Margetuximab (Monograph)

Brand name: Margenza
Drug class: Antineoplastic Agents
Molecular formula: C₆₄₈₄H₁₀₀₁₀N₁₇₂₆O₂₀₂₄S₄₂
CAS number: 1350624-75-7

Medically reviewed by Drugs.com on Nov 30, 2022. Written by ASHP.

Warning

Left Ventricular Dysfunction: Margetuximab-cmkb may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue margetuximab-cmkb treatment for a confirmed clinically significant decrease in left ventricular function. (See Left Ventricular Dysfunction under Cautions.)
Embryo-Fetal Toxicity: Exposure to margetuximab-cmkb during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. (See Embryo-Fetal Toxicity under Cautions.)

Introduction

Antineoplastic agent; a recombinant DNA-derived anti-HER2 monoclonal antibody.

Uses for Margetuximab

Metastatic Breast Cancer

Treatment of adults with metastatic HER2-positive breast cancer who have received ≥2 prior anti-HER2 regimens, at least one of which was for metastatic disease, in combination with chemotherapy.

In clinical practice guidelines, margetuximab is recommended among several potential third-line treatment options in patients with advanced, HER2-positive breast cancer.

Margetuximab Dosage and Administration

General

Pretreatment Screening

Evaluate left ventricular ejection fraction (LVEF) within 4 weeks prior to starting therapy.
Obtain pregnancy test in females of reproductive potential prior to initiating therapy.

Patient Monitoring

Monitor LVEF every 3 months during and upon completion of therapy. Repeat LVEF at 4 week intervals if therapy is withheld for significant left ventricular cardiac dysfunction.
Monitor for infusion-related reactions (IRRs) during infusion of margetuximab and as clinically indicated after completion.

Premedication and Prophylaxis

Consider premedications including antihistamines, corticosteroids, and antipyretics for patients who experience mild or moderate IRRs.

Other General Considerations

Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with margetuximab.

Administration

IV Administration

Administer by IV infusion. Administer through a sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 micron filter.

Must dilute prior to IV infusion.

Dilution

Determine required volume (to the nearest 0.1 mL) of margetuximab needed to obtain the dose based on the patient’s body weight. Withdraw the required volume and add to infusion bag containing 100 or 250 mL of 0.9% sodium chloride injection (final concentration 0.5–7.2 mg/mL); do not use 5% dextrose injection as a diluent.

Mix the final diluted solution for infusion by gentle inversion; do not shake.

Rate of Administration

Administer the initial IV infusion over 120 minutes, administer subsequent infusions over ≥30 minutes.

Dosage

Adults

Metastatic Breast Cancer

IV

Initial dosage: 15 mg/kg over 120 minutes.

Maintenance dosage: 15 mg/kg given over a minimum of 30 minutes every 3 weeks.

Continue treatment until disease progression or unacceptable toxicity.

On days when both margetuximab-cmkb and chemotherapy are to be administered, administer margetuximab immediately after chemotherapy completion.

If a dose of margetuximab-cmkb is missed, administer the dose as soon as possible, then adjust the administration schedule to maintain a 3-week interval between doses.

Dosage Modification for Toxicity

Cardiovascular Toxicity

Discontinue margetuximab for ≥4 weeks in patients with an absolute decrease in LVEF ≥16% from baseline or those with an LVEF below institutional limits of normal (or 50% if no limits are available) and a ≥10% absolute decrease in LVEF from pretreatment values. Resume if the LVEF returns to normal within 8 weeks and the absolute decrease from baseline is ≤15%. Permanently discontinue if LVEF decline persists for >8 weeks or therapy is interrupted on >3 occasions for LVEF decline.

Infusion-related Reactions

Decrease infusion rate for mild or moderate infusion-related reactions. Stop the infusion for dyspnea or clinically significant hypotension. Permanently discontinue margetuximab in patients with severe or life-threatening infusion-related reactions.

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations.

Renal Impairment

The manufacturer makes no specific dosage recommendations.

Geriatric Patients

The manufacturer makes no specific dosage recommendations.

Cautions for Margetuximab

Contraindications

None.

Warnings/Precautions

Warnings

Left Ventricular Dysfunction

Risk of left ventricular dysfunction (i.e., LVEF reduction). Evaluate cardiac function prior to and during treatment. Not studied in patients with a pretreatment LVEF value of <50%, prior history of MI or unstable angina within 6 months, or NYHA class II-IV CHF.

Withhold margetuximab for a ≥16% decrease in LVEF from pretreatment values or LVEF value below institutional limits of normal (or 50% if no limits are available) and ≥10% absolute decrease in LVEF from pretreatment values. Permanently discontinue margetuximab if LVEF decline persists for >8 weeks, or if dosing is interrupted on >3 occasions due to LVEF decline.

Conduct a thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or multigated acquisition scan with therapy.

Embryo-fetal Toxicity

Risk of fetal harm based on findings in animals and mechanism of action.

Verify pregnancy status of females of reproductive potential prior to initiation of margetuximab. Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of margetuximab.

Other Warnings and Precautions

Infusion-related Reactions

Risk of infusion-related reactions (IRRs). Symptoms may include fever, chills, arthralgia, cough, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, rash, urticaria, and dyspnea.

Monitor patients for IRRs during administration and as clinically indicated after completion of infusion. Ensure that medications and emergency equipment are available to treat IRRs.

Premedications (e.g., antihistamines, corticosteroids, antipyretics) may be considered for mild or moderate IRRs.

Decrease infusion rate for mild or moderate IRRs, and interrupt infusion for dyspnea or clinically significant hypotension. Intervene with medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen) as appropriate. Carefully monitor patients until complete resolution of signs and symptoms. Permanently discontinue margetuximab in patients with severe or life-threatening IRRs.

Immunogenicity

Potential for immunogenicity with margetuximab. Treatment-emergent anti-margetuximab antibodies observed in clinical studies. However, impact on pharmacokinetics, safety, and efficacy not known.

Specific Populations

Pregnancy

May cause fetal harm. Advise patients of potential risks to fetus.

There are clinical considerations if margetuximab is used during pregnancy or within 4 months prior to conception. Monitor women who received margetuximab during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

Lactation

Not known whether distributed into human milk or if the drug has any effect on milk production or the nursing infant.

Consider known benefits of breast-feeding along with the mother’s clinical need for margetuximab and any potential adverse effects of the drug or disease on the infant.

Females and Males of Reproductive Potential

Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of childbearing potential to use effective contraception while receiving margetuximab and for 4 months after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy relative to younger patients. There was a higher incidence of grade 3 and higher adverse reactions observed in patients ≥65 years compared to younger patients, as well as adverse reactions associated with potential cardiotoxicity.

Hepatic Impairment

The effect of moderate (total bilirubin >1.5 to ≤3 times the upper limit of normal [ULN] and any AST) or severe (total bilirubin >3 times the ULN and any AST) hepatic impairment on the pharmacokinetics of margetuximab is unknown. No clinically significant differences in pharmacokinetics were observed in mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 ULN and any AST).

Renal Impairment

The effect of severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease (with or without hemodialysis) on the pharmacokinetics of margetuximab is unknown. No clinically significant differences in pharmacokinetics were observed in mild to moderate renal impairment (Cl_cr 30–89 mL/minute).

Common Adverse Effects

Adverse effects reported in >10% of patients receiving margetuximab-cmkb in combination with chemotherapy include fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

Drug Interactions

Anthracyclines

Increased risk of cardiac toxicity in patients who receive anthracyclines and HER2-directed antibodies. Avoid anthracycline-based chemotherapy for up to 4 months after stopping margetuximab. If concomitant use cannot be avoided, monitor cardiac function closely.

Margetuximab Pharmacokinetics

Absorption

Onset

Time to steady state is approximately 2 months.

Elimination

Metabolism

Expected to be metabolized into small peptides via catabolic pathways.

Half-life

19.2 days.

Special Populations

Pharmacokinetics do not appear to be affected by sex, age, race, mild or moderate renal impairment, or mild hepatic impairment.

The effect of severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease (with or without hemodialysis) on the pharmacokinetics of margetuximab is unknown.

The effect of moderate (total bilirubin >1.5 to ≤3 times the ULN and any AST) or severe (total bilirubin >3 times the ULN and any AST) hepatic impairment on the pharmacokinetics of margetuximab is unknown.

Stability

Storage

Parenteral

Injection concentrate

2–8°C in original carton; protect from light. Do not freeze or shake.

Diluted solution

If diluted product not used immediately, may store at room temperature for up to 4 hours or refrigerate at 2–8°C up to 24 hours.

Compatibility

Parenteral

May use infusion bags made of polyvinyl chloride, polyolefins and polyamide, polyolefins, or copolymer of olefins.

Dilute only in 0.9% sodium chloride injection to a final concentration of 0.5–7.2 mg/mL; do not use 5% dextrose injection.

Actions

A chimeric, Fc-engineered anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody that shares epitope specificity and Fc-independent antiproliferative effects with trastuzumab.
Produced by recombinant DNA technology in a mammalian cell culture.
Binds to extracellular domain of the HER2 receptor. Upon binding, inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain, and mediates antibody-dependent cellular cytotoxicity (ADCC).
The modified Fc region of margetuximab-cmkb increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes are thought to increase activation of innate and adaptive anti-HER2 immune responses relative to trastuzumab.

Advice to Patients

Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness, or loss of consciousness.
Advise women to inform their clinician if they are or plan to become pregnant or plan to breastfeed. Advise pregnant women and females of reproductive potential that exposure to margetuximab during pregnancy or within 4 months prior to conception can result in fetal harm.
Advise females of reproductive potential to use effective contraception during treatment with margetuximab and for 4 months following the last dose
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.