Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Breast Cancer Research

Antonio Lopez-Alonso¹  Silvana Mouron¹  Manuel Muñoz¹  Ramon Colomer²  Juan V. Apala³  Miguel Quintela-Fandino⁴  Vega Iranzo⁵  Santos Mañes⁶  María C. Moreno-Ortíz⁶  Raquel Blanco⁶  Orlando Dominguez⁷  Eduardo Caleiras⁸  Javier Cortes⁹  Begoña Bermejo^1,10  Ariadna Gasol Cudos^1,11  Serafin Morales^1,11  Luis Manso^1,12  Javier Hornedo^1,13  Lucia Gonzalez-Cortijo^1,13  Esther Holgado^1,14  Diego Malon^1,15  Mario Martinez^1,16 

[1] Breast Cancer Clinical Research Unit – Clinical Research Program, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain;Breast Cancer Clinical Research Unit – Clinical Research Program, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain;Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain;Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;Breast Cancer Clinical Research Unit – Clinical Research Program, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain;Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain;Breast Cancer Clinical Research Unit – Clinical Research Program, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain;Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain;Medical Oncology Department, Hospital Universitario Quiron, Pozuelo de Alarcon, Spain;CIBERONC, Instituto Carlos III, Madrid, Spain;Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain;Medicine Department, Universitat de Valencia, Valencia, Spain;Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin, 3, 28049, Madrid, Spain;Genomics Core Unit – Biotechnology Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain;Histopathology Core Unit – Biotechnology Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain;ION Institute of Oncology, Quironsalud Group – Madrid & Barcelona, Barcelona, Spain;Vall d’Hebron Institute of Oncology, Barcelona, Spain;Medical Oncology Department, Hospital Clínico Universitario, Valencia, Spain;INCLIVA, Valencia, Spain;CIBERONC, Instituto Carlos III, Madrid, Spain;Medical Oncology Department, Hospital Universitari Arnau Vilanova, Lleida, Spain;Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain;Medical Oncology Department, Hospital Universitario Quiron, Pozuelo de Alarcon, Spain;Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain;Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain;Pathology Department, Hospital Universitario 12 de Octubre, Madrid, Spain;

关键词: Durvalumab;    Bevacizumab;    HER2-negative breast cancer;    Vascular normalization;    Immuno-priming;   

DOI  :  10.1186/s13058-020-01362-y

来源: Springer

【 摘 要 】

BackgroundPreclinical 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.MethodsPatients 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.ResultsTwenty-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 TREG 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 TREGs in non-progressors.ConclusionsThis 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 TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting.Trial registration(www.clinicaltrials.gov): NCT02802098. Registered on June 16, 2020.

【 授权许可】

CC BY