MacroGenics’ Margenza Approved for Metastatic Breast Cancer

The FDA has approved Margenza (margetuximab-cmkb) plus chemotherapy as a treatment option for adults with HER2-postive advanced breast cancer.

Margenza (margetuximab-cmkb), from biopharmaceutical company MacroGenics, plus chemotherapy has been approved by the FDA as a treatment option for adults with metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. The drug works by inhibiting tumor cell proliferation and reducing shedding of HER2 extracellular domain.

The monoclonal antibody/chemotherapy combination is targeted at patients with this type of breast cancer who have failed 2 or more previous anti-HER2 therapies—at least 1 for metastasis—with the recommended first margetuximab dose being 15 mg/kg intravenously over 2 hours and all subsequent doses being 15 mg/kg for at least 30 minutes every 3 weeks. It should immediately follow the chosen chemotherapy on days when both treatments are administered.

“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head Phase 3 clinical trial, MARGENZA with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Hope S. Rugo, MD, professor of medicine and director of Breast Oncology and Clinical Trials Education, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, in a statement announcing the results.

The head-to-head randomized, multicenter, open-label, phase 3 SOPHIA trial evaluated the efficacy of 15-mg/kg intravenous (IV) margetuximab (n = 266) vs 6-mg/kg IV Herceptin (trastuzumabl; n = 270), both plus chemotherapy and given every 3 weeks, in 536 patients with immunohistochemistry 3+ or in situ hybridization–amplified HER2-positive breast cancer. Three criteria were used to randomize the participants:

  • Chemotherapy choice (capecitabine, eribulin, gemcitabine, vinorelbine)
  • Therapy lines for metastatic disease (< 2 or > 2)
  • Metastatic sites (< 2 or > 2)

Results for the primary (progression-free survival [PFS]) and secondary (objective response rate [ORR] and duration of response [DOR]) efficacy measures proved to be superior in the margetuximab arm compared with the trastuzumab arm.

For median PFS, the margetuximab arm had superior efficacy, at 5.8 (95% CI, 5.5-7.0) vs 4.9 months (95% CI, 4.2-5.6). There also was a 24% reduction in risk of disease progression or death (HR, 0.76; 95% CI, 0.59-0.98; P = .033), a 22% (95% CI, 17%-27%) ORR, and a 6.1-month (95% CI, 4.1-9.1) median DOR. In comparison, the trastuzumab arm had a 16% ORR (95% CI, 12.0%-20.0%) and 6.0-month (95% CI, 4.0-6.9) median DOR.

Fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%) were the most common adverse events in the margetuximab arm, followed by constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain were the most common (> 10%). Infusion-related reactions, which occurred in 13% of the trial patients, are also common; however, most were grade 2 or less and resolved withing 24 hours.

With this approval, margetuximab becomes “the first HER-2 targeted therapy to have improved progression-free survival versus Herceptin (trastuzumab), both combined with chemotherapy, in a head-to-head phase 3 clinical trial,” MacroGenics stated.

A margetuximab/checkpoint blockade combination also is being evaluated for use in HER2-positive gastroesophageal cancer in the MAHOGANY trial, while margetuximab/tebotelimab is being studied for application in various HER2-positve tumors.

Carrying with it boxed warnings of teratogenic risk during pregnancy and left ventricular dysfunction, the drug is targeted for a March 2021 launch, with final OS analysis expected in the latter half of the year.


Margenza—now approved. MacroGenics. December 17, 2020. Accessed December 20, 2020.