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

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

doi:10.1007/s10637-018-0562-4

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

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 MoisanGeorgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes

^*Corresponding author for this work

Department of Clinical Medicine

20 Citations (Scopus)

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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.

Original language	English
Journal	Investigational New Drugs
Volume	36
Issue number	5
Pages (from-to)	848-859
Number of pages	12
ISSN	0167-6997
DOIs	https://doi.org/10.1007/s10637-018-0562-4
Publication status	Published - 2018

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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 cancerFinal published version, 1.02 MBLicence: CC BY

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Schneeweiss, A., Park-Simon, T. W., Albanell, J., Lassen, U., Cortés, J., Dieras, V., May, M., Schindler, C., Marmé, F., Cejalvo, J. M., Martinez-Garcia, M., Gonzalez, I., Lopez-Martin, J., Welt, A., Levy, C., Joly, F., Michielin, F., Jacob, W., Adessi, C., ... Cervantes, A. (2018). 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, 36(5), 848-859. https://doi.org/10.1007/s10637-018-0562-4

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. / Schneeweiss, Andreas; Park-Simon, Tjoung Won; Albanell, Joan et al.
In: Investigational New Drugs, Vol. 36, No. 5, 2018, p. 848-859.

Research output: Contribution to journal › Journal article › Research › peer-review

Schneeweiss, A, Park-Simon, TW, Albanell, J, Lassen, U, Cortés, J, Dieras, V, May, M, Schindler, C, Marmé, F, Cejalvo, JM, Martinez-Garcia, M, Gonzalez, I, Lopez-Martin, J, Welt, A, Levy, C, Joly, F, Michielin, F, Jacob, W, Adessi, C, Moisan, A, Meneses-Lorente, G, Racek, T, James, I, Ceppi, M, Hasmann, M, Weisser, M & Cervantes, A 2018, '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, vol. 36, no. 5, pp. 848-859. https://doi.org/10.1007/s10637-018-0562-4

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title = "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",

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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year = "2018",

doi = "10.1007/s10637-018-0562-4",

language = "English",

volume = "36",

pages = "848--859",

journal = "Investigational New Drugs",

issn = "0167-6997",

publisher = "Springer",

number = "5",

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TY - JOUR

T1 - 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

AU - Schneeweiss, Andreas

AU - Park-Simon, Tjoung Won

AU - Albanell, Joan

AU - Lassen, Ulrik

AU - Cortés, Javier

AU - Dieras, Veronique

AU - May, Marcus

AU - Schindler, Christoph

AU - Marmé, Frederik

AU - Cejalvo, Juan Miguel

AU - Martinez-Garcia, Maria

AU - Gonzalez, Iria

AU - Lopez-Martin, Jose

AU - Welt, Anja

AU - Levy, Christelle

AU - Joly, Florence

AU - Michielin, Francesca

AU - Jacob, Wolfgang

AU - Adessi, Céline

AU - Moisan, Annie

AU - Meneses-Lorente, Georgina

AU - Racek, Tomas

AU - James, Ian

AU - Ceppi, Maurizio

AU - Hasmann, Max

AU - Weisser, Martin

AU - Cervantes, Andrés

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Biomarker

KW - ErbB3

KW - Heregulin (HRG)

KW - Human epidermal growth factor receptor 2 (HER2)

KW - Human epidermal growth factor receptor 3 (HER3)

KW - Metastatic breast cancer

KW - Pertuzumab

KW - Phase I

U2 - 10.1007/s10637-018-0562-4

DO - 10.1007/s10637-018-0562-4

M3 - Journal article

C2 - 29349598

AN - SCOPUS:85040796871

SN - 0167-6997

VL - 36

SP - 848

EP - 859

JO - Investigational New Drugs

JF - Investigational New Drugs

IS - 5

ER -