Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study

PURPOSE: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological i...

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Autores principales: Mery, Benoîte, Ménétrier-Caux, Christine, Montané, Laure, Heudel, Pierre-Etienne, Ray-Coquard, Isabelle, Bachelot, Thomas, Derbel, Olfa, Augereau, Paule, Treilleux, Isabelle, Berthet, Justine, Nkodia, Axelle, Bardin-Dit-Courageot, Christine, Attignon, Valery, Ferrari, Anthony, Garin, Gwenaele, Perol, David, Caux, Christophe, Dubois, Bertrand, Trédan, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150792/
https://www.ncbi.nlm.nih.gov/pubmed/37139242
http://dx.doi.org/10.2147/BCTT.S400055
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author Mery, Benoîte
Ménétrier-Caux, Christine
Montané, Laure
Heudel, Pierre-Etienne
Ray-Coquard, Isabelle
Bachelot, Thomas
Derbel, Olfa
Augereau, Paule
Treilleux, Isabelle
Berthet, Justine
Nkodia, Axelle
Bardin-Dit-Courageot, Christine
Attignon, Valery
Ferrari, Anthony
Garin, Gwenaele
Perol, David
Caux, Christophe
Dubois, Bertrand
Trédan, Olivier
author_facet Mery, Benoîte
Ménétrier-Caux, Christine
Montané, Laure
Heudel, Pierre-Etienne
Ray-Coquard, Isabelle
Bachelot, Thomas
Derbel, Olfa
Augereau, Paule
Treilleux, Isabelle
Berthet, Justine
Nkodia, Axelle
Bardin-Dit-Courageot, Christine
Attignon, Valery
Ferrari, Anthony
Garin, Gwenaele
Perol, David
Caux, Christophe
Dubois, Bertrand
Trédan, Olivier
author_sort Mery, Benoîte
collection PubMed
description PURPOSE: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide. EXPERIMENTAL DESIGN: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon’s minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS). RESULTS: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4(+) T cells and higher CD8(+) T cells to macrophage ratios in the tumor. This impact on CD4(+) and CD8(+) T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4(+) and CD8(+) memory T cells was observed in other patients. CONCLUSION: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.
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spelling pubmed-101507922023-05-02 Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study Mery, Benoîte Ménétrier-Caux, Christine Montané, Laure Heudel, Pierre-Etienne Ray-Coquard, Isabelle Bachelot, Thomas Derbel, Olfa Augereau, Paule Treilleux, Isabelle Berthet, Justine Nkodia, Axelle Bardin-Dit-Courageot, Christine Attignon, Valery Ferrari, Anthony Garin, Gwenaele Perol, David Caux, Christophe Dubois, Bertrand Trédan, Olivier Breast Cancer (Dove Med Press) Original Research PURPOSE: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide. EXPERIMENTAL DESIGN: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon’s minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS). RESULTS: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4(+) T cells and higher CD8(+) T cells to macrophage ratios in the tumor. This impact on CD4(+) and CD8(+) T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4(+) and CD8(+) memory T cells was observed in other patients. CONCLUSION: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations. Dove 2023-04-27 /pmc/articles/PMC10150792/ /pubmed/37139242 http://dx.doi.org/10.2147/BCTT.S400055 Text en © 2023 Mery et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Mery, Benoîte
Ménétrier-Caux, Christine
Montané, Laure
Heudel, Pierre-Etienne
Ray-Coquard, Isabelle
Bachelot, Thomas
Derbel, Olfa
Augereau, Paule
Treilleux, Isabelle
Berthet, Justine
Nkodia, Axelle
Bardin-Dit-Courageot, Christine
Attignon, Valery
Ferrari, Anthony
Garin, Gwenaele
Perol, David
Caux, Christophe
Dubois, Bertrand
Trédan, Olivier
Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title_full Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title_fullStr Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title_full_unstemmed Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title_short Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study
title_sort pembrolizumab in lymphopenic metastatic breast cancer patients treated with metronomic cyclophosphamide: a clinical and translational prospective study
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150792/
https://www.ncbi.nlm.nih.gov/pubmed/37139242
http://dx.doi.org/10.2147/BCTT.S400055
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