Margetuximab-cmkb – Uses, Dosage, Side Effects, Interaction

Margetuximab (formerly MGAH22) is an Fc-engineered human/mouse chimeric anti-HER2 IgG1κ monoclonal antibody derived from the same mouse 4D5 clone that trastuzumab is derived from and is produced in Chinese Hamster Ovary? (CHO) culture.^[rx] Margetuximab binds to the same epitope on the HER2 extracellular domain and induces the same effects as trastuzumab. However, due to its modified Fc region, margetuximab binds with higher affinity to both CD16A variants and exhibits weaker binding to the inhibitory CD32B Fc receptor, resulting in more efficient antibody-dependent cell-mediated cytotoxicity (ADCC) and increased efficacy compared to trastuzumab.

Margextuximab was granted FDA approval on December 16, 2020, and is currently marketed under the trademark MARGENZA™ by MacroGenics, Inc.^[rx]

Mechanism of action

The HER family of transmembrane receptor tyrosine kinases (RTKs) includes the epidermal growth factor receptor (EGFR/HER1), HER2, HER3, and HER4 proteins; HER family members are generally involved in cell proliferation, angiogenesis, cell motility and invasiveness, and resistance to apoptosis.^[rx] HER2 is an oncoprotein whose overexpression is observed in breast, gastric, and other cancers.^[rx,rx] HER2 undergoes both ligand-independent homodimerization and ligand-dependent heterodimerization with other HER family members, followed by RTK phosphorylation and induction of downstream oncogenic signaling pathways. EGFR/HER2 dimerization promotes EGFR recycling and prolonged signalling while HER2/HER3 dimerization potently stimulates the downstream PI3K/AKT pathway; HER2 homodimerization directly activates the RAS/MAPK pathway and indirectly activates the PI3K/AKT pathway.^[rx]

The prototypical anti-HER2 therapy is trastuzumab, a monoclonal antibody (mAb) that binds the HER2 extracellular domain. Trastuzumab works through several mechanisms: trastuzumab binding induces receptor internalization and c-CBL-mediated HER2 degradation; effector cell binding to the Fc region of trastuzumab through CD16A results in antibody-mediated cell-dependent cytotoxicity (ADCC); finally, trastuzumab binding dampens HER2 activation, phosphorylation, and subsequent downstream oncogenic signalling.^[rx]

Despite demonstrated clinical? efficacy, trastuzumab efficacy is dependent on polymorphisms in CD16A. Effector cells such as natural killer (NK) cells and macrophages bind to mAbs through Fc receptors such as CD16A (FcγRIIIA), CD32A (FcγRIIA), and the inhibitory CD32B (FcγRIIB). CD16A has both high affinity (with valine at position 158; 158V) and low affinity (158F) variants; patients heterozygous or homozygous for the 158F variant have poorer responses to trastuzumab. Margetuximab is derived from the same mouse 4D5 clone as trastuzumab, but with a modified (MGFc0264) Fc region encoding five amino acid substitutions (L235V, F243L, R292P, Y300L, and P396L) to alter Fc receptor binding. Comparatively, margetuximab exhibits increased binding to both the high affinity (K_D of 89 nM vs 415 nM) and low affinity (K_D of 161 nM vs 1059 nM) CD16A receptors and decreased binding to the inhibitory CD32B receptor (K_D of 437 nM vs 52 nM). This, in turn, increases ADCC and anti-tumour? effect, especially in cells expressing lower levels of HER2 and in patients with the lower affinity 158F CD16A variant.^[rx,rx]

Margetuximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against the extracellular domain of the human epidermal growth factor receptor 2 (HER2) cell-surface protein. Also, margetuximab has an engineered Fc region that alters its affinity for the CD16A and CD32B effector cell receptors resulting in increased antibody-dependent cell-mediated cytotoxicity (ADCC). To date, the exposure-response and time course pharmacodynamic relationships of margetuximab remain incompletely characterized. Although generally well-tolerated, margetuximab carries a risk of infusion-related reactions, including symptoms such as fever?, fatigue?, nausea?, vomiting?, headache?, tachycardia?, hypotension?, and cutaneous manifestations such as a rash? or urticaria?; infusion reactions may require alterations to the infusion or, in serious reactions, discontinuation.^[rx]

Indications

• Margetuximab is an anti-HER2 monoclonal antibody indicated, in combination with chemotherapy?, for the treatment of metastatic HER2-positive breast cancer in adult patients who have received two or more prior anti-HER2 regimens with at least one prior regimen for metastatic disease.^[rx]
• Metastatic Breast Cancer With HER2 Positive
• Margetuximab is indicated, in combination with chemotherapy, for the treatment of adults 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.
• 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.

Use in Cancer

Margetuximab-cmkb is approved to be used with chemotherapy to treat:

• Breast cancer is HER2 positive (HER2+) and has metastasized (spread to other parts of the body). It is used in adults who have received two or more anti-HER2 treatments, including at least one for metastatic disease.

Margetuximab-cmkb is also being studied in the treatment of other types of cancer.

Contraindications

• Pregnancy
• Lactation
• Severe? Kidney? disease
• Severe Hepatic disease
• Anemia?,
• Low Wbc Count?
• Electrolyte Imbalance

Dosage?

Strengths: 25 mg/mL

Breast Cancer

• 15 mg/kg IV every 3 weeks
• Infuse the initial dose over 120 minutes and subsequent doses over 30 minutes.
• This drug may be administered immediately after the completion of chemotherapy.
• Continue treatment until the disease progresses or unacceptable toxicity.
• All therapeutic? proteins, including this drug, have the potential to produce an immune response.

Dose Adjustments

LEFT VENTRICULAR EJECTION FRACTION (LVEF):
Withhold dosing for at least 4 weeks for any of the following:

• If 16% or greater absolute decrease in LVEF from pretreatment values.
• LVEF below institutional limits of normal or 50% if no limits are available.
• If 10% or greater absolute decrease in LVEF from pretreatment values
• The dosing may be resumed if, within 8 weeks, LVEF returns to normal limits, and a total reduction from baseline? is 15% or less.
• Permanently discontinue 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 (IRRs):

• For mild? or moderate? IRRs, decrease the rate of infusion.
• For dyspnea? or clinically significant hypotension, interrupt the infusion.
• For patients with severe or life-threatening IRRs, permanently discontinue treatment.

Administration advice:

• Administer as an IV infusion after dilution.
• Infuse initial dose over 120 minutes and subsequent doses over 30 minutes.
• This drug may be administered immediately after the completion of chemotherapy.
• Do not administer as an IV push or bolus.
• Do not mix this drug with other drugs.
• Do not co-administer other drugs through the same infusion line.
• If a patient misses a dose, administer the scheduled dose as soon as possible, and then adjust the administration schedule to maintain a 3-week interval between doses.

Reconstitution/preparation techniques:

• The manufacturer product information should be consulted
• Cardiovascular: Left ventricular dysfunction by echocardiogram? or MUGA scan.
• Immunologic: Monitor or sign and symptoms for infusion-related reactions.
• Pregnancy: Monitor females who received this drug for oligohydramnios? during pregnancy or within 4 months prior to conception.

Patient advice:

• Advise pregnant women and females of reproductive potential that exposure to this drug 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 4 months after the last dose.
• Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
• Advise patients to report immediately any 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.

Side Effects

The Most Common

• headache
• fatigue
• nausea
• diarrhea
• vomiting
• constipation
• loss of appetite
• stomach pain
• hair loss
• pain in hands or feet
• joint or muscle pain
• rash with blisters on hands and feet

More common

• Back pain
• chest pain or tightness
• chills
• cough
• decreased urine output
• difficulty in moving
• dilated neck veins
• fever
• flushing
• headache
• irregular breathing
• irregular heartbeat
• muscle aches, cramps, pain, or stiffness
• nausea and vomiting
• pain in the joints
• redness, swelling, pain of the skin
• scaling of the skin on the hands and feet
• swelling of the face, fingers, feet, or lower legs
• swollen joints
• tingling of the hands and feet
• trouble breathing
• ulceration of the skin
• unusual tiredness or weakness
• weakness
• weight gain

Rare

• Arm or leg pain
• burning, numbness, tingling, or painful sensations
• constipation
• decreased appetite
• diarrhea
• hair loss, thinning of hair
• stomach pain
• unsteadiness or awkwardness
• weakness in the arms, hands, legs, or feet

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

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, the 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. The 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.

Lactation

There is no information regarding the presence of MARGENZA in human milk, its effects on the breastfed child, or its 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 the 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.