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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., Competing Interests: Benoîte Mery and Christine Ménétrier-Caux are co-first authors for this study. Bertrand Dubois and Olivier Trédan are co-last authors for this study. Dr Pierre-Etienne Heudel reports personal fees, non-financial support from PFIZER, GILEAD, NOVARTIS, SEAGEN, LILLY; personal fees from MSD, during the conduct of the study. Professor Isabelle Ray-Coquard reports grants, personal fees from MSD and BMS; personal fees from Astra ZENECA, GSK, CLOVIS, ROCHE, DAICHI, MERSANA, Immunogen, Pharmamar, during the conduct of the study. Dr Thomas Bachelot reports grants, personal fees, non-financial support from Novartis, AstraZeneca, Daiichi, Pfizer; grants, personal fees from SeaGen, outside the submitted work. Dr Paule Augereau reports personal fees, non-financial support from AstraZeneca, GSK, Seagen; personal fees from Novartis, outside the submitted work. Dr David Perol reports personal fees, travel funding from ROCHE, personal fees from TAKEDA, ASTRAZENECA, BAYER, BOEHRINGHER-INGELHEIM, BRISTOL-MYERS SQUIBB, DAIICHI-SANKYO, ELI-LILLY, IPSEN, NOVARTIS, MERCK SHARP AND DOHME, JANSSEN, PFIZER, outside the submitted work. Dr Olivier Trédan reports grants, personal fees from MSD, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Mery et al.)

Background: Diffuse-type tenosynovial giant cell tumour (D-TGCT) is a non-malignant but locally aggressive tumour driven by overexpression of colony-stimulating factor-1 (CSF1). CSF1R inhibitors are potential therapeutic strategies for patients not amenable to surgery. We report here the long-term outcome of nilotinib in patients with advanced D-TGCT treated within a phase II prospective international study (ClinicalTrials.gov: NCT01261429)., Methods: Patients were enrolled between December 2010-September 2012 at 11 cancer centres. Eligible patients had histologically confirmed D-TGCT, not amenable to surgery. Patients received nilotinib until evidence of progression, toxicity or a maximum of one year. Long-term data were retrospectively collected after the completion of the phase II trial. Patients with nilotinib treatment ≥12 weeks and follow-up ≥12 months were included for long-term analysis., Results: Forty-eight of 56 enrolled patients were included. Median treatment duration was 11 months; 31 (65%) patients completed the treatment protocol. After 102 months of follow-up (median; range 12-129), 25 patients (52%) had progression. The median progression-free survival (PFS) was 77 months. The five-year PFS rate was 53%. Fifteen patients (n = 15/46; 33%) experienced clinical worsening after 11 months (median). Twenty-seven patients (58%) received additional treatment, after which eleven patients (n = 11/27; 41%) had a second relapse. Nine patients required a subsequent treatment, primarily other CSF1R inhibitors (n = 6/9; 67%). No unfavourable long-term effects were observed., Conclusion: This long-term analysis of nilotinib for advanced D-TGCT showed that about half of the patients had progression and underwent additional treatment after 8.5 years follow-up. Contrarily, several patients had ongoing disease control after limited treatment duration, demonstrating the mixed effect of nilotinib., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Grimison, Christine Chevreau, Sophie Piperno-Neumann, Axel Le Cesne, Virginia Ferraresi, Antoine Italiano, Florence Duffaud, Nicolas Penel, Severine Metzger, Sylvia Chabaud, Lizz van der Heijden, Jean-Yves Blay, Hans Gelderblom declare no conflict of interest within the present study. Silvia Stacchiotti has no conflict of interest to declare within the present study; she reports institutional research funding from Amgen Dompe, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi Sankyo Pharma, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, and Hutchinson MediPharma International Inc; honoraria from Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, and Novartis; invited speaker fees/meeting support from GSK and PharmaMar; fees for expert testimony from Bavarian Nordic and Epizyme; and participation on a Data Safety Monitoring Board or Advisory Board for Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, and Novartis outside the submitted work. Geert Spierenburg and Michiel van de Sande report institutional research funding from Daichii-Sankyo outside the submitted work. David Perol received personal fees from AstraZeneca, Bayer, Boehringher-Ingelheim, Bristol Myers Squibb, Eli-Lilly, Ipsen, Roche, Novartis, Merck Sharp and Dohme, Takeda., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)