Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing
Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing
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DOI：
10.1200/jco.2017.75.3384
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发表时间：
2018-03-01
影响因子：
45.3
通讯作者：
Hellmann, Matthew D.
中科院分区：
文献类型：
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作者：
Rizvi, Hira;Sanchez-Vega, Francisco;Hellmann, Matthew D.
目的免疫检查点抑制剂(ICIS)治疗晚期非小细胞肺癌具有持久的疗效和改善部分患者的生存率的特点。需要临床上可用的工具来优化ICIS的使用并了解反应的分子决定因素。靶向下一代测序(NGS)日益成为常规，但其在识别ICIS应答预测因素中的作用尚不清楚。方法收集接受抗程序性死亡-1或抗程序性死亡配体1[抗程序性细胞死亡(PD)-1]治疗的晚期非小细胞肺癌患者的详细临床注释和应答数据，并通过靶向NGS(MSK-IMPACT；n=240)进行描述。根据实体瘤反应评估标准(RECIST)1.1版评估疗效，持久临床受益(DCB)定义为持续6个月的部分反应/稳定疾病。比较接受DCB和无持久受益(NDB)的患者的肿瘤突变负担(TMB)、拷贝数改变的基因组比例和基因改变。对49例患者进行全外显子组测序(WES)，比较靶向NGS和WES对TMB的定量。结果靶向NGS估计的TMB与WES有很好的相关性(P=0.86；P<；.001)。DCB患者的TMB大于NDB患者(P=0.006)。DCB更常见，当TMB的阈值高于或低于50%时，患者的无进展生存期更长(38.6%比25.1%；P<；.001；风险比，1.38；P=.024)。拷贝数改变的基因组比例在NDB患者中最高。EGFR和STK11的变异与缺乏益处相关。TMB和PD-L1的表达是自变量，TMB和PD-L1的组合进一步丰富了对ICIS的益处。结论目标性NGS准确地估计了TMB和升高的TMB，进一步提高了对ICIS的益处。TMB与PD-L1表达无相关性；两个变量具有相似的预测能力。将TMB和PD-L1的表达结合到多变量预测模型中应该会产生更大的预测能力。(C)2018年美国临床肿瘤学会
PurposeTreatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known.MethodsDetailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [antiprogrammed cell death (PD)-1]therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES.ResultsEstimates of TMB by targeted NGS correlated well with WES (p = 0.86; P < .001). TMB was greater in patients with DCB than with NDB (P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1 %; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number-altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs.ConclusionTargeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power. (C) 2018 by American Society of Clinical Oncology