Version May 2024
Margetuximab may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue margetuximab treatment for a confirmed clinically significant decrease in left ventricular function.
Exposure to margetuximab during pregnancy can cause embryofetal harm. Advise patients of the risk and need for effective contraception.
Note: Consider premedications (including antihistamines, corticosteroids, and antipyretics) with future cycles if a mild to moderate infusion reaction occurs. Actively manage modifiable cardiac risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) before initiating treatment (Ref).
B reast cancer, metastatic, HER2+: IV: 15 mg/kg once every 3 weeks (in combination with chemotherapy); continue until disease progression or unacceptable toxicity (Ref).
Missed dose:If a dose is missed, administer the scheduled dose as soon as possible and adjust the administration schedule to maintain a 3-week interval between doses.
Kidney function estimated with the Cockroft-Gault equation.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, mild to moderate impairment had no clinically significant effect on margetuximab pharmacokinetics.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
End stage renal disease (with or without hemodialysis): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, mild impairment had no clinically significant effect on margetuximab pharmacokinetics.
Moderate (total bilirubin >1.5 to ≤3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).
|
Adverse reaction |
Severity |
Margetuximab modification |
|---|---|---|
|
a Asymptomatic heart disease: Consider initiating heart failure medications (eg, angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker, and/or beta-blockers) in patients with asymptomatic (stage B) heart disease (ASCO [Armenian 2017], ESC (Lyon 2022]). For mild cardiac dysfunction, continue treatment with close cardiovascular monitoring; for moderate dysfunction, consider continuing treatment with close cardiovascular monitoring - initiation of heart failure medications is recommended; for severe dysfunction, interrupt treatment and utilize a multidisciplinary approach when deciding if/when to restart - initiation of heart failure medications is recommended (ESC [Lyon 2022]). Symptomatic heart disease: Initiate heart failure medications; for mild cardiac dysfunction, consider a multidisciplinary approach for decisions regarding treatment interruption versus continuation; for moderate or severe cardiac dysfunction, interrupt treatment and consider a multidisciplinary approach for decisions regarding treatment reinitiation (ESC [Lyon 2022]). b Medications and emergency equipment to treat infusion reactions should be available for immediate use during margetuximab administration. | ||
|
Cardiovascular toxicitya: left ventricular dysfunction |
Left ventricular ejection fraction (LVEF) ≥16% absolute decrease from pretreatment values |
Withhold margetuximab for at least 4 weeks; may resume if LVEF returns to normal limits and absolute decrease from baseline is ≤15% within 8 weeks. Permanently discontinue margetuximab if LVEF decline persists for >8 weeks, or if dosing is interrupted for LVEF decline on more than 3 occasions. |
|
LVEF below institutional limits of normal (or <50% if no limits are available) and ≥10% absolute decrease in LVEF from pretreatment values |
Withhold margetuximab for at least 4 weeks; may resume if LVEF returns to normal limits and absolute decrease from baseline is ≤15% within 8 weeks. Permanently discontinue margetuximab if LVEF decline persists for >8 weeks, or if dosing is interrupted for LVEF decline on more than 3 occasions. | |
|
Infusion-related reactionsb |
Mild or moderate reactions |
Decrease margetuximab infusion rate. Consider premedications (including antihistamines, corticosteroids, and antipyretics) with future cycles. |
|
Dyspnea or clinically significant hypotension |
Interrupt margetuximab infusion. | |
|
Severe or life-threatening reaction |
Permanently discontinue margetuximab. May require medical therapy intervention with epinephrine, corticosteroids, diphenhydramine, bronchodilators, and/or oxygen. | |
Refer to adult dosing.
Patients treated with margetuximab may be at an increased risk of developing left ventricular dysfunction. Decreased left ventricular ejection fraction (LVEF) has been observed with anti-human epidermal growth factor receptor 2 (HER2) therapies, including margetuximab. In addition, hypertension and syncope occurred with margetuximab in clinical trials. Therapy interruption and/or permanent discontinuation of therapy may be warranted, depending on degree of dysfunction; during clinical trials, decreases in LVEF were reversible for all patients with follow up (Ref). Patients with a history of clinically significant cardiac disease or LVEF <50% prior to treatment have not been studied.
Mechanism: Not clearly established; cardiac dysfunction may be, in part, directly due to human epidermal growth factor receptor 2 (HER2) inhibition (Ref).
Risk factors:
• Presence of risk factors for cardiovascular disease (eg, hypertension, diabetes, dyslipidemia, obesity, smoking) (Ref)
• In patients receiving other anti-HER2 therapies (ie, trastuzumab), risk is greater in (Ref):
- Patients with multiple cardiovascular risk factors during or after completion of therapy
- Age ≥60 at cancer treatment
- Compromised cardiac function at any time before or during treatment
- Use of anthracycline prior to anti-HER2 therapy (aka, sequential therapy)
Margetuximab administration may result in an infusion related reaction (IRR), including grade 3 IRRs. Symptoms may include fever, chills, arthralgia, cough, dyspnea, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, skin rash, and/or urticaria. Depending on the severity, patients who develop an IRR may require a decrease in the infusion rate, treatment interruption, premedications prior to future infusions, and/or discontinuation. In clinical trials, all IRRs resolved within 24 hours (regardless of severity).
Onset: Rapid; during clinical trials, most infusion reactions occurred during cycle 1.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions and incidences are for combination therapy with margetuximab + chemotherapy.
>10%:
Dermatologic: Alopecia (18%), palmar-plantar erythrodysesthesia (13%)
Gastrointestinal: Abdominal pain (17%), constipation (19%), decreased appetite (14%), diarrhea (25%), increased serum lipase (30%), nausea (33%) (table 1), vomiting (21%) (table 2)
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
33% |
32% |
264 |
266 |
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
21% |
14% |
264 |
266 |
Hematologic & oncologic: Decreased hemoglobin (52%; grades 3/4: 3%), increased INR (24%; grades 3/4: 1%), leukopenia (40%; grades 3/4: 5%), lymphocytopenia (31%; grade 3/4: 4%), prolonged partial thromboplastin time (32%; grade 3/4: 3%)
Hepatic: Increased serum alanine aminotransferase (32%), increased serum alkaline phosphatase (21%), increased serum aspartate aminotransferase (23%)
Nervous system: Fatigue (≤57%) (table 3), headache (19%) (table 4), peripheral neuropathy (16%; grade 3/4: 1%)
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
Comments |
|---|---|---|---|---|
|
57% |
47% |
264 |
266 |
Described as "Fatigue/Asthenia" |
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
19% |
16% |
264 |
266 |
Neuromuscular & skeletal: Arthralgia (≤14%) (table 5), asthenia (≤57%), limb pain (11%), myalgia (≤14%)
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
Comments |
|---|---|---|---|---|
|
14% |
12% |
264 |
266 |
Described as "Arthralgia/Myalgia" |
Renal: Increased serum creatinine (68%)
Respiratory: Cough (14%) (table 6), dyspnea (13%) (table 7)
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
14% |
12% |
264 |
266 |
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
13% |
11% |
264 |
266 |
Miscellaneous: Fever (19%) (table 8), infusion related reaction (13%; severe infusion related reaction: 1%)
|
Drug (Margetuximab + Chemotherapy) |
Comparator (Trastuzumab + Chemotherapy) |
Number of Patients (Margetuximab + Chemotherapy) |
Number of Patients (Trastuzumab + Chemotherapy) |
|---|---|---|---|
|
19% |
14% |
264 |
266 |
1% to 10%:
Cardiovascular: Hypertension (5%), left ventricular dysfunction (2%), syncope (2%)
Dermatologic: Skin rash (6%)
Endocrine & metabolic: Weight loss (6%)
Gastrointestinal: Dysgeusia (6%), stomatitis (10%)
Hematologic & oncologic: Febrile neutropenia (2%), neutropenia (2%)
Immunologic: Immunogenicity (2%)
Nervous system: Dizziness (10%), insomnia (6%)
<1%: Respiratory: Aspiration pneumonia, viral pneumonia
Frequency not defined: Cardiovascular: Decreased left ventricular ejection fraction
There are no contraindications listed in the manufacturer's labeling.
Special populations:
• Older adult: Patients ≥65 years of age experienced a higher incidence of ≥ grade 3 adverse reactions and a potential for cardiotoxicity compared to patients <65 years of age.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Margenza: Margetuximab-cmkb 250 mg/10 mL (10 mL) [contains polysorbate 80]
No
Solution (Margenza Intravenous)
250 mg/10 mL (per mL): $276.52
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Available through specialty distribution channels. Information regarding distribution is available at https://www.margenza.com/access-and-support or at 1-844-633-6469.
IV: Infuse the initial dose over 120 minutes; infuse subsequent doses over at least 30 minutes. Infuse via a sterile, nonpyrogenic, low-protein binding polyethersulfone 0.2 micron (in-line or add-on) filter. Do not administer as an IV push or bolus. If refrigerated, allow solution (diluted for infusion) to reach room temperature prior to administration. Do not infuse other medications through the same infusion line. Monitor for signs/symptoms of infusion reactions.
When administered on the same day with chemotherapy, administer chemotherapy first, followed by margetuximab immediately after chemotherapy.
Breast cancer, HER2-positive, metastatic: Treatment of metastatic HER2-positive breast cancer (in combination with chemotherapy) in adults who have received 2 or more prior anti-HER2 regimens, at least 1 of which was for metastatic disease.
Sound-alike/look-alike issues:
Margetuximab may be confused with brentuximab vedotin, cetuximab, dinutuximab, isatuximab, mepolizumab, mogamulizumab, rituximab, siltuximab, trastuzumab.
High alert medication:
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Anthracyclines: May enhance the adverse/toxic effect of Margetuximab. Specifically, the risk of cardiac dysfunction may be increased. Management: Avoid anthracycline-based therapy for up to 4 months after discontinuing margetuximab due to an increased risk of cardiac dysfunction. If anthracyclines must be used with margetuximab monitor cardiac function closely. Risk D: Consider therapy modification
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
[US Boxed Warning]: Exposure to margetuximab during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.
Verify pregnancy status prior to treatment initiation.
Exposure to margetuximab during pregnancy and within 4 months prior to pregnancy may cause fetal harm. Therefore, patients who may become pregnant should use effective contraception during treatment and for 4 months after the last margetuximab dose.
[US Boxed Warning]: Exposure to margetuximab during pregnancy can cause embryo-fetal harm.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to margetuximab may cause fetal harm. Patients should be monitored for oligohydramnios if exposure to margetuximab occurs during pregnancy or within 4 months prior to conception.
It is not known if margetuximab is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. In addition, consider that margetuximab has a washout period of 4 months following the last dose.
Conduct thorough cardiac assessment, including history, physical examination, and left ventricular ejection fraction (LVEF) determination (by echocardiogram or multiple-gated acquisition [MUGA] scan). Evaluate baseline LVEF measurement within 4 weeks prior to margetuximab initiation, LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of margetuximab treatment, and repeat LVEF measurement at 4-week intervals if margetuximab is withheld for significant left ventricular cardiac dysfunction.
Evaluate pregnancy status prior to treatment initiation (in females of reproductive potential). Monitor for signs/symptoms of infusion reactions during infusion (and after infusion as clinically indicated); monitor carefully until resolution of symptoms.
Additional cardiovascular monitoring (guideline recommendations): Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017], ESC [Lyon 2022]). Obtain a baseline echocardiography (transthoracic preferred) and repeat every 3 months during treatment (may reduce to every 4 to 6 months if normal and asymptomatic), assess more frequently if clinically indicated and obtain echocardiography within 12 months after completion; in high- and very high-risk patients, assess troponin and natriuretic peptide at baseline and consider assessing every 2 to 3 cycles, and at 3 and 12 months after completion of therapy; in low- and moderate-risk patients, consider troponin and natriuretic peptide at baseline (post-anthracycline), every 3 months and 12 months after completion of therapy (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends hepatitis B virus (HBV) screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Margetuximab is a chimeric Fc-engineered IgG1 kappa monoclonal antibody and human epidermal growth factor receptor (HER2) antagonist. Margetuximab binds to HER2-expressing tumor cells and inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain, and mediates antibody-dependent cellular cytotoxicity (ADCC). The modified Fc region of margetuximab increases in vitro binding to the activating Fc receptor and decreases binding to the inhibitory Fc receptor, leading to greater in vitro ADCC and NK cell activation.
Distribution: Vdss: 5.47 L.
Metabolism: Metabolized via catabolic pathways into small peptides.
Half-life elimination: 19.2 days.
Excretion: Clearance: 0.22 L/day.
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