U.S. Food and Drug Administration (FDA)-Approved Indications

Compendial Uses

Margetuximab-cmkb (Margenza) is a HER2/neu receptor antagonist 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. Margenza (margetuximab-cmkb), a HER2/neu receptor antagonist, is a chimeric Fc-engineered IgG1 kappa monoclonal antibody. Margetuximab-cmkb is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture.

Margenza 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).

Margenza carries a black box warning to include left ventricular dysfunction and embryo-fetal toxicity (

. 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. Exposure to Margenza during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.

Margetuximab-cmkb (Margenza) carries additional warnings and precautions that include infusion-related reactions (IRRS) (

. Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Per the prescribing information (

, the most common adverse drug reactions geater than 10% with margetuximab-cmkb in combination with chemotherapy include 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, and extremity pain.

Breast Cancer

Human epidermal growth factor receptor 2 (HER2) is a protein that is found on the surface of some cancer cells that promotes growth and is associated with aggressive disease and poor prognosis. The incidence of HER-2 positive breast cancer cases is estimated to be 15-20%. Monoclonal antibodies targeting HER2 have greatly improved outcomes; however, a significant number of patients progress to later lines of therapy. There continues and remains to be an unmet need for effective treatments for metastatic HER2-positive breast cancer (MacroGenics, 2020a).

On December 16, 2020, the FDA approved margetuximab-cmkb 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. The approval for Margenza was established on data from the SOPHIA, a randomized Phase 3 clinical trial.

In this study, Rugo et al. (2021) compared the clinical efficacy of margetuximab versus trastuzumab, each with chemotherapy, in patients with pretreated ERBB2 (formerly HER2)-positive advanced breast cancer (ABC). 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. This international, randomized, open-label, phase 3 clinical trial was comprised by a total of 536 patients who were randomized to receive margetuximab (n=266) or trastuzumab (n=270). The primary endpoints of the study were sequentially-assessed progression-free survival (PFS), determined by blinded, centrally-reviewed radiological review, followed by overall survival (OS). Additional key secondary endpoints were PFS by investigator assessment, objective response rate (ORR) and duration of response. The investigators determined that margetuximab improved primary PFS evidenced by a statistically significant 24% reduction in the risk of disease progression or death in margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy (hazard ratio [HR] = 0.76; 95% CI, 0.59-0.98; p=0.033; median PFS 5.8 vs 4.9 months). Following the second planned interim analysis of 270 deaths, the median OS was 21.6 months with margetuximab versus 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; p=0.33). Furthermore, margetuximab improved objective response rate over trastuzumab: 22% and 16% (p=0.06; October 10, 2018), and 25% vs 14% (p<0.001; September 10, 2019). The results of final OS analysis is anticipated in the second half of 2021. There was a greater incidence of infusion-related reactions with margetuximab (35 [13.3%] versus 9 [3.4%]); otherwise, safety was comparable. In conclusion, margetuximab with chemotherapy demonstrated acceptable safety with a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC following progression on 2 or more prior anti-ERBB2 therapies.

Requires Precertification:

Precertification of margetuximab-cmkb (Margenza) is required of all Aetna participating providers and members in applicable plan designs. For precertification of margetuximab-cmkb (Margenza), call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Criteria for Initial Approval

Breast Cancer

Aetna considers margetuximab-cmkb (Margenza) medically necessary for treatment of HER2-positive breast cancer with no response to preoperative systemic therapy or HER2-positive recurrent unresectable or metastatic breast cancer, in combination with chemotherapy, for members who have received two or more prior regimens.

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of

therapy medically necessary in members requesting reauthorization for breast cancer when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Margetuximab-cmkb is available as Margenza 250 mg/10 mL (25 mg/mL) in a single-dose vial.

For intravenous infusion only. Do not administer as an intravenous push or bolus.

Breast Cancer

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.

Source: MacroGenics, Inc., 2020b.