Background

In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear.

Patient and methods

Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis.

Result

Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4±6.5% vs. 12.8±6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9±15.3% vs. 33.2±15.6%, p<0.01) and CTLs (15.5±7.2% vs. 21.2±5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression.

Conclusion

Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9⁺ MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.

中文翻译：

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贝伐单抗可降低与EGFR突变型肺腺癌患者颅内控制相关的S100A9 ⁺ MDSC

背景

体外模型已证明贝伐单抗具有免疫调节作用。的组合EGFR酪氨酸激酶抑制剂（TKI）与贝伐单抗提高无进展的患者存活（PFS）EGFR突变的肺腺癌。贝伐单抗如何赋予这种临床效果，其潜在机制尚不清楚。

患者和方法

入选了55例4期EGFR突变的肺腺癌患者。通过流式细胞仪分析了骨髓来源的抑制细胞（MDSCs），T辅助细胞（Th1 / Th2）和细胞毒性T淋巴细胞（CTL）。收集临床数据进行分析。

结果

25例患者接受EGFR-TKI和BEV联合治疗（BEV / TKI组），而30例患者接受EGFR-TKI（TKI组）单药治疗。BEV / TKI组的PFS较长（23.0 vs. 8.6个月，p = 0.001），尤其是颅内控制率更高（80.0％vs. 43.0％，p = 0.03），颅内进展时间更长（49.1 vs. 12.9个月） ，p = 0.002）和新发脑转移瘤的比例（38.0％对71.0％，p = 0.03）少于TKI组。BEV / TKI组的循环MDSCs较低（分别为治疗前和治疗后的20.4±6.5％vs.12.8±6.6％，p = 0.02）和较高的Th1（22.9±15.3％vs.33.2±15.6％，p <0.01）和CTL（15.5±7.2％对21.2±5.6％，p<0.01），仅TKI组未见变化。预处理MDSC与PFS相关，Bev / TKI治疗后相关性减弱。MDSC还与较短的颅内进展时间有关。

结论

将EGFR-TKI与贝伐单抗联合使用可延长PFS并保护其免受脑转移。这些作用可能是由于贝伐单抗降低了循环中的S100A9 ⁺ MDSCs，从而导致有效的抗肿瘤免疫力得以恢复。我们的数据也支持BEV免疫检查点抑制剂组合的基本原理。