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Background <p>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 (<i>EGFR</i>ex20+). Plasma-derived circulating tumor DNA (ctDNA) is promising in monitoring responses and detecting resistance mechanisms to therapy.</p> Objective <p>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 <i>EGFR</i>ex20+ 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 <i>EGFR</i>ex20+ variants.</p> Patients and Methods <p>Twenty-five patients with <i>EGFR</i>ex20+ 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 <i>EGFR</i>ex20+ variants were linked to response or resistance.</p> Results <p>Collected ctDNA samples were analyzed retrospectively. Baseline ctDNA showed somatic alterations in 19/20 patients (95%) and the corresponding tumor biopsy NGS <i>EGFR</i>ex20+ 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 <i>EGFR</i>ex20+ levels, with eight also showing tumor shrinkage. At disease progression, 9/14 (64%) patients had increased <i>EGFR</i>ex20+ levels, correlating with tumor growth. Variants potentially associated with resistance were found in 11/18 patients (61%): single nucleotide variants (SNV, <i>n</i> = 14), insertions (<i>n</i> = 2), and gene fusions (<i>n</i> = 1). Mutations previously related to osimertinib resistance were found, including <i>EGFR</i> p.C797S (<i>n</i> = 1).</p> Conclusions <p>ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with <i>EGFR</i>ex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.</p>

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Circulating Tumor DNA in Advanced EGFRex20+ NSCLC: Concordance with Tissue Biopsy, Monitoring of Response, and Resistance to High-Dose Osimertinib

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月5日

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  • Fenneke Zwierenga,
  • M. Benthe Muntinghe-Wagenaar,
  • Pim Rozendal,
  • Adrianus J. de Langen,
  • Lizza E. L. Hendriks,
  • Michel van den Heuvel,
  • Cor van der Leest,
  • Sayed M. S. Hashemi,
  • Paul van der Leest,
  • T. Jeroen N. Hiltermann,
  • Ed Schuuring,
  • Anthonie J. van der Wekken

摘要

Background

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.

Objective

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.

Patients and Methods

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.

Results

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).

Conclusions

ctDNA analysis tracks variant dynamics and can identify resistance mechanisms in patients with EGFRex20+ NSCLC treated with high-dose osimertinib, offering valuable new insights.