Margenza

Margetuximab-cmkb (Margenza™) was approved by the U.S. Food and Drug Administration (FDA) in December 2020 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 is indicated in combination with chemotherapy. Margetuximab-cmkb is a chimeric Fc-engineered IgG1 kappa monoclonal antibody, that 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). In vitro, the modified Fc region of margetuximab-cmkb increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater in vitro ADCC and NK cell activation. The safety and efficacy of margetuximab-cmkb plus chemotherapy were evaluated in a phase 3 randomized open-label trial (SOPHIA) of patients with HER2-positive, unresectable or metastatic breast cancer previously treated with two or more prior anti-HER2 therapies (N=536). Patients were excluded for history of clinically significant cardiac disease, active brain metastases, and life expectancy less than 12 weeks. Patients were randomized to margetuximab-cmkb 15 mg/kg (N=266) plus chemotherapy or trastuzumab 6 mg/kg (N=270) plus chemotherapy, each administered in 3-week cycles. The sequential primary endpoints for the study were progression-free survival (PFS) and overall survival (OS). All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab-cmkb improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab-cmkb compared to 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab-cmkb (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab-cmkb (35 [13.3%] vs 9 [3.4%]). Margetuximab-cmkb is included in NCCN guidelines for treatment of Breast Cancer (version 1.2024). >