On December 16, the U.S. Food and Drug Administration (FDA) approved margetuximab-cmkb (Margenza) 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.
Margetuximab is an Fc-optimized chimeric monoclonal antibody designed to increase HER2 immune targeting. Tighter binding to the immune effector cells enhances the immune response.
Efficacy was evaluated in SOPHIA, a randomized, multicenter, open-label trial of 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. Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Random assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (≤ 2, > 2), and number of metastatic sites (≤ 2, > 2).
The main efficacy outcome measures were progression-free survival by blinded independent central review and overall survival. Additional efficacy outcome measures were objective response rate and duration of response assessed by blinded independent central review.
Median progression-free survival in the margetuximab arm was 5.8 months (95% confidence interval [CI] = 5.5–7.0) compared with 4.9 months (95% CI = 4.2–5.6) in the control arm (hazard ratio [HR] = 0.76, 95% CI = 0.59–0.98, P = .033). Confirmed objective response rate was 22% (95% CI = 17–27), with a median duration of response of 6.1 months (95% CI = 4.1–9.1) in the margetuximab arm compared to an objective response rate of 16% (95% CI = 12–20) and median duration of response of 6.0 months (95% CI = 4.0–6.9) in the control arm.
The most commonly reported adverse drug reactions (> 10%) with margetuximab in combination with chemotherapy were 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. The prescribing information includes a Boxed Warning to advise health professionals of the risks of left-ventricular dysfunction and embryofetal toxicity.
The recommended margetuximab dose is 15 mg/kg by intravenous infusion 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 margetuximab and chemotherapy are to be administered, margetuximab may be administered immediately after chemotherapy completion. Refer to the respective prescribing information for each therapeutic agent administered in combination with margetuximab for the recommended dosage information.