Journal Article

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

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

2020

Overview

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 T REG 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 REGs 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 T REGs 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Angiogenesis Inhibitors - administration & dosage / Angiogenesis Inhibitors - adverse effects / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antigens / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Agents, Immunological - adverse effects / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Automation / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - immunology / B7-H1 Antigen - metabolism / Bevacizumab / Bevacizumab - administration & dosage / Bevacizumab - adverse effects / Biomedical and Life Sciences / Biomedicine / Biopsy / Brain cancer / Breast - pathology / Breast cancer / Breast Neoplasms - blood / Breast Neoplasms - drug therapy / Breast Neoplasms - immunology / Breast Neoplasms - pathology / Cancer Research / Cancer therapies / Chemotherapy / Clinical trials / Cloning / Cytometry / Disease Progression / Durvalumab / ErbB-2 protein / Female / Gene expression / HER2-negative breast cancer / Humans / Immune checkpoint inhibitors / Immuno-priming / Immunohistochemistry / Immunotherapy / Leukocytes (mononuclear) / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Middle Aged / Monoclonal antibodies / Oncology / Patients / PD-L1 protein / Peripheral blood / Peripheral blood mononuclear cells / Pilot Projects / Progression-Free Survival / Proof of Concept Study / Receptor, ErbB-2 - analysis / Research Article / Surgical Oncology / T cells / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Targeted cancer therapy / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / Vascular endothelial growth factor / Vascular normalization