Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.
Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.
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DOI：
10.1200/po.21.00372
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发表时间：
2022-08
影响因子：
4.6
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随着免疫检查点抑制剂（ICI）越来越多地用于一线环境，需要确定早期反应指标。最近的研究表明循环肿瘤DNA （ctDNA）在监测对ICI的反应中起作用，但这些研究的普遍性存在不确定性。在这里，ctDNA在监测ICI应答中的作用通过标准化的方法进行评估，通过评估来自五项独立研究的临床试验数据。患者水平的临床和ctDNA数据汇集并协调了来自5项独立临床试验的200名患者的数据，这些试验研究了非小细胞肺癌患者的程序性细胞死亡-1 (PD-1)/程序性死亡配体-1 （PD-L1）定向单药治疗或联合化疗的治疗。在研究中使用不同的CtDNA检测来测量CtDNA水平。使用每个独特患者样本中所有体细胞肿瘤衍生的变异来计算最大变异等位基因频率，以将ctDNA变化与总生存期（OS）和无进展生存期（PFS）相关联。我们观察到治疗前液体活检中ctDNA水平的降低与改善OS （OS；风险比2.28;95% CI， 1.62至3.20;P < 0.001）和PFS （PFS；风险比1.76;95% CI， 1.31至2.36;P < 0.001）之间有很强的相关性。最大变异等位基因频率、ctDNA值的变化在不同结果之间显示出很强的相关性。在这项对五项独立临床试验的汇总分析中，在ICI治疗的非小细胞肺癌患者的多个终点评估中，发现ctDNA的减少与结果之间存在一致且强大的关联。未来的分析应包括其他肿瘤类型、分期和药物类别，以进一步验证这一点。CtDNA可以作为临床开发的重要工具和治疗效果的早期指标。
As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies. Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non–small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)–directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS). We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes. In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non–small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.