Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort
Stephen R Fairclough1, Lesli A Kiedrowski1, Jessica J Lin2
1Guardant Health, Inc., 505 Penobscot Dr, Redwood City, CA 94063 USA.
Abstract:
Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.
Insights
Guardant360 detected EGFR L792 mutations, a new resistance mechanism to osimertinib, in non-small cell lung cancer patients. This finding aids in understanding and managing acquired resistance to targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) with EGFR mutations often develops resistance to targeted therapies like osimertinib.
- Cell-free DNA (cfDNA) next-generation sequencing (NGS) offers a non-invasive method to track tumor heterogeneity and treatment resistance.
- Acquired resistance mechanisms are crucial to understand for optimizing treatment strategies in EGFR-mutant NSCLC.
Purpose of the Study:
- To report the detection of EGFR L792 mutations, a novel non-covalent resistance mechanism, using cfDNA testing.
- To investigate the prevalence of concomitant EGFR L792 mutations in a large cohort of T790M-positive NSCLC patients.
- To assess the functional impact of EGFR L792 mutations on osimertinib resistance in vitro.
Main Methods:
- Utilized Guardant360 cfDNA testing for genomic analysis in a patient with metastatic EGFR-mutant NSCLC progressing on osimertinib.
- Analyzed a cohort of over 1800 cfDNA samples from patients with EGFR T790M mutations.
- Performed in vitro functional assays to evaluate the resistance conferred by specific EGFR mutations.
Main Results:
- Successfully detected EGFR L792 mutations, a non-covalent resistance mechanism, in a patient with NSCLC resistant to osimertinib.
- Identified concomitant EGFR L792 mutations in 22 out of 1800+ (1.2%) T790M-positive NSCLC cases.
- Demonstrated that EGFR L858R/T790M/L792F/H mutations confer intermediate resistance to osimertinib in vitro.
Conclusions:
- EGFR L792 mutations represent an emerging mechanism of acquired resistance to osimertinib in EGFR-mutant NSCLC.
- cfDNA testing is a valuable tool for detecting resistance mutations non-invasively.
- Understanding these resistance mechanisms can guide future treatment decisions for NSCLC patients.
