结合基因组生物标志物指导非小细胞肺癌免疫疗法
Joris van de Haar1,2,3, Joanne M Mankor4, Karlijn Hummelink5
1Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
概括
瘤突变负担 (TMB) 与STK11,KEAP1和EGFR变异相结合,可以预测非小细胞肺癌 (NSCLC) 的免疫检查点阻塞 (ICB) 反应. 高TMB甚至预测了这些生物标志物的反应,避免过度处理.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 基因组学就是基因组学.
背景情况:
- 在预测非小细胞肺癌 (NSCLC) 免疫检查点阻塞 (ICB) 反应中,STK11,KEAP1和EGFR变化的临床实用性受到争议.
- 矛盾的是,一些患有这些遗传变化的NSCLC患者对ICB治疗有持久的反应.
- 需要精细的组合生物标志物策略来准确识别可能受益于ICB的患者.
研究的目的:
- 开发一种更具体的组合生物标记方法,用于预测NSCLC中的ICB不响应.
- 评估STK11,KEAP1和EGFR变化的预测价值与瘤突变负担 (TMB) 结合用于ICB响应.
主要方法:
- 对254名接受PD-L1阻断单疗治疗的NSCLC患者进行了全面分析.
- 在发现队列 (n=75) 中使用全基因组测序 (WGS) 和在验证队列 (n=169) 中使用大面板测序.
- 评估了STK11/KEAP1/EGFR变化的特异性,用于低 (<10 muts/Mb) 和高 (≥10 muts/Mb) TMB层的ICB不响应.
主要成果:
- 在低TMB NSCLC中,STK11/KEAP1/EGFR变异对于ICB耐药性 (0-2.9%的应答率) 具有高度特异性.
- 在高TMB NSCLC中,这些变化的显著比例的患者仍然显示了持久的ICB益处 (44-85%的应答率).
- 无进展和整体存活分析支持了这些发现.
结论:
- 在STK11,KEAP1或EGFR变异的患者中,意外的ICB反应主要在高TMB患者中观察到.
- 整合TMB与STK11,KEAP1和EGFR变异提供了一个高度特定的组合生物标志物策略.
- 这种方法可以帮助限制接受ICB治疗的NSCLC患者的过度治疗.
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