On December 16, 2020, 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 previously received two or more anti-HER2 regimens, at least one of which was for metastatic disease. 

Efficacy was evaluated in a randomized, multicenter, open-label trial (SOPHIA; NCT02492711) of 536 patients with immunohistochemistry 3+ or isolated systolic hypertension-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Patients were randomized one to one to margetuximab-cmkb plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (less than two or two or more), and number of metastatic sites (less than two or two or more). 

The main efficacy outcome measures were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by BICR. 

Median PFS in the margetuximab-cmkb arm was 5.8 months (95% CI = 5.5, 7.0) compared to 4.9 months (95% CI = 4.2, 5.6) in the control arm (hazard ratio = 0.76; 95% CI = 0.59, 0.98; p = 0.033). Confirmed ORR was 22% (95% CI = 17, 27) with a median DOR of 6.1 months (95% CI = 4.1, 9.1) in the margetuximab-cmkb arm compared to ORR of 16% (95% CI = 12, 20) and median DOR of 6.0 months (95% CI = 4.0, 6.9) in the control arm. 

The most common adverse drug reactions (> 10%) with margetuximab-cmkb in combination with chemotherapy were asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia or myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain. The prescribing information includes a boxed warning about risk of left ventricular dysfunction and embryo-fetal toxicity. 

The recommended margetuximab-cmkb dose is 15 mg/kg by IV infusion over 120 minutes for the initial dose, then over a minimum of 30 minutes every three weeks for all subsequent doses. On days when both margetuximab-cmkb and chemotherapy are administered, give margetuximab-cmkb immediately after chemotherapy is complete. Refer to the respective prescribing information for each therapeutic agent administered in combination with margetuximab-cmkb for the recommended dosage information, as appropriate. 

View full prescribing information for margetuximab-cmkb. 

The review used Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA granted the application fast-track designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.  

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.        

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.