title: First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors.
abstract: OBJECTIVE
  A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.
  
  
  METHODS
  Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.
  
  
  RESULTS
  There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).
  
  
  CONCLUSIONS
  Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany. wolfgang.jacob@roche.com.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jacob
authors.affiliation: Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Garcia
authors.affiliation: Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Taus
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Medical Oncology, Erasmus Medical Center Cancer Institute and Cancer Genomics, Rotterdam, the Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marlies H G
authors.initials: MH
authors.lastname: Langenberg
authors.affiliation: Department of Hematology and Medical Oncology, Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Fleitas Kanonnikoff
authors.affiliation: Department of Hematology and Medical Oncology, Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center Cancer Institute and Cancer Genomics, Rotterdam, the Netherlands.
authors.forename: Maja J
authors.initials: MJ
authors.lastname: De Jonge
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center Cancer Institute and Cancer Genomics, Rotterdam, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten Mau
authors.initials: MM
authors.lastname: Soerensen
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Marlene
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ceppi
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn, United Kingdom.
authors.forename: Georgina
authors.initials: G
authors.lastname: Meneses-Lorente
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Adessi
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Michielin
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Keelara
authors.initials: K
authors.lastname: Abiraj
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Bossenmaier
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weisser
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ulrik N
authors.initials: UN
authors.lastname: Lassen
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D061067:Antibodies, Monoclonal, Humanized; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C000597969:lumretuzumab