In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann-Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5-9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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通过靶向NGS评估的肿瘤突变负担预测了非小细胞肺癌中免疫检查点抑制剂的临床获益。

在非小细胞肺癌（NSCLC）中，免疫检查点抑制剂（ICIs）可以显着提高整体生存率（OS）。肿瘤突变负担（TMB）已经成为ICI治疗患者的一种预测性生物标志物。在这里，我们评估了通过Oncomine™肿瘤突变负荷靶向测序测定法对76名接受ICI治疗的NSCLC患者的TMB预测能力。回顾性评估了接受ICI治疗的76例NSCLC患者的TMB。收集临床数据（RECIST 1.1），将患者分为具有持久性临床获益（DCB）或无持久性益处（NDB）的患者。此外，评估了遗传改变和PD-L1表达，并将其与TMB和反应率进行了比较。DCB患者的TMB明显高于NDB患者（中位TMB = 8.5对6.0突变/ Mb，Mann-Whitney p = 0.0244）。高TMB（截止值=第三三分位数，TMB≥9）的患者中有64％是响应者（DCB），而中TMB和低TMB的患者分别为33％和29％（截止值=第二和第一三分位数， TMB = 5-9和TMB≤4）。高TMB的患者显示出更长的无进展生存期（PFS）和OS（对数秩检验p = 0.0014（PFS）和0.0197（OS））。在确定患者的不同亚组时，将PD-L1表达和TMB结合使用可提高预测能力（从AUC 0.63到AUC 0.65）。我们的结果表明，TML面板是对ICI治疗患者进行分层的有效工具。生物标记物的组合可能会最大程度地提高患者分层的预测准确性。我们的研究通过靶向NSCLC患者样品中的NGS来支持TMB评估，以此作为预测对ICI治疗反应的工具。我们提供了在常规诊断环境中对TMB进行可靠且具有成本效益的评估的建议。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。