Reduced sensitivity for EGFR T790M mutations using the Idylla EGFR Mutation Test

Area of Science:

• Oncology
• Molecular Diagnostics
• Genetics

Background:

• Osimertinib targets EGFR T790M mutations in non-small cell lung cancer (NSCLC).
• The Idylla EGFR Mutation Test offers rapid detection of EGFR mutations, including T790M.
• Uncertainty exists regarding the sensitivity of the Idylla assay for T790M detection, with reported false negatives.

Purpose of the Study:

• To evaluate the sensitivity of the Idylla EGFR Mutation Test for detecting the T790M mutation in NSCLC.
• To compare the performance of the Idylla assay against next-generation sequencing (NGS) and droplet digital PCR (ddPCR).
• To identify factors associated with false-negative T790M results from the Idylla assay.

Main Methods:

• Eighty NSCLC samples were analyzed using both the Idylla EGFR Mutation Test and an NGS assay.
• Samples with T790M mutations confirmed by NGS were further validated using ddPCR.
• Variant allele frequencies (VAF) and specific EGFR polymorphisms were assessed.

Main Results:

• The Idylla assay detected 14 out of 19 T790M mutations with VAF >5%, yielding a sensitivity of 74% (95% CI 49% to 90%).
• False negative results were linked to higher EGFR control Cq values, presence of the EGFR Q787Q polymorphism in cis, and invalid T790M amplification curves.
• The assay also failed to detect an EGFR exon 19 indel with VAF >5% in two samples.

Conclusions:

• The Idylla EGFR Mutation Test demonstrates reduced sensitivity for T790M detection compared to NGS and ddPCR.
• An invalid T790M amplification curve may signal a false negative result, requiring confirmation with an orthogonal method.
• Clinical utility of the Idylla assay for T790M requires careful consideration due to potential false negatives.