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 af dette arbejde

Institut for Klinisk Medicin

20 Citationer (Scopus)

31 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Investigational New Drugs
Vol/bind	36
Udgave nummer	5
Sider (fra-til)	848-859
Antal sider	12
ISSN	0167-6997
DOI	https://doi.org/10.1007/s10637-018-0562-4
Status	Udgivet - 2018

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1007/s10637-018-0562-4Licens: CC BY

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 cancerForlagets udgivne version, 1,02 MBLicens: CC BY

Fingeraftryk

Dyk ned i forskningsemnerne om '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'. Sammen danner de et unikt fingeraftryk.

Citationsformater

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.

I: Investigational New Drugs, Bind 36, Nr. 5, 2018, s. 848-859.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 36, nr. 5, s. 848-859. https://doi.org/10.1007/s10637-018-0562-4

@article{fdcbcbf2bf5d4448bc407c52da83ad73,

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",

author = "Andreas Schneeweiss and Park-Simon, {Tjoung Won} and Joan Albanell and Ulrik Lassen and Javier Cort{\'e}s and Veronique Dieras and Marcus May and Christoph Schindler and Frederik Marm{\'e} and Cejalvo, {Juan Miguel} and Maria Martinez-Garcia and Iria Gonzalez and Jose Lopez-Martin and Anja Welt and Christelle Levy and Florence Joly and Francesca Michielin and Wolfgang Jacob and C{\'e}line Adessi and Annie Moisan and Georgina Meneses-Lorente and Tomas Racek and Ian James and Maurizio Ceppi and Max Hasmann and Martin Weisser and Andr{\'e}s Cervantes",

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",

}

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 -