Distinct Resistant Mechanism And Genomic Evolution During Tki Treatment In Non-Small Cell Lung Cancer Patients With Or Without Acquired T790m Mutation.

e20603 Background: EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied. Methods: We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Correlation between genomic features and patients’ progression-free survival (PFS) was evaluated. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns. Results: We observed new pathways limiting EGFR-inhibitor response, including NOTCH1/ STK11 co-deletion, and TGF-beta alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Interestingly, we observed a death-and-birth process of RTK-RAS mutations during TKI treatment, and baseline and acquired RTK-RAS mutations had opposite effects on PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones. Conclusions: T790M-positive and T790M-negative patients display divergent landscape of acquired somatic events. Subgroups of patients were identified within T790M-positive and T790M-negative patients with distinct survival. Our results point the importance of clonal competition between T790M and non-T790M resistant subclones.