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Updated: Sep 19, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Circulating Tumor DNA in Advanced EGFRex20+ NSCLC: Concordance with Tissue Biopsy, Monitoring of Response, and
Fenneke Zwierenga1, M Benthe Muntinghe-Wagenaar2, Pim Rozendal3
1Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, HPC AA11, Postbus 30.001, 9700RB, Groningen, The Netherlands.
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.
Insights
High-dose osimertinib shows modest efficacy in advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations (EGFRex20+). Circulating tumor DNA (ctDNA) monitoring effectively tracks treatment response and identifies resistance mechanisms to osimertinib therapy.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations (EGFRex20+) has limited treatment options.
- High-dose osimertinib demonstrates modest anti-tumor activity and acceptable toxicity in this patient population.
- Plasma-derived circulating tumor DNA (ctDNA) offers a promising non-invasive method for monitoring treatment response and detecting resistance mechanisms.
Purpose of the Study:
- To evaluate the concordance of variants detected in ctDNA versus tissue samples at baseline and progression.
- To determine if alterations in mutant ctDNA levels predict response to high-dose osimertinib.
- To identify resistance mechanisms to high-dose osimertinib and analyze changes in ctDNA levels of EGFRex20+ variants.
Main Methods:
- Twenty-five patients with EGFRex20+ NSCLC received high-dose (160 mg daily) osimertinib.
- Blood plasma was collected at baseline, 6 weeks (T6), and at disease progression for ctDNA analysis using NGS Guardant360 CDx.
- Comparison of molecular profiles at progression with baseline/T6 and correlation of ctDNA level changes with treatment response or resistance.
Main Results:
- Baseline ctDNA detected somatic alterations in 95% of patients, with 65% concordance for EGFRex20+ variants in tumor biopsies.
- No significant correlation was found between changes in mutant ctDNA levels and osimertinib response across all timepoints.
- Decreased EGFRex20+ levels at T6 in nine patients correlated with tumor shrinkage; increased levels at progression in 64% of patients correlated with tumor growth.
- Resistance-associated variants, including EGFR p.C797S, were identified in 61% of patients at progression.
Conclusions:
- ctDNA analysis is a valuable tool for tracking variant dynamics in patients with EGFRex20+ NSCLC treated with high-dose osimertinib.
- This approach aids in the identification of emerging resistance mechanisms during therapy.
- ctDNA monitoring provides crucial insights into treatment response and resistance in this challenging NSCLC subtype.
