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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

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 phas...

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Main Authors: Schneeweiss, Andreas (Author) , Park-Simon, Tjoung-Won (Author) , Albanell, Joan (Author) , Lassen, Ulrik (Author) , Cortes, Javier (Author) , Dieras, Veronique (Author) , May, Marcus (Author) , Schindler, Christoph (Author) , Marmé, Frederik (Author) , Cejalvo, Miguel Juan (Author) , Martinez-Garcia, Maria (Author) , Gonzalez, Iria (Author) , Lopez-Martin, Jose (Author) , Welt, Anja (Author) , Levy, Christelle (Author) , Joly, Florence (Author) , Michielin, Francesca (Author) , Jacob, Wolfgang (Author) , Adessi, Céline (Author) , Moisan, Annie (Author) , Meneses-Lorente, Georgina (Author) , Racek, Tomáš (Author) , James, Ian (Author) , Ceppi, Maurizio (Author) , Hasmann, Max (Author) , Weisser, Martin (Author) , Cervantes, Andrés (Author)
Format: Article (Journal)
Language:English
Published: 19 January 2018
In: Investigational new drugs
Year: 2018, Volume: 36, Issue: 5, Pages: 848-859
ISSN:1573-0646
DOI:10.1007/s10637-018-0562-4
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s10637-018-0562-4
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Author Notes: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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Summary: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.govwith the identifier NCT01918254 first registered on 3rd July 2013.
Item Description:Published online: 19 January 2018
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Physical Description:Online Resource
ISSN:1573-0646
DOI:10.1007/s10637-018-0562-4

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