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作者：SCI天天读
SCI
27 April 2024
Clinical utility of circulating tumor DNA in patients with advanced KRASG12C-mutated non-small cell lung cancer treated with sotorasib.
(Journal of Thoracic Oncology, IF: 20.40)
Sophie M. Ernst, Ronald van Marion, Peggy N. Atmodimedjo, Evert de Jonge, Ron H.J. Mathijssen, Marthe S. Paats, Peter de Bruijn, Stijn L. Koolen, Jan H. von der Thüsen, Joachim G.J.V. Aerts, Ron H.N. van Schaik, Hendrikus J. Dubbink, Anne- Marie C. Dingemans
CORRESPONDENCE TO: a.dingemans@erasmusmc.nl
Introduction 引言
For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA), as well as treatment-emergent alterations upon disease progression.
针对接受Sotorasib治疗的KRASG12C突变非小细胞肺癌（NSCLC）患者，目前缺乏用于指导治疗决策的生物标志物。因此，我们研究了治疗前及治疗中循环肿瘤DNA（ctDNA）的临床效用，以及疾病进展时因治疗出现的新变异。
Methods 方法
Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected prior to sotorasib treatment, at first response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency (VAF) analysis. Tumor response and progression-free survival (PFS) was assessed per RECIST v1.1.
接受Sotorasib治疗的KRASG12C突变非小细胞肺癌患者，被前瞻性纳入我们的生物标志物研究（NCT05221372）。在Sotorasib治疗前、首次反应评估及疾病进展时收集血浆样本。使用TruSight Oncology 500 板进行ctDNA及变异等位基因频率（VAF）分析。根据RECIST v1.1标准评估肿瘤反应和无进展生存期（PFS）。
Results 结果
Pre-treatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior PFS (HR 2.13 [95% CI 1.06 – 4.30], p=0.031) and overall survival (OS) (HR 2.61 [95% CI 1.16 – 5.91], p=0.017). At first response evaluation (n=40), 29 patients (73%) had a molecular response. Molecular non-responders had inferior OS (HR 3.58 [95% CI 1.65 – 7.74], p<0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p=0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations.
在66名患者中，有50名（76%）在治疗前检测到KRASG12C ctDNA。检测到KRASG12C的患者具有较差的PFS（HR 2.13 [95% CI 1.06 – 4.30], p=0.031）和较差的总生存期（OS）（HR 2.61 [95% CI 1.16 – 5.91], p=0.017）。在首次反应评估时（n=40），29名患者（73%）出现了分子反应。分子无反应者的OS较差（HR 3.58 [95% CI 1.65 – 7.74], p<0.00059）。具有分子反应的患者的疾病控制率显著更高（97%对比64%，p=0.015）。KRAS扩增被识别为反复出现的治疗新变异。
Conclusions 结论
Our data suggest detectable pre-treatment KRASG12C ctDNA as a marker for poor prognosis, and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.
我们的数据表明，治疗前可检测到的KRASG12C ctDNA是预后不良的标志，治疗中ctDNA清除率是治疗产生反应的标志。我们识别出KRAS扩增是潜在的对Sotorasib治疗耐药的机制。识别具有更佳预后的患者可能有助于优化治疗启动时间，而识别有早期进展风险的患者可更早做出治疗决策。
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