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

Benoîte Mery; Christine Ménétrier-Caux; Laure Montané; Pierre-Etienne Heudel; Isabelle Ray-Coquard; Thomas Bachelot; Olfa Derbel; Paule Augereau; Isabelle Treilleux; Justine Berthet; Axelle Nkodia; Christine Bardin-Dit-Courageot; Valery Attignon; Anthony Ferrari; Gwenaele Garin; David Perol; Christophe Caux; Bertrand Dubois; Olivier Trédan

doi:10.2147/BCTT.S400055

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

Breast Cancer (Dove Med Press). 2023 Apr 27:15:311-325. doi: 10.2147/BCTT.S400055. eCollection 2023.

Authors

Benoîte Mery^#^{1

2}, Christine Ménétrier-Caux^#^{2

3}, Laure Montané⁴, Pierre-Etienne Heudel¹, Isabelle Ray-Coquard¹, Thomas Bachelot¹, Olfa Derbel⁵, Paule Augereau⁶, Isabelle Treilleux^{2

7}, Justine Berthet^{2

3}, Axelle Nkodia³, Christine Bardin-Dit-Courageot³, Valery Attignon⁸, Anthony Ferrari⁹, Gwenaele Garin⁴, David Perol⁴, Christophe Caux^{2

3}, Bertrand Dubois^#^{2

3}, Olivier Trédan^#^{1

2}

Affiliations

¹ Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
² Inserm U1052, CNRS 5286, Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, Lyon, France.
³ Laboratory of Cancer Immunotherapy of LYON (LICL), Centre Léon Bérard, Lyon, France.
⁴ Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France.
⁵ Department of Medical Oncology, Hôpital Privé Jean-Mermoz, Lyon, France.
⁶ Department of Medical Oncology, Institut de Cancérologie de L'ouest- Paul Papin, Angers, France.
⁷ Biopathology Department, Centre Léon Bérard, Lyon, France.
⁸ Genomic of Cancer Platform, Centre Léon Bérard, Lyon, France.
⁹ Gilles Thomas Bioinformatics Platform, Synergie Lyon Cancer Foundation, Centre Léon Bérard, Lyon, France.

^# Contributed equally.

Abstract

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.

Keywords: chemotherapy; immunomonitoring; immunotherapy; lymphopenia; metastatic breast cancer.

Grants and funding

This work was an investigator-initiated trial (no grant number is applicable). CLB was the legal sponsor. MSD provided the investigational agent and funding, but had no role in the study design, data collection, analysis, interpretation, writing of the report, or decision to publish this report. The database is held by CLB, and CLB statisticians carried out the analysis. Research grants were perceived from “INCa” (PRT-K INCA 2009-113 (BreastImmun), Transla13-097 (Camel), Transla13-061 (TNBT)), “Lyrican” (LYRICAN INCa-DGOS-Inserm_12563), “Ruban Rose” for the blood immuno-monitoring and “Région Rhône-Alpes” (IRICE project) for the development of multiplex immunofluorescence staining.