) of human epidermal growth receptor 2 (HER2)-overexpressing node-positive or node-negative either estrogen receptor or progesterone receptor-negative or with 1 high-risk feature, breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel.
    • It can also be used as part of a treatment regimen with docetaxel and carboplatin or as a single agent following multi-modality anthracycline-based therapy.
  • Breast cancer, metastatic:
    • it is also used as a first-line treatment of HER2-overexpressing metastatic breast cancer in combination with paclitaxel or a single agent treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.
  • Gastric cancer, metastatic:
    • It is used in the management of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and either capecitabine or 5-fluorouracil in patients who have not received prior treatment for metastatic disease.
    • Its limitations for use in patients depend upon selectivity for breast and gastric cancer therapy based on an approved companion diagnostic test for tumor specimen for HER2 overexpression or HER2 gene amplification.

Note: Kanjinti (trastuzumab-anns) and Ontruzant (trastuzumab-dttb) are approved as biosimilars to Herceptin (trastuzumab).

  • Off Label Use of Trastuzumab in Adults:
    • It can be used for locally advanced breast cancer, inflammatory or early in nature, and in those for whom human epidermal growth receptor 2 (HER2) is positive,  as neoadjuvant treatment.
    • it is used in metastatic breast cancer, who are HER2-positive in combination with pertuzumab and docetaxel, in patients who have not received prior anti-HER2 therapy or chemotherapy to treat metastatic disease.
    • In metastatic breast cancer which is HER2-positive in combination with pertuzumab and weekly paclitaxel.
    • In metastatic breast cancer which is HER2-positive in combination with either docetaxel or vinorelbine.
    • In metastatic breast cancer which is HER2-positive, hormone-receptor-positive in combination with an aromatase inhibitor.
    • In metastatic breast cancer which is HER2-positive in combination with lapatinib which has progressed on prior trastuzumab containing therapy.
    • It is used in Endometrial cancer which are advanced or recurrent, and HER2-positive

Trastuzumab (Herceptin) Dose in Adults

Note: It's important to remember that trastuzumab has different forms, and they are not the same or interchangeable. Two approved biosimilars to Herceptin are Kanjinti (trastuzumab-anns) and Ontruzant (trastuzumab-dttb). Therefore, it is crucial not to substitute conventional trastuzumab products with ado-trastuzumab emtansine or trastuzumab/hyaluronidase. These products have distinct characteristics and should not be used interchangeably.

Trastuzumab (Herceptin) Dose in the adjuvant treatment of human epidermal growth receptor 2-positive (HER2+) breast cancer: IV:

Note: Extending adjuvant treatment beyond 1 year is not recommended.

In the adjuvant treatment of breast cancer that is positive for the human epidermal growth receptor 2 (HER2+), trastuzumab is given intravenously (IV). The recommended dose depends on the concurrent chemotherapy being used. Here are the dosing regimens:

With concurrent paclitaxel or docetaxel:

  • Initial loading dose: 4 mg/kg infused over 90 minutes
  • Maintenance dose: 2 mg/kg infused over 30 minutes weekly for a total of 12 weeks
  • Followed by a 1-week break after completing concurrent chemotherapy
  • Then, 6 mg/kg infused over 30 to 90 minutes every 3 weeks for a total therapy duration of 52 weeks.

With concurrent docetaxel/carboplatin:

  • Initial loading dose: 4 mg/kg infused over 90 minutes
  • Maintenance dose: 2 mg/kg infused over 30 minutes weekly for a total of 18 weeks
  • Followed by a 1-week break after completing concurrent chemotherapy
  • Then, 6 mg/kg infused over 30 to 90 minutes every 3 weeks for a total therapy duration of 52 weeks.

Following completion of multimodality anthracycline-based chemotherapy:

  • Initial loading dose: 8 mg/kg infused over 90 minutes
  • Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks for a total therapy duration of 52 weeks.

Duration of therapy:

  • It's important to note that the standard duration of adjuvant trastuzumab therapy is 1 year (52 weeks).
  • However, a study comparing 12 months versus 6 months of adjuvant trastuzumab therapy suggests that a 6-month duration may be non-inferior in terms of disease-free survival for patients who cannot tolerate 1 year of treatment.

Trastuzumab (Herceptin) Dose in the treatment of Breast cancer (early stage, locally advanced, or inflammatory), neoadjuvant treatment, HER2+ (off-label): IV:

In the treatment of early-stage, locally advanced, or inflammatory breast cancer that is HER2+, trastuzumab can be used in combination with pertuzumab and docetaxel as neoadjuvant therapy (before surgery). Please note that this use is considered off-label, which means it's not officially approved for this specific purpose, but it may be prescribed by doctors based on clinical judgment and evidence.

The recommended intravenous (IV) dosing regimen is as follows:

  • Initial dose: 8 mg/kg (given in the first cycle)
  • Followed by subsequent doses of 6 mg/kg every 3 weeks for a total of 4 neoadjuvant cycles.

After surgery, additional treatment is administered:

  • Administer 3 cycles of adjuvant FEC chemotherapy (fluorouracil, epirubicin, and cyclophosphamide).
  • Trastuzumab should be continued to complete a total duration of 1 year of treatment.

Trastuzumab (Herceptin) Dose in the treatment of metastatic, HER2+ Breast cancer (either as a single agent or in combination with paclitaxel): IV:

In the treatment of metastatic breast cancer that is HER2+, trastuzumab can be administered as a single agent or in combination with paclitaxel chemotherapy.

The recommended intravenous (IV) dosing regimen is as follows:

  • Initial loading dose: 4 mg/kg infused over 90 minutes.
  • Maintenance dose: 2 mg/kg infused over 30 minutes weekly.
  • The treatment continues on a weekly basis until there is evidence of disease progression.

Trastuzumab (Herceptin) Dose in the treatment of metastatic, HER2+ breast cancer (off-label combinations): IV:

In the treatment of metastatic breast cancer that is HER2+, trastuzumab is used in various combinations that are considered off-label. Here are some commonly used regimens with their corresponding dosing information:

  • Trastuzumab, pertuzumab, and docetaxel (in patients without prior anti-HER2 therapy or chemotherapy for metastatic disease):
    • Initial dose: 8 mg/kg
    • Maintenance dose: 6 mg/kg every 3 weeks
    • Treatment is continued until there is disease progression or unacceptable toxicity.
  • Trastuzumab, pertuzumab, and weekly paclitaxel:
    • Initial dose: 8 mg/kg
    • Maintenance dose: 6 mg/kg every 3 weeks
    • Treatment is continued until there is disease progression.
  • Trastuzumab and lapatinib (in patients with progression on prior trastuzumab-containing therapy):
    • Initial dose: 4 mg/kg
    • Maintenance dose: 2 mg/kg every week
  • Trastuzumab and an aromatase inhibitor (in combination with anastrozole):
    • Initial dose: 4 mg/kg
    • Maintenance dose: 2 mg/kg every week
    • Treatment is continued until there is disease progression.

Other trastuzumab combinations may include:

  • Trastuzumab with docetaxel or vinorelbine:
    • Initial dose of 8 mg/kg
    • Maintenance dose of 6 mg/kg every 3 weeks
    • Treatment is continued until there is disease progression.
  • Trastuzumab with docetaxel:
    • Initial dose of 4 mg/kg
    • Maintenance dose of 2 mg/kg weekly
    • Treatment is continued until there is disease progression.

It's important to remember that these regimens are considered off-label, meaning they are not officially approved for these specific combinations.

Trastuzumab (Herceptin) Dose in the treatment of advanced or recurrent, HER2-positive endometrial cancer (uterine serous) (off-label): IV:

In the treatment of advanced or recurrent HER2-positive (HER2+) endometrial cancer, which is considered off-label, trastuzumab is used intravenously (IV) in combination with carboplatin and paclitaxel chemotherapy. The dosing regimen is as follows:

  • Initial dose: 8 mg/kg (given in the first cycle)
  • Maintenance dose: 6 mg/kg every 3 weeks, starting from the second cycle and continuing for approximately 6 cycles, in combination with carboplatin and paclitaxel chemotherapy.
  • After completing the initial combination therapy, trastuzumab maintenance is continued at a dose of 6 mg/kg every 3 weeks.
  • The treatment with trastuzumab is continued until there is evidence of disease progression or unacceptable toxicity.

Trastuzumab (Herceptin) Dose in the treatment of metastatic, HER2+ Gastric cancer:

In the treatment of metastatic HER2+ gastric cancer, trastuzumab is used in combination with cisplatin and either capecitabine or fluorouracil chemotherapy.

The dosing regimen, based on a study by Bang in 2010, is as follows:

  • Initial loading dose: 8 mg/kg infused over 90 minutes.
  • Maintenance dose: 6 mg/kg infused over 30 to 90 minutes every 3 weeks.
  • The treatment is continued until there is disease progression.

If a dose of trastuzumab is missed, the following guidelines apply:

  • Missed dose by 1 week or less:
    • Administer the usual maintenance dose (2 mg/kg weekly or 6 mg/kg every 3 weeks) as soon as possible.
    • Subsequent maintenance doses should be administered 7 or 21 days later, depending on the patient's maintenance dose/schedule.
  • Missed dose by more than 1 week:
    • Administer a reloading dose (4 mg/kg if receiving trastuzumab weekly; 8 mg/kg if on an every-3-week schedule) over 90 minutes as soon as possible.
    • After the reloading dose, administer the usual maintenance dose 7 or 21 days later, based on the patient's maintenance dose/schedule.

Use in Children:

Not indicated.

Trastuzumab (Herceptin) Pregnancy Category: D

  • Trastuzumab is a medication that blocks a protein called human epidermal growth receptor 2 (HER2), which plays a role in the development of embryos.
  • It is important to note that using trastuzumab during pregnancy can be harmful to the baby.
  • It may cause a condition called oligohydramnios, which leads to low levels of amniotic fluid and can result in problems with the baby's lungs, bones, and even death.
  • Patients need to be aware of these risks and use effective contraception while taking trastuzumab.
  • If a patient is pregnant or becomes pregnant within 7 months after treatment, they should inform their healthcare provider.
  • It is generally recommended to delay trastuzumab treatment until after delivery in pregnant patients with HER2-positive disease.

Trastuzumab is not recommended for use while breastfeeding

  • The presence of trastuzumab in human milk is unknown.
  • Since certain antibodies can be passed through breast milk and may cause serious side effects in the nursing baby, it is important to carefully consider whether to discontinue trastuzumab or stop breastfeeding during treatment.
  • The decision should weigh the benefits of the treatment for the mother.
  • After completing the treatment, it is advisable to wait for a 7-month period before considering breastfeeding.
  • This period allows for the medication to be cleared from the body.

Trastuzumab (Herceptin) Dose in Kidney Disease:

  • For patients with a creatinine clearance (CrCl) between 30 to 90 mL/minute, no dosage adjustments are necessary for trastuzumab according to the manufacturer's labeling. This is because no clinically significant differences in drug levels have been observed in this range.
  • For patients with a CrCl less than 30 mL/minute or those with end-stage renal disease (ESRD), including those on hemodialysis, no specific dosage adjustments are recommended in the manufacturer's labeling. However, it is important to note that the use of trastuzumab in these patients has not been extensively studied.

Dose in Liver disease:

Dose adjustment in liver disease has not yet been studied.

Trastuzumab Side effects (Common):

  • Cardiovascular:
    • Decreased Left Ventricular Ejection Fraction
  • Central Nervous System:
    • Pain
    • Chills
    • Headache
    • Insomnia
    • Dizziness
  • Dermatologic:
    • Skin Rash
  • Gastrointestinal:
    • Nausea
    • Diarrhea
    • Vomiting
    • Abdominal Pain
    • Anorexia
  • Infection:
    • Infection
  • Neuromuscular & Skeletal:
    • Weakness
    • Back Pain
  • Respiratory:
    • Cough
    • Dyspnea
    • Rhinitis
    • Pharyngitis
  • Miscellaneous:
    • Infusion Related Reaction
    • Fever

Trastuzumab (Herceptin) Side effects (Less Common):

  • Cardiovascular:
    • Peripheral Edema
    • Edema
    • Cardiac Failure
    • Tachycardia
    • Hypertension
    • Arrhythmia
    • Palpitations
  • Central Nervous System:
    • Paresthesia
    • Depression
    • Peripheral Neuritis
    • Neuropathy
  • Dermatologic:
    • Acne Vulgaris
    • Nail Disease
    • Pruritus
  • Gastrointestinal:
    • Constipation
    • Dyspepsia
  • Genitourinary:
    • Urinary Tract Infection
  • Hematologic & Oncologic:
    • Anemia
    • Leukopenia
  • Hypersensitivity:
    • Hypersensitivity Reaction
  • Infection:
    • Influenza
    • Herpes Simplex Infection
  • Neuromuscular & Skeletal:
    • Arthralgia
    • Ostealgia
    • Myalgia
    • Muscle Spasm
  • Respiratory:
    • Flu-Like Symptoms
    • Sinusitis
    • Nasopharyngitis
    • Upper Respiratory Tract Infection
    • Epistaxis
    • Pharyngolaryngeal Pain
  • Miscellaneous:
    • Accidental Injury

Contraindications to Trastuzumab (Herceptin):

  • In the manufacturer's US labeling, there are no specific contraindications listed for trastuzumab.
  • In the Canadian labeling, trastuzumab is contraindicated in individuals who have a known hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or any component of the formulation. It is important to be aware of this contraindication when considering the use of trastuzumab in Canadian patients.

Warnings and precautions

Cardiomyopathy [US Boxed Warning]

  • Trastuzumab carries a boxed warning regarding its potential to cause reductions in left ventricular ejection fraction (LVEF) and heart failure (HF), particularly when used with anthracycline-containing chemotherapy.
  • Therefore, it is crucial to assess LVEF before and during treatment and discontinue trastuzumab if cardiomyopathy develops.
  • Patients with pre-existing heart conditions require extreme caution when using trastuzumab.
  • Risk factors for cardiomyopathy include age, body mass index, smoking, diabetes, hypertension, and thyroid disorders.
  • Concurrent or prior exposure to anthracyclines or radiation therapy further increases the risk.
  • Close monitoring of cardiac function is necessary, and treatment adjustments should be made if clinically significant reductions in LVEF occur.
  • Cardiomyopathy caused by trastuzumab is generally reversible after discontinuation.
  • Other cardiac-related risks associated with trastuzumab include arrhythmias, hypertension, blood clot formation, stroke, and cardiac death.
  • Guidelines from the American Society of Clinical Oncology (ASCO) recommend a comprehensive assessment of cardiovascular health, risk factor management, and regular cardiac monitoring for patients receiving potentially cardiotoxic therapies like trastuzumab.

Infusion reactions: [US Boxed Warning]

  • Trastuzumab carries a boxed warning regarding the risk of infusion reactions, some of which can be severe and even fatal.
  • Anaphylaxis or angioedema are serious reactions that may occur during trastuzumab infusion, and treatment should be discontinued immediately in such cases.
  • Most infusion reactions happen during or within 24 hours of the first infusion, and if a patient experiences shortness of breath or significant low blood pressure, the infusion should be temporarily paused until the symptoms subside.
  • Close monitoring is necessary during this time.
  • Infusion reactions can manifest as fever, chills, nausea, vomiting, pain, headache, dizziness, shortness of breath, low blood pressure, rash, and weakness.
  • In some cases, patients who had severe hypersensitivity reactions may be re-treated with trastuzumab using premedication.
  • However, it's important to note that while some patients tolerate re-treatment, others may experience a second severe reaction.

Pulmonary toxicities: [US Boxed Warning]

  • Trastuzumab carries a boxed warning regarding the potential for serious pulmonary toxicity.
  • This can include various pulmonary complications such as dyspnea (difficulty breathing), hypoxia (low oxygen levels), interstitial pneumonitis (inflammation of lung tissue), pulmonary infiltrates (abnormal substances in the lungs), pleural effusion (accumulation of fluid around the lungs), noncardiogenic pulmonary edema (fluid accumulation in the lungs unrelated to heart problems), pulmonary insufficiency (impaired lung function), acute respiratory distress syndrome (ARDS), and pulmonary fibrosis (scarring of lung tissue).
  • If a patient develops ARDS or interstitial pneumonitis, treatment with trastuzumab should be discontinued.
  • It is important to exercise caution when using trastuzumab in patients with pre-existing pulmonary disease or those with extensive tumor involvement in the lungs, as these individuals may be at higher risk for severe pulmonary toxicity.
  • Pulmonary events can occur during or within 24 hours of trastuzumab administration, but delayed reactions have also been reported.

Toxicity in the renal system:

  • In rare cases, trastuzumab has been associated with renal toxicity.
  • There have been reports of nephrotic syndrome, a kidney disorder characterized by increased protein in the urine and other symptoms, along with evidence of glomerulopathy (a condition affecting the kidney's filtering units).
  • These cases typically occurred between 4 to 18 months after starting trastuzumab treatment.
  • Complications of nephrotic syndrome may include volume overload and heart failure.
  • Additionally, the incidence of renal impairment appears to be higher in patients with metastatic gastric cancer when trastuzumab is used in combination with chemotherapy.

Trastuzumab (intravenous) including biosimilars of trastuzumab: Drug Interaction

Risk Factor C (Monitor therapy)

Immunosuppressants

Trastuzumab may enhance the neutropenic effect of Immunosuppressants. Exceptions: Cytarabine (Liposomal).

PACLitaxel (Conventional)

Trastuzumab may decrease the serum concentration of PACLitaxel (Conventional). PACLitaxel (Conventional) may increase the serum concentration of Trastuzumab.

Risk Factor D (Consider therapy modification)

Anthracyclines

Trastuzumab may enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab.

Monitoring parameters:

Assessment before treatment:

  • Check for HER2 overexpression and gene amplification using validated immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) tests. Ensure the test is specific to the type of cancer being treated (breast or gastric cancer).
  • Conduct a pregnancy test for women of reproductive potential before starting treatment.

Ongoing monitoring during treatment:

  • Monitor vital signs during the infusion of trastuzumab.
  • Watch for signs and symptoms of cardiac dysfunction.
  • Evaluate left ventricular ejection fraction (LVEF) at baseline, every 3 months during treatment, upon therapy completion, and every 6 months for at least 2 years (if part of adjuvant therapy).
  • If treatment is interrupted due to significant LVEF dysfunction, monitor LVEF at 4-week intervals.
  • Be vigilant for signs and symptoms of infusion reactions or pulmonary toxicity.
  • In case of inadvertent pregnancy during treatment, monitor the volume of amniotic fluid.

Additional Cardiovascular Monitoring (ASCO [Armenian 2017]):

  • Before starting treatment, conduct a comprehensive assessment that includes a medical history and physical examination.
  • Screen for cardiovascular disease risk factors like hypertension, diabetes, dyslipidemia, obesity, and smoking.
  • In patients showing signs or symptoms of cardiac dysfunction during therapy:
    • Perform an echocardiogram for diagnostic evaluation. If not possible, a cardiac MRI or MUGA scan may be used.
    • Obtain serum cardiac biomarkers.
  • Patients with metastatic breast cancer receiving trastuzumab indefinitely may undergo routine echocardiographic surveillance.

Note: Regular monitoring and assessment are crucial to ensure patient safety and detect any potential cardiac or other adverse effects associated with trastuzumab treatment.

How to administer Trastuzumab (Herceptin)?

  • Verify the label to ensure the correct trastuzumab product is being administered. Different products like conventional trastuzumab, ado-trastuzumab emtansine, and trastuzumab/hyaluronidase are not interchangeable.
  • Administer trastuzumab through intravenous (IV) infusion.
  • Loading doses should be infused over 90 minutes.
  • Maintenance doses can be infused over 30 minutes if well-tolerated.
  • Do not mix trastuzumab with any other medications.
  • Avoid administering with D5W (5% dextrose in water).
  • Do not administer trastuzumab via IV push or rapid bolus.
  • Monitor patients closely during the infusion for any signs of fever, chills, or other symptoms related to the infusion.
  • Infusion-related symptoms can usually be managed by administering acetaminophen, diphenhydramine, and/or meperidine.

Note: It is important to follow these administration guidelines to ensure the safe and effective delivery of trastuzumab treatment.

Mechanism of action of Trastuzumab (Herceptin):

  • Trastuzumab is a type of monoclonal antibody.
  • It specifically targets and binds to the extracellular domain of a protein called human epidermal growth factor receptor 2 (HER-2).
  • By binding to HER-2, trastuzumab inhibits the proliferation (growth and division) of cells that have an overexpression of HER-2 protein.
  • It can also mediate antibody-dependent cellular cytotoxicity, which means it stimulates the immune system to destroy these HER-2 overexpressing cells.
  • Overall, trastuzumab works by blocking the activity of HER-2 and reducing the growth of cells that rely on HER-2 signaling for their growth and survival.

Excretion and Clearance of Trastuzumab

  • Trastuzumab is eliminated from the body over time.
  • After discontinuation of treatment, trastuzumab concentrations typically decrease to approximately 3% (97% washout) within about 7 months.
  • The clearance of trastuzumab refers to the rate at which it is removed from the body.
  • In patients receiving trastuzumab on a weekly dosing schedule, the clearance ranges from 0.201 to 0.244 L/day.
  • For patients receiving trastuzumab on a three-week dosing schedule, the clearance ranges from 0.173 to 0.337 L/day.
  • Clearance values indicate the amount of trastuzumab that is eliminated from the body per day, helping to determine how quickly the drug is metabolized and excreted.

International Brand Names of Trastuzumab:

  • Herceptin
  • Kanjinti
  • Ogivri
  • Herticad
  • Hertraz
  • Herzemab
  • Kanjinti
  • Ogivri
  • Ontrozant
  • Trastunix
  • Trazimera
  • Vivitra

Trastuzumab Brand Names in Pakistan:

Trastuzumab Injection IV 440 mg in Pakistan

Herceptin

Roche Pakistan Ltd.

You can check its availability and price in Pakistan here: https://wa.me/message/HV6M3JGTA6RJB1