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

Y J Bang; G Giaccone; S A Im; D Y Oh; T M Bauer; J L Nordstrom; H Li; G R Chichili; P A Moore; S Hong; S J Stewart; J E Baughman; R J Lechleider; H A Burris

doi:10.1093/annonc/mdx002

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

Ann Oncol. 2017 Apr 1;28(4):855-861. doi: 10.1093/annonc/mdx002.

Authors

Y J Bang¹, G Giaccone², S A Im¹, D Y Oh¹, T M Bauer³, J L Nordstrom⁴, H Li⁴, G R Chichili⁴, P A Moore⁴, S Hong⁴, S J Stewart⁵, J E Baughman⁶, R J Lechleider⁴, H A Burris³

Affiliations

¹ Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
² Department of Medical Oncology, National Cancer Institute, Bethesda, MD, USA.
³ Department of Drug Development, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
⁴ MacroGenics, Inc, Rockville, Maryland 20850, USA.
⁵ Departamento de Física, Facultad de Ciencias Exactas, UNLP, IFLP-CONICET C.C.No. 67, 1900 La Plata, Argentina.
⁶ MacroGenics, Inc, South San Francisco, USA.

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.

Publication types

Clinical Trial, Phase I
Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal / administration & dosage*
Antibodies, Monoclonal / adverse effects
Antibodies, Monoclonal / pharmacokinetics
Antibodies, Monoclonal / therapeutic use
Antibody-Dependent Cell Cytotoxicity / drug effects
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / adverse effects
Antineoplastic Agents / pharmacokinetics
Disease-Free Survival
Dose-Response Relationship, Drug
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms / drug therapy*
Receptor, ErbB-2 / biosynthesis

Substances

Antibodies, Monoclonal
Antineoplastic Agents
ERBB2 protein, human
Receptor, ErbB-2
margetuximab

Associated data

ClinicalTrials.gov/NCT01148849