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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
EGFR Mutation Analysis for Prospective Patient Selection in Two Phase II Registration Studies of Osimertinib
Suzanne Jenkins1, James Chih-Hsin Yang2, Pasi A Jänne3
1AstraZeneca, Macclesfield, United Kingdom.
Introduction:
Osimertinib is an oral, central nervous system-active, EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR T790M-positive advanced NSCLC. Here we have evaluated EGFR mutation frequencies in two phase II studies of osimertinib (AURA extension and AURA2).
Methods:
After progression while receiving their latest line of therapy, patients with EGFR mutation-positive advanced NSCLC provided tumor samples for mandatory central T790M testing for the study selection criteria. Tumor tissue mutation analysis for patient selection was performed with the Roche cobas EGFR Mutation Test (European Conformity-in vitro diagnostic, labeled investigational use only) (Roche Molecular Systems, Pleasanton, CA). Patients should not have been prescreened for T790M mutation status. The cobas test results were compared with those of the MiSeq next-generation sequencing system (Illumina, San Diego, CA), which was used as a reference method.
Results:
Samples from 324 and 373 patients screened for AURA extension and AURA2, respectively, produced valid cobas test results. The T790M detection rates were similar between AURA extension and AURA2 (64% and 63%, respectively). The pooled T790M rate was 63%, with no difference by ethnicity (63% for Asian and non-Asian patients alike) or immediately prior treatment with an EGFR TKI (afatinib, 69%; erlotinib, 69%; and gefitinib, 63%). A higher proportion of patients had T790M detected against a background of exon 19 deletions versus L858R mutation (73% versus 58% [p = 0.0002]). In both trials the cobas test demonstrated high sensitivity (positive percent agreement) and specificity (negative percent agreement) for T790M detection when compared with the next-generation sequencing reference method: positive percent agreement of 91% versus 89% and negative percent agreement of 97% versus 98%.
Conclusions:
In both trials, the rate of detection of T790M mutation in patients with advanced NSCLC was approximately 63% and was unaffected by immediately prior treatment with an EGFR TKI or ethnicity.
Insights
The Roche cobas EGFR Mutation Test detected the T790M mutation in 63% of advanced non-small cell lung cancer (NSCLC) patients, regardless of ethnicity or prior EGFR TKI treatment. This test showed high accuracy compared to next-generation sequencing.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) for EGFR T790M-positive advanced non-small cell lung cancer (NSCLC).
- Evaluating EGFR mutation frequencies is crucial for optimizing targeted therapies in NSCLC.
Purpose of the Study:
- To assess EGFR T790M mutation frequencies in patients with advanced NSCLC within two Phase II studies of osimertinib (AURA extension and AURA2).
- To evaluate the diagnostic performance of the Roche cobas EGFR Mutation Test for T790M detection against a next-generation sequencing reference method.
Main Methods:
- Tumor samples from patients with EGFR mutation-positive advanced NSCLC, after disease progression, were tested for T790M mutation using the Roche cobas EGFR Mutation Test.
- The cobas test results were compared with those obtained from the Illumina MiSeq next-generation sequencing system, used as the reference standard.
- Patient selection for the studies required mandatory central T790M testing, but prescreening for T790M status was not permitted.
Main Results:
- A total of 324 and 373 patients' samples yielded valid cobas test results in the AURA extension and AURA2 studies, respectively.
- The T790M detection rate was consistent across both studies, with a pooled rate of 63%.
- Detection rates were similar across ethnicities and unaffected by prior EGFR TKI treatment (afatinib, erlotinib, gefitinib). A higher T790M detection rate was observed in patients with EGFR exon 19 deletions compared to L858R mutations (73% vs. 58%).
- The cobas test demonstrated high sensitivity (91% positive percent agreement) and specificity (97% negative percent agreement) compared to next-generation sequencing.
Conclusions:
- The T790M mutation was detected in approximately 63% of advanced NSCLC patients across both trials.
- The detection rate was not influenced by ethnicity or the specific EGFR TKI used in prior therapy.
- The Roche cobas EGFR Mutation Test proved to be a sensitive and specific method for T790M detection in this patient population.
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