Zwierenga Fenneke, Muntinghe-Wagenaar M Benthe, Rozendal Pim, de Langen Adrianus J, Hendriks Lizza E L, van den Heuvel Michel, van der Leest Cor, Hashemi Sayed M S, van der Leest Paul, Hiltermann T Jeroen N, Schuuring Ed, van der Wekken Anthonie J
Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, HPC AA11, Postbus 30.001, 9700RB, Groningen, The Netherlands.
Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Target Oncol. 2025 Jun 5. doi: 10.1007/s11523-025-01153-5.
High-dose osimertinib shows modest anti-tumor activity and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor exon 20 mutation (EGFRex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.
We aimed to assess the concordance between variants detected in ctDNA to those found in corresponding tissue samples at baseline and progression, to analyze alterations in mutant ctDNA levels of EGFRex20+ variants as predictors of therapy response, and to identify resistance mechanisms to high-dose osimertinib as well as examine changes in mutant ctDNA levels of EGFRex20+ variants.
Twenty-five patients with EGFRex20+ NSCLC received double dose (160 mg) osimertinib daily. Blood plasma was collected at baseline, 6 weeks after therapy start (T6), and at progression. ctDNA analysis was performed using the NGS Guardant360 CDx panel. The molecular profile at progression was compared with baseline/T6, and changes in ctDNA levels of the EGFRex20+ variants were linked to response or resistance.
Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS EGFRex20+ variant in 65%. Among 14 patients with profiling at all timepoints, there was no significant correlation between changes in mutant ctDNA levels and osimertinib response. At T6, nine patients showed decreased EGFRex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased EGFRex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, n = 14), insertions (n = 2), and gene fusions (n = 1). Mutations previously related to osimertinib resistance were found, including EGFR p.C797S (n = 1).
ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.
高剂量奥希替尼对携带表皮生长因子受体第20外显子突变（EGFRex20+）的晚期非小细胞肺癌（NSCLC）患者显示出适度的抗肿瘤活性和可接受的毒性。血浆来源的循环肿瘤DNA（ctDNA）在监测治疗反应和检测耐药机制方面具有前景。
我们旨在评估基线和疾病进展时ctDNA中检测到的变异与相应组织样本中发现的变异之间的一致性，分析EGFRex20+变异的突变ctDNA水平变化作为治疗反应的预测指标，并确定对高剂量奥希替尼的耐药机制以及检查EGFRex20+变异的突变ctDNA水平变化。
25例EGFRex20+ NSCLC患者每天接受双倍剂量（160 mg）奥希替尼治疗。在基线、治疗开始后6周（T6）和疾病进展时采集血浆。使用NGS Guardant360 CDx检测板进行ctDNA分析。将疾病进展时的分子特征与基线/T6进行比较，并将EGFRex20+变异的ctDNA水平变化与反应或耐药相关联。
对收集的ctDNA样本进行回顾性分析。基线ctDNA显示19/20例患者（95%）存在体细胞改变，相应肿瘤活检的NGS检测显示EGFRex20+变异的比例为65%。在所有时间点均进行分析的14例患者中，突变ctDNA水平变化与奥希替尼反应之间无显著相关性。在T6时，9例患者的EGFRex20+水平降低，其中8例患者肿瘤缩小。在疾病进展时，9/14例（64%）患者的EGFRex20+水平升高，与肿瘤生长相关。11/18例（61%）患者中发现了可能与耐药相关的变异：单核苷酸变异（SNV，n = 14）、插入（n = 2）和基因融合（n = 1）。发现了先前与奥希替尼耐药相关的突变，包括EGFR p.C797S（n = 1）。
ctDNA分析可追踪变异动态，并能识别接受高剂量奥希替尼治疗的EGFRex20+ NSCLC患者的耐药机制，并提供有价值的新见解。
