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

BACKGROUND: 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 1(st) generation EGFR-tyrosine kinase inhibitor (TKI) treatment. However, which subgroup of patients carry concurrent resistance mechanisms and have poor responsiveness to osimertinib remains unknown. METHODS: Matched re-biopsy tissue and plasma samples obtained from 32 patients who had progression following 1(st) 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. RESULTS: 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 T790M RAF (<20%) had significantly lower objective response rates (ORRs) (0 vs. 68.8%, P=0.03) and disease control rates (DCRs) (60% vs. 100%, P=0.048) in response to osimertinib compared to patients with high T790M RAF. CONCLUSIONS: In patients with progressive NSCLC post 1(st) generation EGFR-TKI treatment, plasma T790M RAFs of less than 20% can be used to identify patients who carry concurrent resistance mechanisms, and can predict a poorer response to osimertinib. TRIAL REGISTRATION: This study was registered on http://www.chictr.org.cn (registration number: ChiCTR-DDD-16007900).