Article open access publication

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

Investigational New Drugs, Springer Nature, ISSN 1573-0646

Volume 36, 5, 2018

DOI:10.1007/s10637-018-0562-4, Dimensions: pub.1100472660, PMC: PMC6153514, PMID: 29349598,



  1. (1) University Hospital Heidelberg, grid.5253.1
  2. (2) Hannover Medical School, grid.10423.34
  3. (3) Hospital Del Mar, grid.411142.3
  4. (4) Rigshospitalet, grid.475435.4, Capital Region
  5. (5) Hospital Universitari Vall d'Hebron, grid.411083.f
  6. (6) Hospital Universitario Ramón y Cajal, grid.411347.4
  7. (7) Institute Curie, grid.418596.7
  8. (8) Institute of Health Carlos III, grid.413448.e
  9. (9) Hospital Universitario 12 De Octubre, grid.144756.5
  10. (10) Essen University Hospital, grid.410718.b
  11. (11) Centre Franois Baclesse, grid.476192.f
  12. (12) Roche (Switzerland), grid.417570.0
  13. (13) Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
  14. (14) Pharma Research and Early Development (pRED), Roche Innovation Center Welwyn, Welwyn Garden City, UK
  15. (15) A4P Consulting Ltd, Sandwich, UK










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 with the identifier NCT01918254 first registered on 3rd July 2013.

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