非小细胞肺癌（NSCLC）患者的免疫检查点抑制剂生物标志物的预测性能有限。本研究旨在调查循环肿瘤DNA（ctDNA）中分子肿瘤负荷指数（mTBI）作为预测非小细胞肺癌患者免疫治疗可行性的可能性。从2017年2月至2020年11月，分析了接受免疫单药治疗或联合治疗的NSCLC患者的治疗前和治疗期（首个免疫治疗周期后3~6周）动态血浆ctDNA样本，利用目标捕获测序分析了1021个基因。使用PyClone推断mTBI。在POPLAR/OAK试验中验证了治疗前mTBI对生存结果的影响。 我们发现，无法检测到基线ctDNA的患者具有更好的生存结果（中位总生存期[OS]：尚未达到vs.12.8个月；风险比[HR]，0.15；p=0.035）。RB1和SMARCA4突变与较差的生存结果明显相关。此外，较低的治疗前mTBI与较好的OS（中位：尚未达到vs.8.1个月；HR，0.22；p=0.024）和PFS（中位：32.9 vs.5.4个月；HR，0.35；p=0.045）相关，但无关客观反应，这在POPLAR/OAK队列中得到了验证，表明基线mTBI是NSCLC免疫治疗的预后因子。mTBI的早期动态变化（ΔmTBI）可明显区分出对治疗有反应的患者，且在最终肿瘤评估中mTBI减少到超过68％的患者具有更长的OS（中位：38.2 vs.4.0个月；HR，0.18；p=0.017）和PFS（中位：尚未达到vs.2.3个月；HR，0.24；p=0.030）。ΔmTBI对鉴定基于最佳效果CT扫描的潜在受益患者具有良好的敏感性，表明mTBI动态是预测免疫检查点阻滞受益的指标。 © 2023中国肺癌学组和约翰威立澳大利亚有限公司出版。《胸腔肿瘤》由中国肺癌学组和约翰威立澳大利亚有限公司出版。

The biomarkers of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC.From February 2017 to November 2020, pretreatment and on-treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials.We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030).ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade.© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.