title: Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.
abstract: BACKGROUND
  This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.
  
  
  METHODS
  On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m2and 5-fluorouracil at a dose of 1000 mg/m2/day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m2) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.
  
  
  RESULTS
  Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses).
  
  
  CONCLUSIONS
  Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: King Albert II Institute, Medical Oncology Service, Saint-Luc University Clinic and Clinical and Experimental Research Institute (Pole MIRO), Catholic University of Louvain, Brussels, Belgium.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lori
authors.initials: L
authors.lastname: Wirth
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Pol
authors.initials: P
authors.lastname: Specenier
authors.affiliation: Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
authors.affiliation: King Albert II Institute, Medical Oncology Service, Saint-Luc University Clinic and Clinical and Experimental Research Institute (Pole MIRO), Catholic University of Louvain, Brussels, Belgium.
authors.forename: Feby
authors.initials: F
authors.lastname: Mardjuadi
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Kapp
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Royer-Joo
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Bruce
authors.initials: B
authors.lastname: McCall
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirzkall
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.|Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Clement
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007074:Immunoglobulin G; C569960:MEHD7945A; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil
keywords: antibody; clinical trial; duligotuzumab; epidermal growth factor receptor (EGFR); human epidermal growth factor receptor 3 (HER3)