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A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer

BACKGROUND: Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally a...

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Autores principales: Schmid, Peter, Sablin, Marie-Paule, Bergh, Jonas, Im, Seock-Ah, Lu, Yen-Shen, Martínez, Noelia, Neven, Patrick, Lee, Keun Seok, Morales, Serafín, Pérez-Fidalgo, J. Alejandro, Adamson, Douglas, Gonçalves, Anthony, Prat, Aleix, Jerusalem, Guy, Schlieker, Laura, Espadero, Rosa-Maria, Bogenrieder, Thomas, Huang, Dennis Chin-Lun, Crown, John, Cortés, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811234/
https://www.ncbi.nlm.nih.gov/pubmed/33451345
http://dx.doi.org/10.1186/s13058-020-01382-8
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author Schmid, Peter
Sablin, Marie-Paule
Bergh, Jonas
Im, Seock-Ah
Lu, Yen-Shen
Martínez, Noelia
Neven, Patrick
Lee, Keun Seok
Morales, Serafín
Pérez-Fidalgo, J. Alejandro
Adamson, Douglas
Gonçalves, Anthony
Prat, Aleix
Jerusalem, Guy
Schlieker, Laura
Espadero, Rosa-Maria
Bogenrieder, Thomas
Huang, Dennis Chin-Lun
Crown, John
Cortés, Javier
author_facet Schmid, Peter
Sablin, Marie-Paule
Bergh, Jonas
Im, Seock-Ah
Lu, Yen-Shen
Martínez, Noelia
Neven, Patrick
Lee, Keun Seok
Morales, Serafín
Pérez-Fidalgo, J. Alejandro
Adamson, Douglas
Gonçalves, Anthony
Prat, Aleix
Jerusalem, Guy
Schlieker, Laura
Espadero, Rosa-Maria
Bogenrieder, Thomas
Huang, Dennis Chin-Lun
Crown, John
Cortés, Javier
author_sort Schmid, Peter
collection PubMed
description BACKGROUND: Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-020-01382-8.
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spelling pubmed-78112342021-01-18 A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer Schmid, Peter Sablin, Marie-Paule Bergh, Jonas Im, Seock-Ah Lu, Yen-Shen Martínez, Noelia Neven, Patrick Lee, Keun Seok Morales, Serafín Pérez-Fidalgo, J. Alejandro Adamson, Douglas Gonçalves, Anthony Prat, Aleix Jerusalem, Guy Schlieker, Laura Espadero, Rosa-Maria Bogenrieder, Thomas Huang, Dennis Chin-Lun Crown, John Cortés, Javier Breast Cancer Res Research Article BACKGROUND: Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-020-01382-8. BioMed Central 2021-01-15 2021 /pmc/articles/PMC7811234/ /pubmed/33451345 http://dx.doi.org/10.1186/s13058-020-01382-8 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Schmid, Peter
Sablin, Marie-Paule
Bergh, Jonas
Im, Seock-Ah
Lu, Yen-Shen
Martínez, Noelia
Neven, Patrick
Lee, Keun Seok
Morales, Serafín
Pérez-Fidalgo, J. Alejandro
Adamson, Douglas
Gonçalves, Anthony
Prat, Aleix
Jerusalem, Guy
Schlieker, Laura
Espadero, Rosa-Maria
Bogenrieder, Thomas
Huang, Dennis Chin-Lun
Crown, John
Cortés, Javier
A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title_full A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title_fullStr A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title_full_unstemmed A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title_short A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
title_sort phase ib/ii study of xentuzumab, an igf-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, her2-negative locally advanced/metastatic breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811234/
https://www.ncbi.nlm.nih.gov/pubmed/33451345
http://dx.doi.org/10.1186/s13058-020-01382-8
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