SABCS 2021 Meeting News Preview - 6

Brief Summary of Full Prescribing Information
MARGENZA®
(margetuximab-cmkb) 250 mg/10 mL injection, for intravenous use
Initial U.S. approval: 2020
WARNING: LEFT VENTRICULAR DYSFUNCTION AND EMBRYO-FETAL TOXICITY
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.
INDICATIONS AND USAGE
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.
DOSAGE AND ADMINISTRATION
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. Dose Modification or Important Dosing Considerations - If a patient misses
a dose of MARGENZA, administer the scheduled dose as soon as possible. Adjust the administration schedule to
maintain a 3-week interval between doses. Left Ventricular Dysfunction - Assess left ventricular ejection fraction (LVEF)
before starting MARGENZA and regularly during treatment. Withhold MARGENZA dosing for at least 4 weeks for any of
the following: ≥ 16% absolute decrease in LVEF from pretreatment values; LVEF below institutional limits of normal (or
50% if no limits are available) and ≥ 10% absolute decrease in LVEF from pretreatment values. MARGENZA dosing may
be resumed if, within 8 weeks, LVEF returns to normal limits and absolute decrease from baseline is ≤ 15%. Permanently
discontinue MARGENZA if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than
3 occasions for LVEF decline. Infusion-Related Reactions - Decrease the rate of infusion for mild or moderate infusionrelated
reactions (IRRs). Interrupt the infusion for dyspnea or clinically significant hypotension. Permanently discontinue
MARGENZA dosing in patients with severe or life-threatening IRRs. Preparation for Administration - Administer as an
intravenous infusion after dilution. Preparation for Intravenous Infusion - Prepare solution for infusion, using aseptic
technique, as follows: Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. The solution is clear to slightly opalescent, colorless
to pale yellow or pale brown. Some visible, translucent, inherent proteinaceous particles may be present; Swirl the
vial(s) gently. Do not shake the vial(s); Calculate the required volume of MARGENZA needed to obtain the appropriate
dose according to patient's body weight. The calculated total dose volume should be rounded to the nearest 0.1 mL;
Withdraw appropriate volume of MARGENZA solution from the vial(s) using a syringe; Transfer MARGENZA into
an intravenous bag containing 100 mL or 250 mL 0.9% Sodium Chloride Injection, USP. Polyvinyl chloride (PVC)
intravenous bags or intravenous bags made with polyolefins (polyethylene and polypropylene) and polyamide or
polyolefins only or copolymer of olefins may be used. Do not use 5% Dextrose Injection, USP solution; The final
concentration of the diluted solution should be between 0.5 mg/mL to 7.2 mg/mL; Gently invert the intravenous bag
to mix the diluted solution. Do not shake the intravenous bag; Discard any unused portion left in the vial(s). Do not
administer as an intravenous push or bolus. Do not mix MARGENZA with other drugs. Storage of Diluted Solution - The
product does not contain a preservative. If diluted infusion solution is not used immediately, it can be stored at room
temperature up to 4 hours or stored refrigerated at 2°C to 8°C (36°F to 46°F) up to 24 hours. If refrigerated, allow
the diluted solution to come to room temperature prior to administration. Do not freeze. 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.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
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 HER2directed
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).
Symptoms 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% in 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
The following adverse reactions are discussed in greater detail in other sections of the label: Left Ventricular
Dysfunction; Embryo-Fetal Toxicity; Infusion-Related 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. Table 1 in the full Prescribing Information
summarizes Adverse Reactions (> 10%) in Patients with Metastatic HER2-Positive Breast Cancer Who Received
MARGENZA in SOPHIA. Percentage values displayed in parentheses reflect: (MARGENZA + Chemotherapy (n = 264)
All Grades, Grade 3 or 4, Trastuzumab + Chemotherapy (n = 266) All Grades, Grade 3 or 4). Adverse Reactions are as
follows: General disorders and administration site conditions: Fatigue/Asthenia (57, 7, 47, 4.5); Pyrexia (19, 0.4, 14,
0.4). Gastrointestinal disorders: Nausea (33, 1.1, 32, 0.4); Diarrhea (25, 2.3, 25, 2.3); Vomiting (21, 0.8, 14, 1.5);
Constipation (19, 0.8, 17, 0.8); Abdominal paina
0); Palmar-plantar erythrodysesthesia (13, 0, 15, 3). Nervous System Disorders: Headacheb
(17, 1.5, 21, 1.5). Skin and Subcutaneous tissue: Alopecia (18, 0, 15,
(19, 0, 16, 0); Peripheral
neuropathyc (16, 1.1, 15, 2.3). Respiratory, thoracic and mediastinal disorders: Cough (14, 0.4, 12, 0); Dyspnea
(13, 1.1, 11, 2.3). Metabolism and nutrition disorders: Decreased appetite (14, 0.4, 14, 0.4). Musculoskeletal and
connective tissue disorders: Arthralgia/Myalgia (14, 0.4, 12, 0.8); Extremity pain (11, 0.8, 9, 0). Injury, poisoning and
procedural complications: Infusion-related reaction (13, 1.5, 3, 0). a
lower abdominal pain and upper abdominal pain; b
Includes headache and migraine; c
Includes abdominal pain, abdominal discomfort,
Includes peripheral neuropathy,
peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy. Clinically relevant adverse reactions in
≤ 10% of patients who received MARGENZA in combination with chemotherapy included: dizziness and stomatitis
(10%) each, decreased weight, dysgeusia, rash, and insomnia (6%) each, hypertension (5%), and syncope
(1.5%). Table 2 in the full Prescribing Information summarizes Select Laboratory Abnormalities (≥ 20%) That
Worsened from Baseline in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in
SOPHIA. Percentage values displayed in parentheses reflect: (MARGENZA + chemotherapy1
4, Trastuzumab + chemotherapy1
All Grades, Grade 3 or
All Grades, Grade 3 or 4). Laboratory abnormalities are as follows: Hematology:
Decreased hemoglobin (52, 3.2, 43, 2.4); Decreased leukocytes (40, 5, 36, 3.2); Decreased neutrophils (34, 9,
28, 9); Increased aPTT (32, 3.4, 34, 4.3); Decreased lymphocytes (31, 4.4, 38, 4.4); Increased INR (24, 1.2, 25,
0.4). Chemistry: Increased creatinine (68, 0.4, 60, 0); Increased ALT (32, 2, 30, 0.8); Increased lipase (30, 6, 24,
3.2); Increased AST (23, 2, 22, 0.8); Increased alkaline phosphatase (21, 0, 23, 0.8). 1
The denominator used to
calculate the rate varied from 229 to 253 based on the number of patients with a baseline value and at least one
post-treatment value. aPTT: activated partial thromboplastin time; INR: prothrombin international normalized ratio;
ALT: alanine aminotransferase; AST: aspartate aminotransferase. Immunogenicity - As with all therapeutic proteins,
there is potential for immunogenicity with MARGENZA. The detection of antibody formation is highly dependent on
assay sensitivity and specificity. Additionally, the observed incidence of antibody (including neutralizing antibody)
positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of
sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence
of antibodies to MARGENZA in the studies described below with the incidence of antibodies in other studies or to other
products may be misleading. In SOPHIA, samples were obtained from patients on MARGENZA for immunogenicity
testing at baseline, every 2 cycles, and at end of study therapy. All patients enrolled in SOPHIA received trastuzumab
previously, and treatment-emergent anti-margetuximab antibodies were observed in 4 patients (1.7%). Of these 4
patients, anti-margetuximab antibodies were detected prior to Cycle 7 of MARGENZA dosing in 1 patient, and more
than 2 months after the last MARGENZA dose in 3 patients. In the infusion substudy, treatment-emergent antimargetuximab
antibodies were observed in 2 patients (3.8%). Of these 2 patients, anti-margetuximab antibodies were
detected prior to Cycle 3 of MARGENZA dosing in 1 patient, and more than 6 months after the last MARGENZA dose
in 1 patient. Due to the limited number of patients who developed anti-margetuximab antibodies during treatment with
MARGENZA, the impact of anti-margetuximab antibodies on the PK, safety and efficacy of MARGENZA is unknown.
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: Risk Summary - 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. Clinical
Considerations - Fetal/Neonatal Adverse Reactions: 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. Data - Animal Data: In an enhanced
pre- and post-natal development study, pregnant cynomolgus monkeys received intravenous doses of 50 or 100 mg/kg
margetuximab-cmkb once every 3 weeks starting on GD 20 and until delivery. Animal exposures at doses of 50 and
100 mg/kg were 3 and 6 times, respectively, the human exposures at the recommended dose, based on Cmax
. Treatment
with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75. An infant mortality
occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb. Clinical findings
included tubular degeneration/necrosis and tubular dilatation in the kidney. Maternal doses of 50 and 100 mg/kg
resulted in decreased infant kidney weights and histologic immature nephrons. Measurable serum concentrations
of margetuximab-cmkb were observed in infant animals, which is consistent with margetuximab-cmkb crossing the
placenta. Lactation: Risk Summary - 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. Females and Males of Reproductive Potential - MARGENZA
can cause fetal harm when administered to a pregnant woman. Pregnancy Testing - Verify pregnancy status of females
of reproductive potential prior to initiation of MARGENZA. Contraception - Females: Advise females of reproductive
potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA.
Pediatric Use: Safety and effectiveness of MARGENZA have not been established in pediatric patients. Geriatric 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%).
HOW SUPPLIED/STORAGE AND HANDLING
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 as: One 250 mg/10 mL (25 mg/mL) single-dose vial -
NDC 74527-022-02; Four 250 mg/10 mL (25 mg/mL) single-dose vials - NDC 74527-022-03. 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.
PATIENT COUNSELING INFORMATION
Left Ventricular Dysfunction - Advise patients to contact a healthcare 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.
Manufactured by:
MacroGenics, Inc.
9704 Medical Center Drive
Rockville, MD 20850-3343
U.S. License No. 2139
MARGENZA is a registered trademark of MacroGenics, Inc.
©2021 MacroGenics, Inc. All rights reserved.
10/2021
US-COM-MGA-2100140
https://www.margenza.com/

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