Low T790M relative allele frequency indicates concurrent resistance mechanisms and poor responsiveness to osimertinib

Translational Lung Cancer Research
Ye WangWeimin Li

Abstract

T790M relative allele frequency (RAF) in plasma, calculated by the ratio of T790M to epidermal growth factor receptor (EGFR)-sensitizing mutation allele frequencies (AF), is associated with osimertinib response in patients with progressive non-small cell lung cancer (NSCLC) post 1st generation EGFR-tyrosine kinase inhibitor (TKI) treatment. However, which subgroup of patients carry concurrent resistance mechanisms and have poor responsiveness to osimertinib remains unknown. Matched re-biopsy tissue and plasma samples obtained from 32 patients who had progression following 1st generation EGFR-TKI treatment were genotyped using next-generation sequencing (NGS) to investigate which subgroup of patients, classified by plasma position 790 (T790M) RAF, were more likely to carry concurrent resistance mechanisms. In another independent cohort, consisting of 21 T790M-positive patients, we validated whether these patients had a poor response to osimertinib treatment. In the discovery cohort, patients with T790M RAF less than 20% were more likely to harbor concurrent resistance mechanisms (P=0.018), such as MET or ERBB2 amplification, and small cell lung cancer transformation. In the validation cohort, we found that patients with low T790...Continue Reading

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