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
  • 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.
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