二线奥希替尼治疗期间的纵向循环肿瘤DNA引导的耐药性分析
Longitudinal Circulating Tumor DNA-Guided Resistance Analysis During Second-Line Osimertinib Treatment.
作者信息
van der Wel J W Tijmen, Jebbink Merel, van der Noort Vincent, Lalezari Ferry, van den Broek Daan, Ruiter Gerrina, Burgers Jacobus A, Baas Paul, van Lindert Anne S R, van der Wall Eva E, Kastelijn Lisanne E A, Vermeulen Marrit, Bosch Linda J W, Monkhorst Kim, Boelens Mirjam C, Smit Egbert F, de Langen Adrianus J
机构信息
Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
出版信息
JTO Clin Res Rep. 2025 May 26;6(9):100853. doi: 10.1016/j.jtocrr.2025.100853. eCollection 2025 Sep.
INTRODUCTION
In osimertinib-treated EGFR mutation (EGFRm)-positive NSCLC, resistance inevitably occurs. Early resistance mechanism (RM) detection by circulating tumor DNA (ctDNA) in plasma and consecutive targeted treatment may delay progressive disease (PD). In this multicenter prospective study, we evaluated the detection rate and time interval of RM emergence in plasma ctDNA before radiologic PD.
METHODS
Patients with EGFRm-positive NSCLC, treated with second- or third-line osimertinib, underwent computed tomography of the thorax and ctDNA analysis (Roche AVENIO expanded panel, research use only [Roche Sequencing Solutions, Roche, Basel, Switzerland]) at baseline and every 8 weeks for response evaluation and EGFRm and RM detection. If MET amplification preceded PD, crizotinib was to be added to osimertinib. Other RMs were monitored but not acted on. After PD, patients underwent a tumor biopsy.
RESULTS
Of the 21 evaluable patients, 18 had detectable ctDNA at baseline. In patients with undetectable ctDNA at baseline, ctDNA remained undetectable during treatment. In the 17 out of 18 (94%) patients with detectable ctDNA, PD occurred. In seven out of 21 patients (33%), the EGFRm variant allele frequency increase preceded radiologic PD with a median interval of 9 weeks (range 7-34). In seven out of 21 patients (33%), at least one RM was detected before PD, and the median interval was 14 weeks (range 7-34). Three had one or more RM in ctDNA at baseline. No MET amplification was observed, and treatment with crizotinib was not initiated in any patient. After PD, 16 biopsies were obtained. Five confirmed the RM detected in plasma, five biopsies revealed additional RMs, and six harbored no RM.
CONCLUSIONS
In 33% of patients treated with second- or third-line osimertinib, RMs in plasma preceded PD by a median of 14 weeks, suggesting an opportunity for early treatment adjustment, potentially extending tyrosine kinase inhibitor treatment duration.
引言
在接受奥希替尼治疗的表皮生长因子受体突变（EGFRm）阳性非小细胞肺癌（NSCLC）中，耐药不可避免地会出现。通过检测血浆中循环肿瘤DNA（ctDNA）来早期发现耐药机制（RM）并进行连续靶向治疗，可能会延迟疾病进展（PD）。在这项多中心前瞻性研究中，我们评估了在影像学显示PD之前，血浆ctDNA中RM出现的检出率和时间间隔。
方法
接受二线或三线奥希替尼治疗的EGFRm阳性NSCLC患者，在基线时以及每8周接受一次胸部计算机断层扫描和ctDNA分析（罗氏AVENIO扩展检测板，仅用于研究[罗氏测序解决方案，罗氏，瑞士巴塞尔]），以评估疗效以及检测EGFRm和RM。如果在PD之前检测到MET扩增，则将克唑替尼添加到奥希替尼治疗方案中。对其他耐药机制进行监测，但不采取相应措施。PD后，患者接受肿瘤活检。
结果
在21例可评估患者中，18例在基线时可检测到ctDNA。基线时ctDNA检测不到的患者，在治疗期间ctDNA仍检测不到。18例可检测到ctDNA的患者中有17例（94%）发生了PD。21例患者中有7例（33%），EGFRm变异等位基因频率增加先于影像学PD出现，中位间隔时间为9周（范围7 - 34周）。21例患者中有7例（33%）在PD之前检测到至少一种耐药机制，中位间隔时间为14周（范围7 - 34周）。3例患者在基线时ctDNA中存在一种或多种耐药机制。未观察到MET扩增，且未对任何患者启动克唑替尼治疗。PD后，获得了16份活检样本。5份样本证实了血浆中检测到的耐药机制，5份活检样本显示出其他耐药机制，6份样本未发现耐药机制。
结论
在接受二线或三线奥希替尼治疗的患者中，33%的患者血浆中的耐药机制比PD提前出现，中位时间为14周，这表明有机会进行早期治疗调整，可能延长酪氨酸激酶抑制剂的治疗持续时间。
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