Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy
Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy
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DOI：
10.1200/po.20.00321
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发表时间：
2021-03-01
影响因子：
4.6
通讯作者：
Aggarwal, Charu
中科院分区：
文献类型：
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作者：
Thompson, Jeffrey C.;Carpenter, Erica L.;Aggarwal, Charu
虽然大多数缺乏可检测靶向突变的转移性非小细胞肺癌（mNSCLC）患者将在一线接受基于pembrolizumab的治疗，但预测哪些患者将获得持久的临床获益（DCB）仍然具有挑战性。材料和方法接受pembrolizumab单药治疗或联合化疗的mNSCLC患者在基线和第9周获得的血液样本上进行了74个基因的下一代测序。使用比率计算定量治疗中循环肿瘤DNA水平的变化（分子应答），其中应答定义为平均变异等位基因分数降低> 50%。使用RECIST 1.1评估患者反应; DCB定义为完全或部分反应或持续> 6个月的稳定疾病。记录无进展生存期和总生存期。结果：在67例患者中，51例（76.1%）在变异等位基因分数> 0.3%时检测到> 1个变异，因此有资格从配对基线和9周样本中计算分子应答。客观放射学缓解患者的分子学缓解值显著较低（对数平均值1.25%对27.7%，P <0.001）。与无持久获益的患者相比，获得DCB的患者的分子学缓解值显著较低（对数平均值3.5% v49.4%，P <0.001）。与分子无应答者相比，分子应答者的无进展生存期（风险比，0.25; 95%CI，0.13 - 0.50）和总生存期（风险比，0.27; 95%CI，0.12 - 0.64）显著延长。结论：使用循环肿瘤DNA进行的分子缓解评估可作为mNSCLC中除标准治疗成像外对基于pembrolizumab治疗的缓解的非侵入性、治疗中预测因子。这一策略需要在独立的前瞻性研究中进行验证。
PURPOSE Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.