PO.CL01.07 · 临床研究
临床级循环肿瘤DNA甲基化预测ALK重排NSCLC患者对brigatinib联合局部巩固治疗的疗效——BRIGHTSTAR试验的液体活检相关性分析
Clinical grade circulating tumor DNA methylation predicts outcome to brigatinib plus local consolidative therapy in patients with ALK rearranged NSCLC - Liquid biopsy correlates from the BRIGHTSTAR trial
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：II期BRIGHTSTAR试验评估了brigatinib联合局部巩固治疗在ALK重排非小细胞肺癌患者中的疗效，显示出令人鼓舞的临床活性，5年无进展生存率达51%（Elamin等，WCLC，2025）。为更好地刻画能从该治疗方案中获益的患者，我们开展了临床级ctDNA甲基化分析，用于检测残留病灶及判断预后。
方法：我们对29例经确认ALK重排、接受局部巩固治疗（LCT）和brigatinib治疗（BRIGHTSTAR；NCT03707938）的IV期或复发性非小细胞肺癌（NSCLC）患者的84份样本进行了分析。样本采集时间点包括治疗前基线、brigatinib诱导治疗8周时（局部巩固治疗前，Pre-LCT）、局部巩固治疗后（Post-LCT）以及疾病进展时。样本采用Guardant INFINITY平台进行分析，利用DNA甲基化检测ctDNA。数据通过Kaplan-Meier分析和cox比例风险比与治疗期间的无进展生存期相关联。
结果：循环肿瘤DNA在各时间点持续被检出，检出率分别为基线时72%（N = 21/29）、Pre-LCT时39%（N = 11/28）、Post-LCT时29%（N = 7/24）以及进展时80%（N = 4/5），表明brigatinib联合LCT治疗方案对ctDNA的清除并不充分。然而，采用DNA甲基化分类器（ctDNA METH）在基线时未检出ctDNA的患者，其无进展生存期显著长于可检出ctDNA的患者（38.2个月对比未达到；log-rank p = 0.04；HR = 0.16（95% CI：0.02-1.19））。对于在LCT前或LCT后清除ctDNA的患者，以及与治疗前时间点相比ctDNA持续被检出的患者，其疗效未见统计学显著差异。
结论：临床级ctDNA甲基化分析能够灵敏地检出ALK重排NSCLC患者的ctDNA，并可预测brigatinib联合LCT治疗的疗效。
查看英文原文 English abstract
Background: The phase II BRIGHTSTAR trial assessing the combination of brigatinib with local consolidative therapy in patients with ALK rearranged non-small cell lung cancer demonstrated promising clinical activity with a 5-year progression-free survival rate of 51% (Elamin et al. WCLC. 2025). To better characterize patients that would benefit of this treatment regimen, we performed clinical grade ctDNA methylation analysis for the detection of residual disease and prognostic.
Methods: We profiled 84 samples from 29 patients with stage IV or recurrent non-small cell lung cancer (NSCLC) and confirmed ALK rearrangement that were treated with local consolidative therapy (LCT) and brigatinib (BRIGHTSTAR; NCT03707938). Sample timepoints included baseline prior to therapy, at 8 weeks of brigatinib induction prior to local consolidative therapy (Pre-LCT) as well as after local consolidative therapy (Post-LCT) and at progression. Samples were profiled using the Guardant INFINITY platform for the detection of ctDNA using DNA methylation. Data was correlated to progression-free survival on treatment using Kaplan-Meier analysis and cox proportional hazard ratio.
Results: Circulating tumor DNA was persistently detected across timepoints with detection rates of 72% (N = 21/29) at baseline, 39% Pre-LCT (N = 11/28), 29% Post-LCT (N = 7/24) and 80% at progression (N = 4/5) demonstrating insufficient ctDNA clearing by brigatinib plus LCT treatment regimen. However, patients without detectable ctDNA at baseline using the DNA methylation classifier (ctDNA METH ) had significantly longer progression-free survival compared to patients with detectable ctDNA (38.2 months versus not reached; log-rank p = 0.04; HR = 0.16 (95% CI: 0.02-1.19)). No statistically significant difference in outcome was reported for patients who clear ctDNA Pre- or Post-LCT and patients with persistently detected ctDNA compared to pretreatment timepoint.
Conclusions: Clinical grade ctDNA methylation analysis allows the sensitive detection of ctDNA in patients with ALK rearranged NSCLC and is prognostic of outcome to brigatinib plus LCT therapy.
利益披露 Disclosure
S. Heeke,
BMS ).
Guardant Health Independent Contractor.
Roche Diagnostics Independent Contractor.
Sophia Genetics Travel.
Thermo Fisher Scientific Independent Contractor, ), Travel.
S. Gandhi,
Nanobiotix ).