title: Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.
abstract: OBJECTIVE
  The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A.
  
  
  METHODS
  Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3.
  
  
  RESULTS
  No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3).
  
  
  CONCLUSIONS
  MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: University of Colorado Cancer Center, Denver, Colorado.
authors.forename: Wells
authors.initials: W
authors.lastname: Messersmith
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Desamparados
authors.initials: D
authors.lastname: Roda
authors.affiliation: Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.affiliation: University of Colorado Cancer Center, Denver, Colorado.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Sandra Sanabria
authors.initials: SS
authors.lastname: Bohórquez
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Leddy
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Littman
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Kapp
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirzkall
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000077544:Panitumumab; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000276:immunology*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; C569960:MEHD7945A; D000077544:Panitumumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000068818:Cetuximab