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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作者
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
机构
[1] Heidelberg University Hospital,National Center for Tumor Diseases
[2] Hannover Medical School,Department of Obstetrics and Gynecology, Division of Gynecological Oncology and Clinical Research Center
[3] Hospital del Mar,Department of Medical Oncology
[4] CIBERONC,Department of Medical Oncology
[5] Rigshospitalet,Department of Medical Oncology, Biomedical Health Research Institute INCLIVA
[6] Ramon y Cajal University Hospital,Department of Medical Oncology
[7] Vall d’Hebron Institute of Oncology,Department of Medical Oncology, West German Cancer Center
[8] Institute Curie,Departments of Clinical Research Unit and Medical Oncology
[9] University of Valencia,undefined
[10] Valencia and CIBERONC,undefined
[11] Institute of Health Carlos III,undefined
[12] Hospital Universitario 12 de Octubre,undefined
[13] University Hospital Essen,undefined
[14] Centre François Baclesse,undefined
[15] Pharma Research and Early Development (pRED),undefined
[16] Roche Innovation Center Basel,undefined
[17] Pharma Research and Early Development (pRED),undefined
[18] Roche Innovation Center Munich,undefined
[19] Pharma Research and Early Development (pRED),undefined
[20] Roche Innovation Center Welwyn,undefined
[21] A4P Consulting Ltd,undefined
来源
Investigational New Drugs | 2018年 / 36卷
关键词
Human epidermal growth factor receptor 3 (HER3); ErbB3; Phase I; Human epidermal growth factor receptor 2 (HER2); Heregulin (HRG); Pertuzumab; Metastatic breast cancer; Biomarker;
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摘要
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.
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页码:848 / 859
页数:11
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