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Updated: Jun 30, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Determining the optimal approach to identify osimertinib resistance; the first line osimertinib cohort of the OSIRIS
J W T van der Wel1, S M Ernst2, M Jebbink1
1Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Background:
Resistance mechanisms (RMs) inevitably develop during osimertinib treatment in EGFR mutation positive (EGFRm+) NSCLC, and may guide subsequent therapy. We hypothesized that a complete RM analysis requires next-generation sequencing (NGS) of tumor tissue and plasma in patients experiencing disease progression (PD) on first-line osimertinib.
Methods:
At time of PD during osimertinib treatment, patients underwent plasma and tissue NGS for RM analysis. Plasma was analyzed with AVENIO ctDNA expanded panel, tissue with DNA and RNA NGS following local standards. Successful sequencing was defined by EGFRm identification.
Results:
Between February 2020 and January 2024, 150 patients were enrolled. Plasma sequencing was successful in 84 %, tissue sequencing in 94 %, both in 81 % of patients. In total, 159 RMs covered by both modalities were identified, 76 % in tissue, 59 % in plasma. Concordance was 34 %. In 54 patients, EGFR, MET and/or ERBB2 were amplified. At least one amplification was found in both sources for 17 patients, in tissue only for 25. Median EGFRm variant allele frequency (VAF) in plasma differed between these groups (25.9 vs 3.0 %, P < 0.05).
Conclusions:
In case of low EGFRm VAF in plasma, combining tumor and plasma sequencing uncovers additional RMs compared to any single modality. Utilizing both for complete RM assessment is therefore recommended.
Clinicaltrials:
gov Identifier: NCT04737382.
Insights
Comprehensive analysis of resistance mechanisms in EGFR-mutated NSCLC requires both tumor and plasma next-generation sequencing. Combining these methods detects more resistance mechanisms than single-modality testing, guiding future treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Acquired resistance to osimertinib is common in EGFR-mutated non-small cell lung cancer (NSCLC).
- Understanding resistance mechanisms (RMs) is crucial for guiding subsequent therapies.
- Next-generation sequencing (NGS) of both tumor tissue and plasma is proposed for comprehensive RM analysis.
Purpose of the Study:
- To evaluate the utility of combined plasma and tissue NGS for identifying RMs in patients with EGFR-mutated NSCLC progressing on osimertinib.
- To compare the concordance and complementary findings between plasma and tissue NGS for RM detection.
Main Methods:
- 150 patients with EGFR-mutated NSCLC experiencing disease progression on first-line osimertinib were enrolled.
- Plasma and tissue samples underwent NGS for RM analysis.
- Successful sequencing was defined by EGFR mutation identification.
Main Results:
- Plasma and tissue NGS were successful in 81% of patients when combined.
- 159 RMs were identified, with 76% in tissue and 59% in plasma; concordance was 34%.
- In 54 patients, EGFR, MET, and/or ERBB2 amplifications were detected; combined analysis identified additional RMs in 17 patients compared to single sources.
Conclusions:
- Combining tumor and plasma sequencing is recommended for a complete assessment of RMs.
- This integrated approach uncovers additional RMs, particularly in cases with low EGFR mutation variant allele frequency (VAF) in plasma.
- Comprehensive RM profiling aids in optimizing treatment strategies for NSCLC patients.
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