Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.

中文翻译：

---

以血液为基础的肿瘤突变负担可作为经atezolizumab治疗的非小细胞肺癌患者临床获益的预测指标。

尽管程序性死亡配体1程序性死亡1（PD-L1-PD-1）抑制剂具有广泛的疗效，但在高PD-L1表达或高肿瘤突变负担（TMB）的患者中观察到了改善的结局。对于一线非小细胞肺癌（NSCLC），检查点抑制剂单药治疗需要进行PD-L1检测。然而，获得足够的肿瘤组织用于晚期疾病患者的分子检测可能具有挑战性。因此，对于诊断方法存在未满足的医学需求，该诊断方法不需要组织来识别可能受益于免疫疗法的患者。在这里，我们描述了一种新颖的，技术上可靠的，基于血液的测定方法来测量血浆中的TMB（bTMB），这与基于组织的方法不同。使用两项大型随机试验的回顾性分析作为测试和验证研究，我们显示，bTMB可重现地鉴定出在第二线及更高级别的NSCLC中，来自atezolizumab（抗PD-L1）的无进展生存期的临床显着改善的患者。总体而言，我们的数据表明，高bTMB是非小细胞肺癌中atezolizumab的可临床操作的生物标志物。