DESCRIPTION
Trastuzumab
Mechanism of Action
• Recombinant humanized monoclonal antibody directed against the
extracellular domain (IV) of the HER2/neu growth factor receptor.
This receptor is overexpressed in several human cancers, including
25%–30% of breast cancers and up to 20% of gastric cancers.
• Precise mechanism(s) of action remains unknown.
• Downregulates expression of HER2/neu receptor.
• Inhibits HER2/neu intracellular signaling pathways.
• Induction of apoptosis through as yet undetermined mechanisms.
• Immunologic mechanisms may also be involved in antitumor activity,
and they include recruitment of antibody-dependent cellular
cytotoxicity (ADCC) and/or complement-mediated cell lysis.
Mechanism of Resistance
• Mutations in the HER2/neu growth factor receptor leading to
decreased binding affinity to trastuzumab.
• Decreased expression of HER2/neu receptors.
• Expression of P95HER2, a constitutively active, truncated form of the
HER2 receptor.
• Increased expression of HER3.
• Activation/induction of alternative cellular signaling pathways, such
as the IGF-1 receptor and/or the c-Met receptor.
Distribution
Distribution in body is not well characterized.
Metabolism
Metabolism of trastuzumab has not been extensively characterized. Halflife
is on the order of 6 days with a weekly schedule and a mean life of 16
days with the every 3-week schedule.
Chemotherapeutic and Biologic Drugs 431
T Indications
1. Metastatic breast cancer—First-line therapy in combination with
paclitaxel. Patient’s tumor must express HER2/neu protein to be
treated with this monoclonal antibody.
2. Metastatic breast cancer—Second- and third-line therapy as a single
agent in patients whose tumors overexpress the HER2/neu protein
.
3. Early-stage breast cancer—FDA-approved for the adjuvant therapy of
node-positive, HER2-overexpressing breast cancer as part of a treatment
regimen containing doxorubicin, cyclophosphamide, and either
paclitaxel or docetaxel.
4. Metastatic gastric and gastroesophageal junction adenocarcinoma—
FDA-approved in combination with cisplatin and capecitabine or
5-fluorouracil for the treatment of patients with HER2 overexpressing
metastatic gastric or gastroesophageal junction adenocarcinoma
who have not received prior treatment for metastatic disease.
Dosage Range
1. Recommended loading dose of 4 mg/kg IV administered over
90 minutes, followed by maintenance dose of 2 mg/kg IV on a
weekly basis. One week following the last weekly dose of Herceptin,
administer Herceptin at 6 mg/kg as an intravenous infusion over
30–90 minutes every three weeks.
2. Alternative schedule is to give a loading dose of 8 mg/kg IV administered
over 30–90 minutes, followed by maintenance dose of 6 mg/kg IV
every 3 weeks.
3. Administer Herceptin, alone or in combination with paclitaxel, at an
initial dose of 4 mg/kg as a 90-minute intravenous infusion followed
by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous
infusions until disease progression.
4. Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute
intravenous infusion followed by subsequent doses of 6 mg/kg as an
intravenous infusion over 30–90 minutes every three weeks until
disease progression.
Drug Interactions
Anthracyclines, taxanes—Increased risk of cardiotoxicity when trastuzumab
is used in combination with anthracyclines and/or taxanes.
Special Considerations
1. Caution should be exercised in treating patients with pre-existing cardiac
dysfunction. Careful baseline assessment of cardiac function (LVEF)
before treatment and frequent monitoring (every 3 months) of cardiac
function while on therapy. Trastuzumab should be held for >16%
absolute decrease in LVEF from a normal baseline value. Trastuzumab
T therapy should be stopped immediately in patients who develop clinically
significant congestive heart failure. When trastuzumab is used
in the adjuvant setting, cardiac function should be assessed every
6 months for at least 2 years following the completion of therapy.
2. Carefully monitor for infusion reactions, which typically occur during
or within 24 hours of drug administration. Administer initial
loading dose over 90 minutes and then observe patient for 1 hour
following completion of the loading dose. May need to treat with
diphenhydramine and acetaminophen. Rarely, in severe cases, may
need to treat with IV fluids and/or pressors.
3. Maintenance doses are administered over 30 minutes if loading dose
was well tolerated without fever and chills. However, if fever and
chills were experienced with loading dose, administer over 90 minutes.
4. Pregnancy category D.
Toxicity 1
Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue,
headache, bronchospasm, dyspnea, angioedema, and hypotension. Occur in
40%–50% of patients. Usually mild to moderate in severity and observed
most commonly with administration of the first infusion.
Toxicity 2
Nausea and vomiting, diarrhea. Generally mild.
Toxicity 3
Cardiotoxicity in the form of dyspnea, peripheral edema, and reduced left
ventricular function. Significantly increased risk when used in combination
with an anthracycline-based regimen. In most instances, cardiac dysfunction
is readily reversible.
Toxicity 4
Myelosuppression. Increased risk and severity when trastuzumab is
administered with chemotherapy.
Toxicity 5
Generalized pain, asthenia, and headache.
Toxicity 6
Pulmonary toxicity in the form of increased cough, dyspnea, rhinitis,
sinusitis, pulmonary infiltrates, and/or pleural effusions.
SPECIFICATION
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