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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
EGFR T790M mutation testing within the osimertinib AURA Phase I study
Simon Dearden1, Helen Brown1, Suzanne Jenkins2
1Personalised Healthcare & Biomarkers, AstraZeneca, Cambridge, UK.
Objectives:
Reliable epidermal growth factor receptor (EGFR) mutation testing techniques are required to identify eligible patients with EGFR mutation/T790M positive advanced non-small cell lung cancer (NSCLC), for treatment with osimertinib (AZD9291), an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR-TKI-sensitizing and T790M resistance mutations over wild-type EGFR. There is no current consensus regarding the best method to detect EGFR T790M mutations. The aim of this study was to describe the concordance between local testing, which used a variety of methods, and central testing, using the cobas® EGFR Mutation Test, for EGFR-sensitizing mutations and the T790M resistance mutation.
Materials And Methods:
Tumor samples were obtained from all patients screened for inclusion onto the osimertinib Phase I expansion component of the AURA Phase I/II study (NCT01802632). Samples underwent central laboratory testing for EGFR-sensitizing mutations and T790M resistance mutation using the cobas® EGFR Mutation Test. Results were compared with local laboratory test results, based on other testing methodologies including Sanger sequencing, therascreen®, PNAClamp™, and Sequenom MassARRAY®.
Results:
Central laboratory testing was successful in 99% of samples passing histopathology review and testing success rates were comparable across the three central laboratories. Concordance between central and local testing for common sensitizing mutations was high (>98%) and concordance for the T790M mutation was also high (>90%). Tumor heterogeneity, along with other technical factors may have influenced this result.
Conclusions:
Within the osimertinib AURA Phase I study, EGFR mutation testing across three centralized laboratories using the cobas® EGFR Mutation Test was feasible and successful, with strong concordance between local and central laboratory results, including for T790M. The cobas® EGFR Mutation Test has subsequently been approved as the companion diagnostic test for osimertinib in the USA and Japan.
Insights
Accurate epidermal growth factor receptor (EGFR) mutation testing is crucial for non-small cell lung cancer (NSCLC) patients. This study found high concordance between local and central testing methods for EGFR mutations, including T790M, supporting the cobas® EGFR Mutation Test.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- Accurate epidermal growth factor receptor (EGFR) mutation testing is essential for identifying patients with advanced non-small cell lung cancer (NSCLC) eligible for targeted therapies like osimertinib.
- The T790M mutation confers resistance to earlier EGFR tyrosine kinase inhibitors (TKIs) and is a key target for newer agents.
- There is a lack of consensus on the optimal method for detecting EGFR T790M mutations.
Purpose of the Study:
- To evaluate the concordance between local and central testing methods for EGFR mutations, specifically sensitizing mutations and the T790M resistance mutation.
- To assess the reliability of the cobas® EGFR Mutation Test for identifying patients suitable for osimertinib treatment.
Main Methods:
- Tumor samples from patients screened for the osimertinib AURA Phase I/II study were analyzed.
- Central testing was performed using the cobas® EGFR Mutation Test.
- Results were compared against local laboratory results obtained through various methods, including Sanger sequencing, therascreen®, PNAClamp™, and Sequenom MassARRAY®.
Main Results:
- Central laboratory testing demonstrated high success rates (99%) across three facilities.
- High concordance was observed between central and local testing for common EGFR sensitizing mutations (>98%) and the T790M resistance mutation (>90%).
- Tumor heterogeneity and technical factors may have influenced the observed concordance rates.
Conclusions:
- EGFR mutation testing using the cobas® EGFR Mutation Test in centralized laboratories is feasible and successful.
- Strong concordance between local and central testing, including for T790M, supports its use in clinical practice.
- The cobas® EGFR Mutation Test has been approved as a companion diagnostic for osimertinib in the USA and Japan.
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