Margetuximab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Black Box Warning
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LEFT VENTRICULAR DYSFUNCTION AND EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
Left Ventricular Dysfunction:: (MARGENZA may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue MARGENZA treatment for a confirmed clinically significant decrease in left ventricular function)
Embryo-Fetal Toxicity: (Exposure to MARGENZA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception)
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Overview
Margetuximab is a HER2/neu receptor antagonist that is FDA approved for the treatment of of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Left Ventricular Dysfunction Embryo-Fetal Toxicity Infusion-Related Reactions.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
MARGENZA is indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease
Recommended Doses and Schedules: The recommended dose of MARGENZA is 15 mg/kg, administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
Administer MARGENZA as an intravenous infusion at 15 mg/kg over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses.
On days when both MARGENZA and chemotherapy are to be administered, MARGENZA may be administered immediately after chemotherapy completion.
Refer to the respective Prescribing Information for each therapeutic agent administered in combination with MARGENZA for the recommended dosage information, as appropriate.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Margetuximab in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Margetuximab in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Margetuximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Margetuximab in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Margetuximab in pediatric patients.
Contraindications
None
Warnings
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LEFT VENTRICULAR DYSFUNCTION AND EMBRYO-FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
Left Ventricular Dysfunction:: (MARGENZA may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue MARGENZA treatment for a confirmed clinically significant decrease in left ventricular function)
Embryo-Fetal Toxicity: (Exposure to MARGENZA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception)
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Left Ventricular Dysfunction: Left ventricular cardiac dysfunction can occur with MARGENZA. In SOPHIA, left ventricular dysfunction occurred in 1.9% of patients treated with MARGENZA. MARGENZA has not been studied in patients with a pretreatment LVEF value of < 50%, a prior history of myocardial infarction or unstable angina within 6 months, or congestive heart failure NYHA class II-IV.
Withhold MARGENZA for ≥ 16% absolute 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 MARGENZA if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than 3 occasions due to LVEF decline
Cardiac Monitoring: Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
*Baseline LVEF measurement within 4 weeks prior to initiation of MARGENZA
- LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of MARGENZA
- Repeat LVEF measurement at 4-week intervals if MARGENZA is withheld for significant left ventricular cardiac dysfunction
Embryo-Fetal Toxicity: Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of MARGENZA in pregnant women to inform the drug-associated risk. 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. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day (GD) 20 until delivery resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax.
Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA. Advise pregnant women and females of reproductive potential that exposure to MARGENZA 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 and for 4 months following the last dose of MARGENZA
Infusion-Related Reactions: MARGENZA can cause infusion-related reactions (IRRs).ymptoms may include fever, chills, arthralgia, cough, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, rash, urticaria, and dyspnea.
In SOPHIA, IRRs were reported by 13% of patients on MARGENZA plus chemotherapy. Most of the IRRs occur during Cycle 1. Grade 3 IRRs were reported in 1.5% of MARGENZA-treated patients. All IRRs resolved within 24 hours, irrespective of severity. In SOPHIA, IRRs leading to interruption of treatment occurred in 9% of patients treated with MARGENZA and chemotherapy. One patient (0.4%) on MARGENZA discontinued treatment due to IRR.
An infusion substudy in 88 patients in SOPHIA evaluated MARGENZA administered over 120 minutes for the initial dose, then 30 minutes from Cycle 2 forward. IRRs were ≤ Grade 2 and most occurred during the first (120 minutes) administration of MARGENZA. From Cycle 2 onward, one patient (1.1%) had an IRR (Grade 1).
Monitor patients for IRRs during MARGENZA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. Monitor patients carefully until resolution of signs and symptoms.
In patients who experience mild or moderate IRRs, consider premedications, including antihistamines, corticosteroids, and antipyretics. Decrease the rate of infusion for mild or moderate IRRs. Interrupt MARGENZA infusion in patients experiencing dyspnea or clinically significant hypotension and intervene with medical therapy which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanently discontinue MARGENZA in all patients with severe or life-threatening IRRs.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. The safety of MARGENZA was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA. Patients were randomized (1:1) to receive either MARGENZA 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy. Among patients who received MARGENZA, 40% were exposed for 6 months or longer and 11% were exposed for greater than one year.
Serious adverse reactions occurred in 16% of patients who received MARGENZA. Serious adverse reactions in > 1% of patients included febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%) and infusion related reactions (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received MARGENZA, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%).
Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received MARGENZA. Adverse reactions which resulted in permanent discontinuation in > 1% of patients who received MARGENZA included left ventricular dysfunction and infusion-related reactions.
Dosage interruptions due to an adverse reaction occurred in 11% of patients who received MARGENZA. Adverse reactions which required dosage interruption in > 5% of patients who received MARGENZA included infusion-related reactions.
Postmarketing Experience
There is limited information regarding Margetuximab Postmarketing Experience in the drug label.
Drug Interactions
Anthracyclines: Patients who receive anthracyclines less than 4 months after stopping MARGENZA may be at increased risk of cardiac dysfunction. While this interaction has not been studied with MARGENZA, clinical data from other HER2-directed antibodies warrants consideration. Avoid anthracycline-based therapy for up to 4 months after stopping MARGENZA. If concomitant use is unavoidable, closely monitor patient's cardiac function.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Margetuximab in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Margetuximab in women who are pregnant.
Labor and Delivery
Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on use of MARGENZA in pregnant women to inform the drug-associated risk. 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. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks, starting at gestational day (GD) 20 until delivery, resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax. Advise patients of potential risks to a fetus. There are clinical considerations if MARGENZA is used during pregnancy or within 4 months prior to conception. Estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 - 4% and 15 - 20%, respectively. Monitor women who received MARGENZA 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.
Nursing Mothers
There is no information regarding presence of MARGENZA in human milk, effects on the breastfed child, or effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother's clinical need for MARGENZA treatment and any potential adverse effects on the breastfed child from MARGENZA or from the underlying maternal condition. This consideration should also take into account the MARGENZA washout period of 4 months
Pediatric Use
Safety and effectiveness of MARGENZA have not been established in pediatric patients.
Geriatic Use
Of the 266 patients treated with MARGENZA 20% were 65 years of age or older and 4% were 75 years or older. No overall differences in efficacy were observed between patients ≥ 65 years of age compared to younger patients. There was a higher incidence of Grade ≥ 3 adverse reactions observed in patients age 65 years or older (56%) compared to younger patients (47%), as well as adverse reactions associated with potential cardiotoxicity (35% vs 18%).
Gender
There is no FDA guidance on the use of Margetuximab with respect to specific gender populations.
Race
There is no FDA guidance on the use of Margetuximab with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Margetuximab in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Margetuximab in patients with hepatic impairment.
Females of Reproductive Potential and Males
Contraception: Females Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA
Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA.
Immunocompromised Patients
There is no FDA guidance one the use of Margetuximab in patients who are immunocompromised.
Administration and Monitoring
Administration
- Administer diluted infusion solution intravenously over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses. Administer through an intravenous line containing a sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 micron in-line or add-on filter.
- Do not co-administer other drugs through the same infusion line.
Monitoring
Cardiac Monitoring: Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
*Baseline LVEF measurement within 4 weeks prior to initiation of MARGENZA
- LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of MARGENZA
- Repeat LVEF measurement at 4-week intervals if MARGENZA is withheld for significant left ventricular cardiac dysfunction
Embryo-Fetal Toxicity: Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of MARGENZA in pregnant women to inform the drug-associated risk. 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. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day (GD) 20 until delivery resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax.
Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA. Advise pregnant women and females of reproductive potential that exposure to MARGENZA 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 and for 4 months following the last dose of MARGENZA
Monitor patients for IRRs during MARGENZA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. Monitor patients carefully until resolution of signs and symptoms.
Monitor women who received MARGENZA 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.
IV Compatibility
There is limited information regarding the compatibility of Margetuximab and IV administrations.
Overdosage
There is limited information regarding Margetuximab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Margetuximab Pharmacology in the drug label.
Mechanism of Action
Margetuximab-cmkb binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). Upon binding to HER2-expressing tumor cells, margetuximab-cmkb inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain and mediates antibody-dependent cellular cytotoxicity (ADCC).
In vitro, 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 lead to greater in vitro ADCC and NK cell activation.
Structure
There is limited information regarding Margetuximab Structure in the drug label.
Pharmacodynamics
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of margetuximab-cmkb have not been fully characterized.
Pharmacokinetics
Following the approved recommended dosage, the steady-state geometric mean (%CV) Cmax of margetuximab-cmkb is 466 (20%) µg/mL and AUC0-21d is 4120 (21%) µg.day/mL in patients with HER2-positive relapsed or refractory advanced breast cancer. Margetuximab-cmkb undergoes both linear and nonlinear elimination. After a single dose, margetuximab-cmkb Cmax and AUC0-21d increase in an approximately dose proportional manner from 10 to 18 mg/kg (0.67 to 1.2 times the approved recommended dose). At the approved recommended dosage, time to steady-state was 2 months, and accumulation ratio was 1.65 based on AUC0-21d. No clinically significant differences in margetuximab-cmkb exposure were observed when infusion time was reduced from 120 minutes to 30 minutes.
Distribution: Margetuximab-cmkb geometric mean (%CV) steady-state volume of distribution is 5.47 L (22%).
Elimination: The geometric mean (%CV) terminal half-life of margetuximab-cmkb is 19.2 days (28%) and clearance is 0.22 L/day (24%). Four months after margetuximab-cmkb discontinuation, concentrations decrease to approximately 3% of the steady-state trough serum concentration.
Metabolism: Margetuximab-cmkb is expected to be metabolized into small peptides by catabolic pathways.
Specific Populations: No clinically significant differences in margetuximab-cmkb PK were observed based on age (29 to 83 years), sex, race (Caucasian, Black, Asian), mild to moderate (CLcr 30 to 89 mL/min estimated using the Cockcroft-Gault equation) renal impairment, mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 ULN and any AST), HER2 expression level (0 to 3 by IHC), tumor burden (2 – 317 mm), ECOG score (0 to 2), albumin (24 to 50 g/L), FCGR3A (CD16A), FCGR2A (CD32A) and FCGR2B (CD32B) genotype, number of metastatic sites (≤ 2 or > 2), number of prior therapy lines (≤ 2 or > 2) or concurrent chemotherapies (capecitabine, gemcitabine, eribulin and vinorelbine).
The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without hemodialysis, and moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin >3 ULN and any AST) on margetuximab-cmkb PK is unknown.
Nonclinical Toxicology
Studies have not been performed to evaluate carcinogenic or mutagenic potential of margetuximab-cmkb.
Animal fertility studies have not been conducted with margetuximab-cmkb. In repeat-dose toxicity studies of up to 13-week duration, margetuximab-cmkb had no effect on male and female reproductive organs in sexually mature cynomolgus monkeys.
Clinical Studies
Metastatic Breast Cancer: The efficacy of MARGENZA plus chemotherapy was evaluated in SOPHIA (NCT02492711), a randomized, multicenter, open-label trial of 536 patients with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Patients were randomized (1:1) to MARGENZA plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (≤ 2, > 2), and number of metastatic sites (≤ 2, > 2). Patients were required to have progressed on or after the most recent line of therapy. Prior radiotherapy and hormonal therapy were allowed. Patients received MARGENZA intravenously at a dose of 15 mg/kg every 3 weeks administered over 120 minutes for the initial administration and then over 30 to 120 minutes thereafter. Trastuzumab was given intravenously at an initial dose of 8 mg/kg over 90 minutes, followed by 6 mg/kg over 30 minutes every 3 weeks thereafter. Patients were treated with MARGENZA or trastuzumab in combination with chemotherapy until disease progression or unacceptable toxicity.
Major efficacy outcome measures were progression-free survival (PFS) by blinded independent central (BICR) review and overall survival (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by BICR.
The median age was 56 years (range: 27-86); 78% of patients were < 65 years. The majority of patients were female (99.4%), and the majority were White (80%). Patients had an ECOG performance status of 0 (58%) or 1 (42%) at baseline. Forty seven percent had visceral disease, 57% had bone metastases, and 13% had brain metastases. Sixty percent were hormone receptor positive. The median number of prior lines of therapy in the locally advanced/metastatic setting was 2 (range: 1-4). All study patients had previously received trastuzumab, all but 1 patient had previously received pertuzumab, and 91% had previously received ado-trastuzumab emtansine.
How Supplied
MARGENZA (margetuximab-cmkb) injection is a clear to slightly opalescent, colorless to pale yellow or pale brown solution in a single-dose vial supplied
Storage
Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light until time of use.
Do not freeze. Do not shake.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Left Ventricular Dysfunction: 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
Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential that exposure to MARGENZA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MARGENZA and for 4 months following the last dose
Precautions with Alcohol
Alcohol-Margetuximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Margenza
Look-Alike Drug Names
There is limited information regarding Margetuximab Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.