Abstract P6-18-11: Long-term responders to single-agent margetuximab, an Fc-modified anti-HER2 monoclonal antibody, in metastatic HER2+ breast cancer patients with prior anti-HER2 therapy
Authors: Im S-A , Bang Y-J , Oh D-Y , Giaccone G , Bauer T , Nordstrom J , Li H , Moore P , Hong S , Baughman J , Rock E , Burris H 
Published: May 2019

Abstract
Background
Margetuximab is an Fc-optimized anti-HER2 antibody that recognizes the same epitope as trastuzumab. Margetuximab has increased affinity for the activating CD16A Fc-receptor on NK cells and macrophages as well as decreased affinity for the inhibitory CD32B receptor compared to trastuzumab. In a Phase 1 study (NCT01148849) of 66 patients with relapsed or metastatic HER2+ cancer across multiple indications, margetuximab was well tolerated at all doses. Among 60 response-evaluable patients, confirmed partial response (PR) and stable disease (SD) were seen in 7 (12%) and 30 (50%) patients, respectively. Tumor reductions occurred in 18/23 (78%) evaluable breast cancer patients. Ex-vivo analyses of patient peripheral blood mononuclear cell samples confirmed margetuximab's ability to enhance antibody dependent cell-mediated cytotoxicity over that from trastuzumab. We report on 3 breast cancer patients with prior anti-HER2 therapy failure with durable (≥ 3.5 years) SD (1) or PR (2).
Methods
Enrolled patients had histologically/cytologically-confirmed carcinoma with documented HER2 overexpression by immunohistochemistry (2+ or 3+) and disease progression during/following last therapy. Eligibility included life expectancy ≥3 months; performance status ≤1; measurable disease by Response Criteria for Solid Tumors 1.1; adequate bone marrow, renal, hepatic function; and left ventricular ejection fraction ≥50%. Margetuximab was given by intravenous infusion at 0.1 – 6.0 mg/kg for 3 of every 4 weeks or once every 3 weeks (10 – 18 mg/kg).
Results
Three of 17 HER2 3+ metastatic breast cancer patients received long-term margetuximab. Patient 35 had 3 prior regimens (adjuvant doxorubicin+cyclophosphamide followed by docetaxol+trastuzumab; gemcitabine+vinorelbine; lapatinib+capecitabine) and received margetuximab at 10 mg/kg q3wk, 88 cycles to date, with PR achieved Cycle 1 Day 43, maintained 4.4 years. Patient 44 had 3 prior regimens for metastatic disease (docetaxel+trastuzumab+pertuzumab; doxorubicin+cyclophosphamide; lapatinib+capecitabine) and received margetuximab at 15 mg/kg q3wk, 79 cycles to date with SD for 4.3 years. Patient 50 had 4 prior regimens for recurrent/metastatic disease (tamoxifen; anastrozole; capecitabine+trastuzumab; lapatinib+capecitabine) and received margetuximab dose of 18 mg/kg q3wk with PR achieved Cycle 1 Day 43, maintained 3.5 years. Progression was noted at Cycle 57, and margetuximab continues at 63 cycles to date. No cardiac toxicities were found during long-term follow-up for these 3 patients and there were no treatment-related adverse events ≥Grade 3.
Conclusions
Margetuximab is well-tolerated without cardiac toxicities in long-term responders, with single-agent activity including durable responses in heavily pre-treated metastatic breast cancer. A Phase 3, randomized, multi-center clinical trial (SOPHIA; NCT02492711) is enrolling patients with metastatic breast cancer, comparing margetuximab plus chemotherapy to trastuzumab plus chemotherapy in patients who have received 1 to 3 lines of therapy for advanced disease.
Citation Format: Im S-A, Bang Y-J, Oh D-Y, Giaccone G, Bauer T, Nordstrom J, Li H, Moore P, Hong S, Baughman J, Rock E, Burris H. Long-term responders to single-agent margetuximab, an Fc-modified anti-HER2 monoclonal antibody, in metastatic HER2+ breast cancer patients with prior anti-HER2 therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-11.