Margetuximab, a recombinant DNA-derived anti-human epidermal growth factor receptor type 2 (HER2) monoclonal antibody, is an antineoplastic agent.1, 2
Margetuximab-cmkb is used, in combination with chemotherapy, for the treatment of adults with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens, at least one of which was for metastatic disease.1
The current indication for margetuximab-cmkb is based principally on the results of a randomized, multicenter, open-label trial (SOPHIA) in 536 adults with HER2-positive (defined as immunohistochemistry assay score of 3+ or amplification of HER2 by in situ hybridization) metastatic breast cancer who had received prior treatment with other anti-HER2 therapies and were progressing on the most recent treatment.1, 2 In this study, patients were randomized (stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting, and number of metastatic sites) to margetuximab-cmkb (15 mg/kg IV every 3 weeks) plus chemotherapy or trastuzumab (8 mg/kg IV initially, followed by 6 mg/kg IV every 3 weeks thereafter) plus chemotherapy. 1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 2
In the SOPHIA study, the primary measures of efficacy were progression-free survival assessed by an independent blinded central review and overall survival.1, 2 The median age of patients enrolled in the study was 56 years; 80% were white, over 99% were female, 57% had bone metastases, 13% had brain metastases, and 60% had hormone receptor-positive disease.1, 2 All patients had previously received trastuzumab, all but one patient had received pertuzumab, and 91% had previously received ado-trastuzumab emtansine.1, 2 Median progression-free survival was longer with margetuximab plus chemotherapy (5.8 months) than trastuzumab plus chemotherapy (4.9 months). 1, 2 Overall, there were 118 (44.4%) patients with disease progression and 12 (4.5%) deaths in the margetuximab plus chemotherapy group compared with 125 (46.3%) patients with disease progression and 10 (3.7%) deaths in the trastuzumab plus chemotherapy group.1 At the second planned interim analysis, the median overall survival was 21.6 months with margetuximab plus chemotherapy and 19.8 months with trastuzumab plus chemotherapy; however, the overall survival results were not mature at the time of analysis.2, 3
The first-line recommended treatment for metastatic HER2-positive breast cancer is a combination of trastuzumab, pertuzumab, and a taxane.11000 Trastuzumab deruxtecan is recommended for second-line treatment in patients whose breast cancer progresses after initial HER2-targeted treatment.11000 Multiple potential treatment options are recommended for third-line treatment, including margetuximab.11000 Although the improvement in progression-free survival observed with margetuximab in the principal efficacy study was only 0.9 months, margetuximab plus chemotherapy may provide an alternative to trastuzumab plus chemotherapy.3 Selection of an appropriate regimen should be made after discussing treatment schedules, routes of administration, and adverse effects with the patient.11000
Administer margetuximab-cmkb by IV infusion after dilution.1 Administer the drug through a sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 micron filter.1 Do not administer other drugs through the same line.1
Store unopened vials of margetuximab-cmkb at 2-8°C in the original packaging and protect from light; do not freeze.1
Margetuximab-cmkb must be diluted prior to administration.1 If not used immediately, store the diluted product at room temperature for up to 4 hours or refrigerated at 2-8°C up to 24 hours.1 Allow diluted refrigerated solutions to come to room temperature prior to administration.1 Do not freeze.1
Inspect the solution prior to administration; the solution should be clear to slightly opalescent, colorless to pale yellow or pale brown.1 Some translucent particles may be present.1 Gently swirl the vials.1
Determine the required volume (to the nearest 0.1 mL) of margetuximab-cmkb needed to obtain the dose based on the patient's body weight.1 Withdraw the required volume of margetuximab-cmkb using a syringe, and add to an infusion bag containing 100 or 250 mL of 0.9% sodium chloride injection (final concentration of 0.5-7.2 mg/mL); do not use 5% dextrose injection as a diluent.1 Infusion bags made of polyvinyl chloride, polyolefins and polyamide, polyolefins, or copolymer of olefins may be used.1 Discard any remaining contents of the vial.1
Mix the final diluted solution for infusion by gentle inversion; do not shake.1
Administer the initial IV infusion of margetuximab-cmkb over 120 minutes, then administer subsequent infusions over a minimum of 30 minutes.1
The recommended adult dosage of margetuximab-cmkb for the treatment of metastatic HER2-positive breast cancer is 15 mg/kg given by IV infusion every 3 weeks.1 Continue treatment until disease progression or unacceptable toxicity occurs.1
On days when both margetuximab and chemotherapy are to be administered, administer margetuximab immediately after chemotherapy completion.1
If a dose of margetuximab-cmkb is missed, administer the scheduled dose as soon as possible, and then adjust the administration schedule to maintain a 3-week interval between doses.1
Dosage Modification for Toxicity
Discontinue margetuximab-cmkb for at least 4 weeks in patients with an absolute decrease in left ventricular ejection fraction (LVEF) of ≥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.1 Margetuximab therapy may be resumed if the LVEF returns to normal within 8 weeks and the absolute decrease from baseline is ≤15%.1 Permanently discontinue margetuximab if LVEF decline persists for more than 8 weeks or therapy is interrupted on more than 3 occasions for LVEF decline.1
Decrease the infusion rate in patients with mild or moderate infusion-related reactions.1 Stop the infusion for dyspnea or clinically significant hypotension.1 Permanently discontinue margetuximab in patients with severe or life-threatening infusion-related reactions.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A black box warning about the cardiac risks associated with use of margetuximab-cmkb is included in the prescribing information.1 Therapy may lead to decreases in left ventricular ejection fraction (LVEF).1 Evaluate cardiac function prior to and during treatment.1 In the SOPHIA study, left ventricular dysfunction occurred in 1.9% of patients treated with margetuximab.1 Margetuximab has not been studied in patients with a pretreatment LVEF value less than 50%, a prior history of myocardial infarction or unstable angina within 6 months, or New York Heart Association (NYHA) class II-IV congestive heart failure.1
Withhold margetuximab for a 16% or greater absolute decrease in LVEF from pretreatment values, or LVEF value below institutional limits of normal (or 50% if no limits are available) and 10% or greater absolute decrease in LVEF from pretreatment values.1 Permanently discontinue margetuximab if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than 3 occasions due to LVEF decline.1
Conduct a thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or multigated acquisition (MUGA) scan with therapy.1
A black box warning about the embryo-fetal toxicity risks associated with margetuximab-cmkb is included in the prescribing information.1 There are no available data on use of margetuximab in pregnant women to inform the drug-associated risk; however, based on findings in animals and mechanism of action, margetuximab may cause fetal harm when administered to a pregnant woman.1
In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.1
In an animal reproduction study, IV administration of margetuximab to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day 20 until delivery resulted in oligohydramnios and delayed infant kidney development.1 Animal exposures were at least 3 times the human exposures at the recommended dose, based on the maximum serum concentration.1
Verify pregnancy status of females of reproductive potential prior to initiation of margetuximab.1 Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of margetuximab.1
Other Warnings and Precautions
Margetuximab can cause infusion-related reactions (IRRs).1 Symptoms may include fever, chills, arthralgia, cough, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, rash, urticaria, and dyspnea.1
Monitor patients for IRRs during margetuximab administration and as clinically indicated after completion of infusion.1 Ensure that medications and emergency equipment to treat IRRs are available for immediate use and monitor patients carefully until resolution of signs and symptoms.1
Consider premedications (e.g., antihistamines, corticosteroids, antipyretics) in patients who experience mild or moderate IRRs.1 Decrease the rate of infusion for mild or moderate IRRs, and interrupt margetuximab infusion in patients with dyspnea or clinically significant hypotension.1 Intervene with medical therapy (e.g., epinephrine, corticosteroids, diphenhydramine, bronchodilators, oxygen) as appropriate.1 Permanently discontinue margetuximab in all patients with severe or life-threatening IRRs.1
In the SOPHIA study, IRRs were reported by 13% of patients on margetuximab-cmkb plus chemotherapy; the majority occurring during cycle 1.1 Grade 3 IRRs occurred in 1.5% of margetuximab-treated patients with all resolving within 24 hours, irrespective of severity.1 Interruption of treatment due to IRRs occurred in 9% of patients treated with margetuximab and chemotherapy.1 One patient (0.4%) receiving margetuximab discontinued treatment due to IRR.1
An infusion substudy in 88 patients in SOPHIA evaluated margetuximab-cmkb administered over 120 minutes for the initial dose, then 30 minutes from cycle 2 forward.1 IRRs were grade 2 or less, and most occurred during the first administration of margetuximab.1 From cycle 2 onward, one patient (1.1%) had an IRR (grade 1).1
As with all therapeutic proteins, there is potential for immunogenicity with margetuximab.1 In the SOPHIA study, treatment-emergent anti-margetuximab antibodies were observed in 4 patients (1.7%).1 Anti-margetuximab antibodies also were detected in an infusion substudy.1 However, the impact of anti-margetuximab antibodies on the pharmacokinetics, safety, and efficacy of margetuximab is unknown due to the limited number of patients who developed such antibodies.1
Margetuximab may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Advise patients of potential risks to a fetus.1 There are clinical considerations if margetuximab is used during pregnancy or within 4 months prior to conception.1 Monitor women who received margetuximab during pregnancy or within 4 months prior to conception for oligohydramnios.1 If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.1
It is not known whether margetuximab is distributed into human milk or whether the drug has any effects on the nursing infant or on milk production.1 The benefits of breast-feeding should be considered along with the importance of margetuximab to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1 This consideration should also take into account the margetuximab-cmkb washout period of 4 months.1
Human IgG is distributed into human milk but does not enter neonatal or infant circulation in substantial amounts.1
Females and Males of Reproductive Potential
Prior to initiation of margetuximab, verify pregnancy status of females of reproductive potential and advise such females to use effective contraceptive methods while receiving the drug and for 4 months after the last dose.1
Safety and efficacy of margetuximab-cmkb in pediatric patients have not been established.1
Of the 266 patients treated with margetuximab-cmkb in the SOPHIA study, 20% were ≥65 years of age and 4% were ≥75 years of age.1 No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients.1 There was a higher incidence of grade 3 and higher adverse reactions observed in patients ≥65 years of age (56%) compared to younger patients (47%), as well as adverse reactions associated with potential cardiotoxicity (35% vs 18%).1
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.1 No clinically significant differences in pharmacokinetics were observed in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 ULN and any AST).1
The effect of severe renal impairment (creatinine clearance 15-29 mL/min) or end-stage renal disease (with or without hemodialysis) on the pharmacokinetics of margetuximab is unknown.1 No clinically significant differences in pharmacokinetics were observed in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute estimated using the Cockcroft-Gault equation).1
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.1
Patients who receive anthracyclines within 4 months of margetuximab discontinuation may be at increased risk of cardiac toxicity based on clinical data with other HER2-directed antibodies.1 Anthracycline-based chemotherapy should be avoided for up to 4 months after stopping margetuximab.1 If concomitant use cannot be avoided, monitor cardiac function closely.1
Margetuximab-cmkb is a chimeric, Fc-engineered anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody that shares epitope specificity and Fc-independent antiproliferative effects with trastuzumab.1, 2 Margetuximab is produced by recombinant DNA technology in a mammalian cell culture.1
Margetuximab binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2).1 Upon binding to HER2-expressing tumor cells, margetuximab inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain, and mediates antibody-dependent cellular cytotoxicity (ADCC).1 The modified Fc region of margetuximab increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B).1 These changes are thought to increase activation of innate and adaptive anti-HER2 immune responses relative to trastuzumab.1, 2
Following administration of margetuximab at the recommended dosage, time to steady state was 2 months.1 The terminal elimination half-life was 19.2 days.1 By 4 months after discontinuation, the serum concentration decreased to 3% of the steady-state trough serum concentration.1 Margetuximab is expected to be metabolized into small peptides via catabolic pathways.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV infusion | 25 mg/mL (250 mg) | Margenza® | MacroGenics |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions November 30, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. MacroGenics, Inc. MARGENZA® (margetuximab-cmkb) intravenous prescribing information. 2020 Dec. [Web]
2. Rugo HS, Im SA, Cardoso F, et al. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol . 2021;7(4):573-584. [Web]
3. US Food and Drug Administration, Center for Drug Evaluation and Research. Multi-discipline review NDA application number 761150Orig1s000. From FDA website. [Web]
11000. Giordano SH, Franzoi MAB, Temin S, et al. Systemic therapy for advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO guideline update. J Clin Oncol. Published online May 31, 2022. [PubMed]