Department of Medical Oncology.
Department of Circulating Tumor Biomarkers Laboratory.
Ann Oncol. 2017 Aug 1;28(8):1996-2001. doi: 10.1093/annonc/mdx212.
Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.
This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.
ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004).
This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
最近的临床结果支持使用新型免疫检查点抑制剂（ICB），如抗 PD-1（如 nivolumab 和 pembrolizumab）和抗 PD-L1 抗体。由于肿瘤免疫浸润，在治疗过程中对 ICB 疗效进行影像学评估具有挑战性。治疗过程中循环肿瘤 DNA（ctDNA）水平的变化可能是一种非常准确监测治疗效果的有前途的工具，但缺乏 ICB 的相关数据。
这项前瞻性的初步研究在巴黎居里研究所接受 nivolumab 或 pembrolizumab 单药治疗的非小细胞肺癌、葡萄膜黑色素瘤或微卫星不稳定结直肠癌患者中进行。根据突变类型，通过双向焦磷酸酶激活聚合、液滴数字 PCR 或下一代测序在基线和 8 周（w8）时评估 ctDNA 水平。通过使用免疫相关反应标准对治疗效果进行影像学评估。
在 15 名患者中，有 10 名患者在基线时检测到 ctDNA。在 w8 时，ctDNA 水平的同步变化与肿瘤大小之间存在显著相关性（r=0.86；P=0.002）。在 w8 时 ctDNA 水平无法检测到的患者对治疗反应明显且持久。w8 时 ctDNA 的检测也是无进展生存期（风险比=10.2；95%置信区间 2.5-41，P<0.001）和总生存期（风险比=15；95%置信区间 2.5-94.9，P=0.004）的显著预后因素。
这项初步研究首次证明，定量 ctDNA 监测是评估接受抗 PD-1 药物治疗的患者肿瘤反应的有价值工具。
