First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors

Abstract

Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.

Patients and methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B).

Results: Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.

Conclusions: Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.

Trial registration id: NCT01148849.

Keywords: HER2; breast cancer; gastric cancer; margetuximab; solid tumor.

Figure 1.

Comparison of ex vivo ADCC activity mediated by margetuximab and trastuzumab against HER2-expressing breast cancer cells using patient PBMC as effector cells. Ex vivo ADCC activity was determined against JIMT-1/Luc cells using PBMC effectors from samples collected from patients on Day 1 (baseline) and Day 22 (prior to the 4th margetuximab dose) in the presence of margetuximab or trastuzumab. Representative ADCC data from Patient 25 are shown in the top panel. Paired analyses of EC₅₀ and maximum cytolysis values for margetuximab and trastuzumab are presented in the middle and lower panels at Day 1 (n = 24) and Day 22 (n = 22).

Figure 2.

Waterfall plot of maximum change in tumor measurements (per RECIST). 58 of 60 patients evaluable for tumor response with both pre- and post-baseline target lesion measurements.