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Bevacizumab Reduces S100A9‐Positive MDSCs Linked to Intracranial Control in Patients with EGFR‐Mutant Lung Adenocarcinoma

P. Feng,Kuan‐Yuan Chen,Yu-Chen Huang,C. Luo,Shen Ming Wu,Tzu-Tao Chen,Chun-Nin Lee,C. Yeh,H. Chuang,Chia-Li Han,Chiou-Feng Lin,Wei-Hwa Lee,C. Kuo,Kang-Yun Lee

Published 2018 in Journal of Thoracic Oncology

ABSTRACT

Introduction: In vitro models have demonstrated immune‐modulating effects of bevacizumab (BEV). Combinations of an EGFR tyrosine kinase inhibitor (TKI) with BEV improve progression‐free survival (PFS) in patients with EGFR‐mutated lung adenocarcinoma. How BEV confers this clinical effect and the underlying mechanisms of its effect are not clear. Methods: A total of 55 patients with stage 4 EGFR‐mutated lung adenocarcinoma were enrolled. Myeloid‐derived suppressor cells (MDSCs), type 1 and type 2 helper T cells, and cytotoxic T lymphocytes were analyzed by flow cytometry. Clinical data were collected for analysis. Result: In all, 25 patients received EGFR TKI and BEV combination therapy (the BEV/TKI group) and 30 patients received EGFR TKI monotherapy (the TKI‐only group). The BEV/TKI group had longer PFS (23.0 versus 8.6 months [p = 0.001]) and, in particular, better intracranial control rates (80.0% versus 43.0% [p = 0.03]), a longer time to intracranial progression (49.1 versus 12.9 months [p = 0.002]), and fewer new brain metastases (38.0% versus 71.0% [p = 0.03]) than the TKI‐only group did. The BEV/TKI group had a lower percentage of circulating MDSCs (20.4% ± 6.5% before treatment versus 12.8% ± 6.6% after treatment, respectively [p = 0.02]), and higher percentages of type 1 helper T cells (22.9% ± 15.3% versus 33.2% ± 15.6% [p < 0.01]) and cytotoxic T lymphocytes (15.5% ± 7.2% versus 21.2% ± 5.6% [p < 0.01]) after treatment, changes that were not seen in the TKI‐only group. Pretreatment percentage of MDSCs was correlated with PFS, with this correlation attenuated after BEV/TKI treatment. Percentage of MDSCs was also associated with shorter time to intracranial progression. Conclusion: Combining a EGFR TKI with BEV extended PFS and protected against brain metastasis. Those effects were probably due to the reduction of circulating S100A9‐positive MDSCs by BEV, which leads to restoration of effective antitumor immunity. Our data also support the rationale for a BEV–immune checkpoint inhibitor combination.

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