On December 16, 2020, margetuximab-cmkb (margetuximab) was approved 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.^1,2

Supporting Efficacy Data

Approval was based on findings in the open-label, phase III SOPHIA trial (ClinicalTrials.gov identifier NCT02492711).² In the trial, 536 patients with immunohistochemistry 3+ or in situ hybridization–amplified HER2-positive metastatic breast cancer who had received prior treatment with other anti-HER2 therapies were randomly assigned to margetuximab plus chemotherapy (n = 266) or trastuzumab plus chemotherapy (control group; n = 270). Chemotherapy consisted of the physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

Median patient age was 56 years (range = 27–86 years, 78% < 65 years), 99.4% were female, and 80% were White. The Eastern Cooperative Oncology Group performance status was 0 (58%) or 1 in all patients; 47% had visceral disease, 57% had bone metastases, and 13% had brain metastases; and 60% had hormone receptor–positive disease. The median number of prior lines of therapy in the locally advanced or metastatic setting was two (range = 1–4), and previous therapy included trastuzumab in all patients, pertuzumab in all but one patient, and ado-trastuzumab emtansine in 91%.

Margetuximab led to a significant, though modest, improvement in progression-free survival. On blinded independent central review, the median progression-free survival was 5.8 months (95% confidence interval [CI] = 5.5–7.0 months in the margetuximab group vs 4.9 months (95% CI = 4.2–5.6 months) in the control group (hazard ratio = 0.76, 95% CI = 0.59–0.98, P = .033). Results were consistent across the stratification factors of chemotherapy choice, number of lines of therapy in the metastatic setting, and number of metastatic sites. Among 262 patients in each group with measurable disease, a confirmed objective response was observed in 22% vs 16%, with a median duration of response of 6.1 months vs 6.0 months. Overall survival data were not mature at the time of this analysis.

How It Works

Margetuximab binds to the extracellular domain of HER2. Upon binding to HER2-expressing tumor cells, margetuximab inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain, and mediates antibody-dependent cellular cytotoxicity. In vitro, the modified Fc region of margetuximab increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater in vitro antibody-dependent cellular cytotoxicity and natural killer cell activation.

How It Is Used

The recommended dose of margetuximab is 15 mg/kg via intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The first dose should be given over 120 minutes, with subsequent doses given over at least 30 minutes. On days when margetuximab and chemotherapy are given together, margetuximab may be administered immediately after chemotherapy completion. Prescribing information for each therapeutic agent administered in combination with margetuximab should be consulted for the recommended dosage information.

Left-ventricular ejection fraction should be assessed before starting margetuximab treatment and regularly during treatment. Prescribing information provides instructions on modification of treatment for left-ventricular ejection fraction declines and infusion-related reactions. Treatment should be permanently discontinued for persistent left-ventricular ejection fraction declines or repeated withholding of doses for left-ventricular ejection fraction declines and for severe or life-threatening infusion-related reactions.

Safety Profile

Among patients who received margetuximab in the SOPHIA trial, 40% were exposed for at least 6 months and 11% for at least 1 year.

The most common adverse events of any grade in the margetuximab group were fatigue/asthenia (57% vs 47% in the control group), nausea (33% vs 32%), diarrhea (25% vs 25%), vomiting (21% vs 14%), constipation (19% vs 17%), headache (19% vs 16%), pyrexia (19% vs 14%), alopecia (18% vs 15%), abdominal pain (17% vs 21%), and peripheral neuropathy (16% vs 15%). The most common grade 3 or 4 adverse events included fatigue/asthenia (7% vs 4.5%), diarrhea (2.3% vs 2.3%), and infusion-related reactions (1.5% vs 0%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (9% vs 9%), increased lipase (6% vs 3.2%), and decreased leukocytes (5% vs 3.2%).

Serious adverse events occurred in 16% of patients in the margetuximab group, the most common being febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%), and infusion-related reactions (1.1%). Dosage interruptions due to adverse events occurred in 11% of patients, with the most common cause (> 5%) being infusion-related reactions. Adverse events led to permanent treatment discontinuation in 3% of patients, with the most common causes (> 1%) being left-ventricular dysfunction and infusion-related reactions. Fatal adverse events occurred in 1.1% of patients, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%). 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves margetuximab for metastatic HER2-positive breast cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-margetuximab-metastatic-her2-positive-breast-cancer. Accessed January 6, 2021.

2. Margenza (margetuximab-cmkb) injection, for intravenous use, prescribing information, MacroGenics, Inc, December 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761150s000lbl.pdf. Accessed January 6, 2021.