2. Academic Validation
  3. Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

  • Invest New Drugs. 2018 Oct;36(5):848-859. doi: 10.1007/s10637-018-0562-4.
Andreas Schneeweiss 1,  Tjoung-Won Park-Simon 2,  Joan Albanell 3,  Ulrik Lassen 4,  Javier Cortés 5 6,  Veronique Dieras 7,  Marcus May 2,  Christoph Schindler 2,  Frederik Marmé 1,  Juan Miguel Cejalvo 8,  Maria Martinez-Garcia 3,  Iria Gonzalez 3,  Jose Lopez-Martin 9,  Anja Welt 10,  Christelle Levy 11,  Florence Joly 11,  Francesca Michielin 12,  Wolfgang Jacob 13,  Céline Adessi 12,  Annie Moisan 12,  Georgina Meneses-Lorente 14,  Tomas Racek 12,  Ian James 15,  Maurizio Ceppi 16,  Max Hasmann 16,  Martin Weisser 16,  Andrés Cervantes 8
Affiliations

Affiliations

  • 1 National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
  • 2 Department of Obstetrics and Gynecology, Division of Gynecological Oncology and Clinical Research Center, Hannover Medical School, Hannover, Germany.
  • 3 Department of Medical Oncology, Hospital del Mar, CIBERONC, Barcelona, Spain.
  • 4 Rigshospitalet, Copenhagen, Denmark.
  • 5 Ramon y Cajal University Hospital, Madrid, Spain.
  • 6 Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 7 Department of Medical Oncology, Institute Curie, Paris, France.
  • 8 Department of Medical Oncology, Biomedical Health Research Institute INCLIVA, University of Valencia, Valencia and CIBERONC, Institute of Health Carlos III, Madrid, Spain.
  • 9 Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 10 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 11 Departments of Clinical Research Unit and Medical Oncology, Centre François Baclesse, Caen, France.
  • 12 Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland.
  • 13 Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany. [email protected].
  • 14 Pharma Research and Early Development (pRED), Roche Innovation Center Welwyn, Welwyn Garden City, UK.
  • 15 A4P Consulting Ltd, Sandwich, UK.
  • 16 Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany.
PMID: 29349598 DOI: 10.1007/s10637-018-0562-4
Abstract

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast Cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development.

Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Keywords

Biomarker; ErbB3; Heregulin (HRG); Human epidermal growth factor receptor 2 (HER2); Human epidermal growth factor receptor 3 (HER3); Metastatic breast cancer; Pertuzumab; Phase I.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P99304
    Anti-HER3 Antibody