许多生物标志物被提出来预测对抗程序性细胞死亡蛋白1 (PD-1) /抗程序性死亡配体1 (PD-L1) 检查点抑制剂 (CPI) 的反应。然而，冲突的观察结果和缺乏一致性需要对其在大规模数据集中进行临床效用评估。我们使用临床试验和实际数据的组合数据集，评估了生物标志物对非小细胞肺癌 (NSCLC) 中 CPI 的临床结果的预测和预后效用。回顾性队列研究使用从电子健康记录中选择的24,152名患者，这些患者是从71,850名晚期 NSCLC 患者中选择出来的，以及9个罗氏阿替麦注射试验。患者被分为高和低生物标志物组。研究不同生物标志物组的治疗结果的相关性，并比较接受 CPI 与化疗的患者之间的差异。持久反应被定义为在270天的研究期内具有完全反应/部分反应且没有进展。标准的血液分析物 (例如白蛋白和淋巴细胞) 仅仅是一种预测因子，与治疗类型无关的临床结果有关。肿瘤 PD-L1 高表达 (≥50% 肿瘤细胞染色) 特别与对 CPI 的反应相关 (OR 0.20; 95% CI 0.13 至 0.30; p<0.001)。该关联在非鳞状组织学、吸烟史或先前化疗的患者中更强，而不是鳞状组织学、无吸烟史或第一线 CPI 的患者中更强。更高的肿瘤突变负荷 (TMB) (≥10.44 mut/Mb) 也特别与对 CPI 的持久反应相关 (OR=0.40; 95% CI 0.29 至 0.54; p<0.001)。高 TMB 和 PD-L1 表达的组合是持久反应对 CPI 的最强预测因子 (OR=0.04; 95% CI 0.00 至 0.18; p<0.001)。PD-L1 或 TMB 水平与化疗的反应之间没有显著关联，这表明了 CPI 特异性的预测效应。标准的血液分析物只有预测效用，而肿瘤 PD-L1 和 TMB 特别预测 NSCLC 中对 CPI 的反应。高 TMB 和 PD-L1 表达组合是持久反应的最强预测因子。PD-L1 在非鳞状组织学、吸烟史或先前化疗的患者中也是更强的预测因子。 © 作者（或其雇主）2023年。根据 CC BY-NC 允许重新使用。不允许商业再利用。由 BMJ 发布。

Many biomarkers have been proposed to be predictive of response to anti-programmed cell death protein-1 (PD-1)/anti-programmed death ligand-1 (PD-L1) checkpoint inhibitors (CPI). However, conflicting observations and lack of consensus call for an assessment of their clinical utility in a large data set. Using a combined data set of clinical trials and real-world data, we assessed the predictive and prognostic utility of biomarkers for clinical outcome of CPI in non-small cell lung cancer (NSCLC).Retrospective cohort study using 24,152 patients selected from 71,850 patients with advanced NSCLC from electronic health records and 9 Roche atezolizumab trials. Patients were stratified into high and low biomarker groups. Correlation with treatment outcome in the different biomarker groups was investigated and compared between patients treated with CPI versus chemotherapy. Durable response was defined as having complete response/partial response without progression during the study period of 270 days.Standard blood analytes (eg, albumin and lymphocyte) were just prognostic, having correlation with clinical outcome irrespective of treatment type. High expression of PD-L1 on tumors (≥50% tumor cell staining) were specifically associated with response to CPI (OR 0.20; 95% CI 0.13 to 0.30; p<0.001). The association was stronger in patients with non-squamous than squamous histology, with smoking history than non-smokers, and with prior chemotherapy than first-line CPI. Higher tumor mutational burden (TMB) (≥10.44 mut/Mb) was also specifically associated with durable response to CPI (OR=0.40; 95% CI 0.29 to 0.54; p<0.001). The combination of high TMB and PD-L1 expression was the strongest predictor of durable response to CPI (OR=0.04; 95% CI 0.00 to 0.18; p<0.001). There was no significant association between PD-L1 or TMB levels with response to chemotherapy, suggesting a CPI-specific predictive effect.Standard blood analytes had just prognostic utility, whereas tumor PD-L1 and TMB specifically predicted response to CPI in NSCLC. The combined high TMB and PD-L1 expression was the strongest predictor of durable response. PD-L1 was also a stronger predictor in patients with non-squamous histology, smoking history or prior chemotherapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.