Title:
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Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer : a pilot clinical trial
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Author:
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Quintela-Fandino, Miguel; Holgado, Esther; Manso, Luis; Morales, Serafin; Bermejo, Begoña; Colomer, Ramon; Apala, Juan V.; Blanco, Raquel; Muñoz, Manuel; Caleiras, Eduardo; Iranzo, Vega; Martínez López, Mario; Dominguez, Orlando; Hornedo, Javier; Gonzalez-Cortijo, Lucia; Cortés, Javier; Gasol Cudos, Ariadna; Malon, Diego; Lopez-Alonso, Antonio; Moreno-Ortíz, María C.; Mouron, Silvana; Mañes, Santos; Universitat Autònoma de Barcelona
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Abstract:
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Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased T signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating T in non-progressors. This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing T cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. (www.clinicaltrials.gov):. Registered on June 16, 2020 |
Subject(s):
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-Durvalumab -Bevacizumab -HER2-negative breast cancer -Vascular normalization -Immuno-priming |
Rights:
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open access
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Document type:
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Article |
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Uri:
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https://ddd.uab.cat/record/253078
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