Generic Name
Trastuzumab
Brand Names
Herceptin
Herclon
Kanjinti (biosimilar)
Ogivri (biosimilar)
Trazimera (biosimilar)
Ontruzant (biosimilar)
Others: Herzuma, Zercepac (biosimilars depending on regulatory region)
Drug Class
Monoclonal antibody
HER2/neu receptor antagonist
Antineoplastic agent
Targeted therapy (anti-HER2)
Mechanism of Action
Trastuzumab is a recombinant humanized IgG1 monoclonal antibody that targets the extracellular domain (subdomain IV) of the human epidermal growth factor receptor 2 (HER2/neu)
HER2 is a transmembrane tyrosine kinase receptor overexpressed in 15–30% of breast cancers and some gastric or gastroesophageal cancers
Mechanisms include
– Inhibition of HER2-mediated signal transduction (via MAPK and PI3K/Akt pathways)
– Prevention of receptor dimerization
– Induction of antibody-dependent cellular cytotoxicity (ADCC)
– Promotion of receptor internalization and degradation
– Cell cycle arrest and apoptosis induction in HER2-overexpressing cells
No direct effect on HER2-negative tumors
Indications
Approved Uses
HER2-positive early breast cancer (EBC)
– Adjuvant therapy following surgery, chemotherapy, and/or radiotherapy
HER2-positive metastatic breast cancer (MBC)
– First-line with paclitaxel or docetaxel
– Second-line as monotherapy
HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma
– In combination with chemotherapy (cisplatin + capecitabine or 5-FU)
HER2-positive locally advanced breast cancer
– In combination with neoadjuvant chemotherapy
Off-label or Investigational Uses
HER2-positive colorectal cancer (in trials)
HER2-positive uterine or bladder carcinoma
Leptomeningeal metastases (intrathecal use, investigational)
Dosage and Administration
Breast Cancer – IV Formulation
Loading dose
8 mg/kg IV infusion over 90 minutes
Maintenance dose
6 mg/kg IV every 3 weeks over 30–90 minutes
OR
4 mg/kg loading then 2 mg/kg weekly
Metastatic Gastric Cancer
Loading: 8 mg/kg IV
Maintenance: 6 mg/kg IV every 3 weeks
Subcutaneous (SC) Fixed-Dose Formulation
600 mg in 5 mL solution
Administered over ~2–5 minutes every 3 weeks
Includes recombinant human hyaluronidase to enhance absorption
Duration of Therapy
12 months standard for adjuvant therapy in EBC
Until disease progression or unacceptable toxicity in MBC or gastric cancer
Pharmacokinetics
Absorption
IV: 100% bioavailability
SC: Tmax ~3 days; bioavailability ~77%
Distribution
Vd ~3.1 L (limited to extracellular fluid)
Does not cross blood-brain barrier efficiently
Metabolism
Degraded via proteolytic pathways in reticuloendothelial system
Not metabolized by CYP450 enzymes
Elimination
Terminal half-life: 5–12 days
Clearance is non-linear, slower at higher doses
Not significantly excreted in urine
Contraindications
Known hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) proteins, or any formulation component
Severe dyspnea or clinically significant pulmonary compromise
Congestive heart failure (CHF) contraindicates rechallenge
Caution in pregnancy and lactation
Warnings and Precautions
Cardiotoxicity
– Major safety concern
– Can cause left ventricular dysfunction, asymptomatic decline in LVEF, or congestive heart failure (CHF)
– Risk increased with prior or concurrent anthracyclines (e.g., doxorubicin)
– Monitor LVEF (e.g., by echocardiogram or MUGA scan) at baseline and every 3 months
– Withhold if LVEF declines >10% below baseline or falls below 50%
– May be irreversible in some cases
Infusion-Related Reactions (IRRs)
– Fever, chills, dyspnea, hypotension, bronchospasm
– Most occur with first infusion
– Pretreatment with acetaminophen and antihistamines may help
– Severe reactions may require permanent discontinuation
Pulmonary Toxicity
– Rare but serious
– Interstitial pneumonitis, pulmonary infiltrates, ARDS
– Greater risk in patients with preexisting lung disease or prior chemotherapy
Fetal Toxicity
– Trastuzumab crosses the placenta
– Linked to oligohydramnios, fetal renal dysfunction, and neonatal death
– Use contraception during therapy and for 7 months after last dose
Hematologic Toxicity
– Neutropenia and anemia reported, usually mild
– Risk increased when combined with cytotoxic chemotherapy
Adverse Effects
Very Common (>10%)
Fever
Chills
Nausea
Vomiting
Headache
Weakness
Infusion reactions
Diarrhea
Myelosuppression
Elevated transaminases
Common (1–10%)
Left ventricular dysfunction
Dyspnea
Cough
Skin rash
Fatigue
Arthralgia
Edema
Infections
Uncommon/Rare (<1%)
Interstitial lung disease
Cardiac failure
Anaphylaxis
Hepatic failure
Arrhythmias
Anemia
Thrombocytopenia
Overdose
No specific antidote
Overdose may result in increased risk of cardiac and pulmonary toxicity
Supportive care recommended
Close monitoring of cardiac function required
Drug Interactions
With Anthracyclines
– Increased risk of cardiotoxicity
– Sequential (not concurrent) administration recommended
With Taxanes (e.g., paclitaxel)
– Used together in HER2-positive MBC
– Administer trastuzumab first to reduce hypersensitivity reactions
No CYP450 interaction
– Does not affect metabolism of oral agents
– Can be combined with endocrine therapy in hormone receptor–positive breast cancer
With Pertuzumab and Docetaxel
– Combination used in first-line MBC
– Shown to improve progression-free and overall survival (CLEOPATRA trial)
Use in Special Populations
Pregnancy
Category D
Embryofetal toxicity confirmed
Avoid unless benefits outweigh risks
Contraception during and 7 months post-therapy
Lactation
Excreted in low amounts in breast milk
Breastfeeding not recommended during and for 7 months after treatment
Pediatrics
Not approved
Safety and efficacy not established
Geriatrics
No dose adjustment required
Monitor cardiac function closely
Hepatic/Renal Impairment
No formal dosing recommendations
Generally well tolerated in renal impairment
Monitor for toxicity
Monitoring Parameters
HER2 overexpression confirmation by IHC 3+ or FISH-positive before initiation
LVEF baseline and every 3 months
Vital signs during infusion
Signs of CHF or pulmonary toxicity
CBC with differential if on combination chemotherapy
Liver function tests periodically
Renal function if clinically indicated
Comparative Pharmacology
Compared to Lapatinib
– Trastuzumab has more cardiotoxicity, but better tumor regression
Compared to Trastuzumab-DM1 (T-DM1, ado-trastuzumab emtansine)
– T-DM1 is used in resistant HER2+ cancers; includes cytotoxic agent
Compared to Pertuzumab
– Pertuzumab inhibits HER2 dimerization at different epitope; often used together
Compared to Biosimilars
– Biosimilars have equivalent efficacy, safety, and immunogenicity
Formulations Available
IV vials: 150 mg and 440 mg (powder for reconstitution)
SC formulation: fixed dose 600 mg/5 mL prefilled syringe
Biosimilars available globally
Requires refrigeration and protection from light
Regulatory and Legal Status
FDA and EMA approved
Included in NCCN and ESMO guidelines for HER2+ cancers
WHO Model List of Essential Medicines (trastuzumab)
Prescription-only
Not a controlled substance
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