Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Republic of China; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Republic of China.
J Thorac Oncol. 2018 Jul;13(7):958-967. doi: 10.1016/j.jtho.2018.03.032. Epub 2018 Apr 21.
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.
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.
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.
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.
在体外模型中，贝伐珠单抗（bevacizumab，BEV）具有免疫调节作用。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）联合 BEV 可改善表皮生长因子受体（EGFR）突变型肺腺癌患者的无进展生存期（progression-free survival，PFS）。但 BEV 发挥这种临床疗效的机制尚不清楚。
共纳入 55 例Ⅳ期 EGFR 突变型肺腺癌患者。采用流式细胞术分析骨髓来源抑制细胞（MDSCs）、辅助性 T 细胞 1（Th1）和辅助性 T 细胞 2（Th2）及细胞毒性 T 淋巴细胞。收集临床资料进行分析。
共 25 例患者接受 EGFR-TKI 联合 BEV 治疗（BEV/TKI 组），30 例患者接受 EGFR-TKI 单药治疗（TKI 组）。与 TKI 组相比，BEV/TKI 组患者 PFS 更长（23.0 个月比 8.6 个月，p=0.001），颅内控制率更高（80.0%比 43.0%，p=0.03），颅内进展时间更长（49.1 个月比 12.9 个月，p=0.002），新发脑转移瘤更少（38.0%比 71.0%，p=0.03）。BEV/TKI 组患者治疗后循环 MDSCs 百分比更低（治疗前 20.4%±6.5%比治疗后 12.8%±6.6%，p=0.02），治疗后 Th1 细胞百分比更高（22.9%±15.3%比 33.2%±15.6%，p<0.01），细胞毒性 T 淋巴细胞百分比更高（15.5%±7.2%比 21.2%±5.6%，p<0.01），而 TKI 组患者治疗前后上述指标差异均无统计学意义。治疗前 MDSCs 百分比与 PFS 相关，BEV/TKI 治疗后这种相关性减弱。MDSCs 百分比与颅内进展时间也有关。
EGFR-TKI 联合 BEV 可延长 PFS 并预防脑转移。这种疗效可能是由于 BEV 减少了循环 S100A9 阳性 MDSCs，从而恢复了有效的抗肿瘤免疫。我们的数据也支持 BEV-免疫检查点抑制剂联合治疗的合理性。
