When combined with chemotherapy, treatment with the investigational monoclonal antibody margetuximab provoked a greater progression-free survival (PFS) benefit than trastuzumab in patients with pretreated HER2-positive metastatic breast cancer, according to an interim analysis of the phase 3 SOPHIA trial presented at the 2019 San Antonio Breast Cancer Symposium.

The greatest benefit was observed in patients with CD16A genotypes harboring the 158F allele.

Photo by © MedMeetingImages/Todd Buchanan 2018

Monoclonal antibodies are regularly used in the treatment of early-stage and advanced HER2-positive breast cancer. There are few established options for patients with relapsed or refractory disease beyond trastuzumab, pertuzumab and ado-trastuzumab emtansine.

Hope S. Rugo, MD, professor of medicine at University of California, San Francisco and director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center, and colleagues established the benefit of margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy for patients with HER2-positive metastatic breast cancer.

“Compared with trastuzumab, margetuximab has higher affinity for both 158V (high binding) and 158F (low binding) alleles of the activating Fc receptor, CD16A,” Rugo and colleagues wrote. “Margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab.”

The study included data from 536 patients who experienced disease progression after at least two previous lines of anti-HER2 therapy, as well as one to three lines of therapy for HER2-positive metastatic breast cancer.

The researchers randomly assigned patients to chemotherapy plus margetuximab (n = 266) or trastuzumab (n = 270). Margetuximab was administered intravenously every 3 weeks. PFS and overall survival (OS) served as the study’s primary endpoints.

Results of the second interim analysis, reported after the study crossed the OS analysis boundary of 270 deaths, showed that treatment with margetuximab significantly prolonged PFS when compared with trastuzumab (median, 5.8 months vs. 4.9 months; hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .0033).

The researchers observed more pronounced results in patients harboring the 158F allele in CD16A genotypes (median PFS, 6.9 months vs. 5.1 months; HR, 0.68; 95% CI, 0.58-0.9; nominal P = .005).

OS results from the second interim analysis will be presented during the meeting. At the first interim analysis, the intent-to-treat population had an HR of 0.95 (95% CI, 0.69-1.31) and the CD16A/FF or FV genotype population (n = 457) had an HR of 0.82 (95% CI, 0.58-1.17).

Safety was comparable between the two treatments. Fifty-two percent (n = 138) of patients assigned margetuximab and 48% (n = 128) of patients assigned trastuzumab experienced grade 3 or higher adverse events. Serious adverse events were observed in 15% (n = 39) of the margetuximab population and 17% (n = 46) of the trastuzumab population.

“Maturing data comparing the OS of pts treated with margetuximab versus trastuzumab with chemotherapy will provide important new insights in characterizing clinical activity of this regimen in patients with metastatic breast cancer,” Rugo and colleagues concluded.