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

Benoîte Mery (1, 2) , Christine Ménétrier-Caux (1) , Laure Montané (2) , Pierre-Etienne Heudel (2) , Isabelle Ray-Coquard (2) , Thomas Bachelot (2) , Olfa Derbel (3) , Paule Augereau (4) , Isabelle Treilleux (1, 2) , Justine Berthet (1, 2) , Axelle Nkodia (2) , Christine Bardin-Dit-Courageot (2) , Valery Attignon (2) , Anthony Ferrari (5) , Gwenaele Garin (2) , David Perol (2) , Christophe Caux (2, 1) , Bertrand Dubois (2, 1) , Olivier Trédan (2, 1)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 Centre Léon Bérard [Lyon]
3 Hôpital privé Jean Mermoz [Lyon]
4 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]
5 Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas

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.

Mots clés: metastatic breast cancer; lymphopenia; immunotherapy; chemotherapy; immunomonitoring

Domaines: Cancer; Immunothérapie

Benoîte Mery, Christine Ménétrier-Caux, Laure Montané, Pierre-Etienne Heudel, Isabelle Ray-Coquard, et al.. Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study. Breast Cancer, 2023, 15, pp.311 - 325. ⟨10.2147/bctt.s400055⟩. ⟨hal-04210158⟩