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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Breast Cancer | Research article

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

Authors: Miguel Quintela-Fandino, Esther Holgado, Luis Manso, Serafin Morales, Begoña Bermejo, Ramon Colomer, Juan V. Apala, Raquel Blanco, Manuel Muñoz, Eduardo Caleiras, Vega Iranzo, Mario Martinez, Orlando Dominguez, Javier Hornedo, Lucia Gonzalez-Cortijo, Javier Cortes, Ariadna Gasol Cudos, Diego Malon, Antonio Lopez-Alonso, María C. Moreno-Ortíz, Silvana Mouron, Santos Mañes

Published in: Breast Cancer Research | Issue 1/2020

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Abstract

Background

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.

Methods

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.

Results

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 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.

Conclusions

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 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.
Appendix
Available only for authorised users
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Metadata
Title
Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial
Authors
Miguel Quintela-Fandino
Esther Holgado
Luis Manso
Serafin Morales
Begoña Bermejo
Ramon Colomer
Juan V. Apala
Raquel Blanco
Manuel Muñoz
Eduardo Caleiras
Vega Iranzo
Mario Martinez
Orlando Dominguez
Javier Hornedo
Lucia Gonzalez-Cortijo
Javier Cortes
Ariadna Gasol Cudos
Diego Malon
Antonio Lopez-Alonso
María C. Moreno-Ortíz
Silvana Mouron
Santos Mañes
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01362-y

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