title: First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors.
abstract: 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 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  NCT01148849.
authors.affiliation: Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Department of Medical Oncology, National Cancer Institute, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.affiliation: Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Drug Development, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Nordstrom
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Chichili
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Moore
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hong
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas, UNLP, IFLP-CONICET C.C.No. 67, 1900 La Plata, Argentina.
authors.forename: S J
authors.initials: SJ
authors.lastname: Stewart
authors.affiliation: MacroGenics, Inc, South San Francisco, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Baughman
authors.affiliation: MacroGenics, Inc, Rockville, Maryland 20850, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lechleider
authors.affiliation: Department of Drug Development, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000617981:margetuximab
keywords: HER2; breast cancer; gastric cancer; margetuximab; solid tumor