Friends of Cancer Research, Washington, DC.
Cancer Research And Biostatistics (CRAB), Seattle, WA.
JCO Precis Oncol. 2022 Aug;6:e2100372. doi: 10.1200/PO.21.00372.
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; < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; < .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.
随着免疫检查点抑制剂（ICI）越来越多地在前线应用，需要确定早期反应的指标。最近的研究表明循环肿瘤 DNA（ctDNA）在监测 ICI 反应方面具有一定作用，但这些研究的普遍性存在不确定性。在此，通过评估五个独立研究的临床试验数据，采用标准化方法评估了 ctDNA 监测 ICI 反应的作用。
汇总并协调了五个独立临床试验的 200 名患者的患者水平临床和 ctDNA 数据，这些临床试验调查了程序性细胞死亡-1（PD-1）/程序性死亡配体-1（PD-L1）靶向单药治疗或联合化疗治疗非小细胞肺癌患者的疗效。使用不同的 ctDNA 检测方法在研究中测量 ctDNA 水平。使用每个独特患者样本中的所有体细胞肿瘤衍生变体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，在接受治疗的液体活检中，ctDNA 水平降低与 OS（OS；危险比，2.28；95%置信区间，1.62 至 3.20；<0.001）和 PFS（PFS；危险比 1.76；95%置信区间，1.31 至 2.36；<0.001）改善之间存在很强的关联。不同结果的最大变异等位基因频率 ctDNA 值的变化具有很强的相关性。
在对 5 项独立临床试验的汇总分析中，在接受 ICI 治疗的非小细胞肺癌患者的多个终点评估中，ctDNA 降低与结果之间存在一致且稳健的关联。应该在未来的分析中纳入更多的肿瘤类型、分期和药物类别，以进一步验证这一点。ctDNA 可能成为临床开发的重要工具和治疗获益的早期指标。
