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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

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  • Andreas Schneeweiss
  • Tjoung-Won Park-Simon
  • Joan Albanell
  • Ulrik Lassen
  • Javier Cortés
  • Veronique Dieras
  • Marcus May
  • Christoph Schindler
  • Frederik Marmé
  • Juan Miguel Cejalvo
  • Maria Martinez-Garcia
  • Iria Gonzalez
  • Jose Lopez-Martin
  • Anja Welt
  • Christelle Levy
  • Florence Joly
  • Francesca Michielin
  • Wolfgang Jacob
  • Céline Adessi
  • Annie Moisan
  • Georgina Meneses-Lorente
  • Tomas Racek
  • Ian James
  • Maurizio Ceppi
  • Max Hasmann
  • Martin Weisser
  • Andrés Cervantes
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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.

Original languageEnglish
JournalInvestigational New Drugs
Issue number5
Pages (from-to)848-859
Number of pages12
Publication statusPublished - Oct 2018

ID: 56060412