The FDA has now approved margetuximab-cmkb (MargenzaTM, MacroGenics) in combination with chemotherapy for adult patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer previously treated with at least two prior anti-HER2 regimens.
"HER2-targeting monoclonal antibodies are the standard of care in early-to-advanced HER2-positive breast cancer," write the authors of the phase 3 SOPHIA trial on which the approval was based, led by Hope S. Rugo, MD, Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco. "However, for relapsed/refractory disease, limited options exist after progression on trastuzumab, pertuzumab, and ado-trastuzumab emtansine."
In SOPHIA, Dr. Rugo and colleagues investigated the efficacy of margetuximab-cmkb in 536 patients with metastatic HER2-positive breast cancer whose disease progressed after at least two prior lines of anti-HER2 therapy. Patients were randomized in a 1:1 ratio to receive 15 mg/kg intravenous margetuximab every three weeks or 6 mg/kg trastuzumab every three weeks, both in combination with chemotherapy consisting of capecitabine, eribulin, gemcitabine, or vinorelbine. The primary end points were progression-free survival (PFS) and overall survival (OS), with secondary end points of objective response rate (ORR), duration of response, and safety.
At the trial's second interim analysis, margetuximab-cmkb plus chemotherapy produced a longer median PFS compared with trastuzumab/chemotherapy (5.8 vs 4.9 months), with a 24% reduction in risk of disease progression or death. Patients receiving margetuximab-cmkb plus chemotherapy also experienced a higher ORR compared with those receiving trastuzumab/chemotherapy (22% vs 16%). In a subgroup of patients with CD16A genotypes containing a 158F allele, median PFS was 6.9 months for the margetuximab-cmkb group and 5.1 months for the trastuzumab group.
Grade ≥3 adverse events occurred in 52% of patients receiving margetuximab-cmkb plus chemotherapy and in 48% of patients receiving trastuzumab/chemotherapy, with serious adverse events experienced by 15% and 17%, respectively. The most common adverse events occurring in patients receiving margetuximab-cmkb plus chemotherapy were fatigue/asthenia (57%), nausea (33%), diarrhea (25%), vomiting (21%), and infusion-related reactions (13%). The prescribing information for margetuximab-cmkb includes a warning that this agent may cause left ventricular dysfunction and embryo-fetal toxicity.
"Margetuximab-cmkb plus chemotherapy in patients with treated HER2-positive metastatic breast cancer improves PFS versus trastuzumab. Safety was comparable," concluded Dr. Rugo and colleagues in their publication in Cancer Research.
The recommended dose of margetuximab-cmkb is 15 mg/kg administered intravenously over 120 minutes for the initial dose, followed by a minimum of 30 minutes once every three weeks for subsequent doses.
For More Information
Rugo HS, Im SA, Cardoso F, et al (2020). Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Cancer Research (San Antonio Breast Cancer Symposium Abstracts), 80(suppl_4). Abstract GS1-02. DOI:10.1158/1538-7445.SABCS19-GS1-02
MacroGenics (2020). MacroGenics announces FDA approval of MARGENZATM for patients with pretreated metastatic HER2-positive breast cancer [news release]. Available at: https://www.globenewswire.com/news-release/2020/12/16/2146569/0/en/MacroGenics-Announces-FDA-Approval-of-MARGENZA-for-Patients-with-Pretreated-Metastatic-HER2-Positive-Breast-Cancer.html
Image credit: GenomeMe Lab, Inc. Licensed under CC BY-SA 4.0