General Information

Margenza (margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that targets the HER2 oncoprotein.

Margenza is specifically indicated for use 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.

Margenza is supplied as a solution for intravenous administration. 

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 Margenzafor the recommended dosage information, as appropriate.

Mechanism of Action

Margenza (margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that targets the HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastroesophageal and other solid tumors. Similar to trastuzumab, margetuximab-cmkb inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain and mediates antibody-dependent cellular cytotoxicity (ADCC). Margetuximab-cmkb has been engineered to enhance the engagement of the immune system through MacroGenics’ Fc Optimization technology. In vitro, the modified Fc region of margetuximab-cmkb increases binding to the activating Fc receptor FCGR3A (CD16A) and decreases binding to the inhibitory Fc receptor FCGR2B (CD32B).  These changes lead to greater in vitro ADCC and NK cell activation. 

Side Effects

Adverse effects associated with the use of Margenza in combination with chemotherapy may include, but are not limited to, the following:

• 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
• extremity pain

The Margenza drug label comes with the following Black Box 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. 

Clinical Trial Results

The FDA approval of Margenza was based on SOPHIA, a randomized, open-label Phase 3 clinical trial evaluating Margenza plus chemotherapy compared to trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. All study patients had previously received trastuzumab, all but one patient had previously received pertuzumab, and 91% had previously received ado-trastuzumab emtansine, or T-DM1.

The study enrolled 536 patients who were randomized 1:1 to receive either Margenza (n=266) given intravenously at 15 mg/kg every three weeks or trastuzumab (n=270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every three weeks in combination with one of four chemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine) given at the standard doses. Intent-to-treat PFS analysis occurred after 265 PFS events.

The study showed a statistically significant 24% reduction in the risk of disease progression or death with Margenza plus chemotherapy compared with trastuzumab plus chemotherapy (median PFS 5.8 vs 4.9 months). The objective response rate  for Margenza plus chemotherapy was 22% and for trastuzumab plus chemotherapy was 16%.