P1.14-24 Characterization of Acquired Receptor Tyrosine Kinase Fusions as Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors

Abstract

Responses to EGFR targeted therapy are generally temporary due to evitable drug resistance. The prevalence and characteristics of receptor tyrosine kinase (RTK) fusions as acquired resistance to EGFR-TKIs are rarely investigated. We retrospectively reviewed genomic profiling data of 3873 EGFR (exon 18-21)-mutant lung cancer patients with more than once NGS detection. A total of 16 patients who acquired RTK fusions during EGFR-TKI treatment with paired pre- and post- EGFR-TKI samples were identified. Their treatment history was collected. The newly acquired RTK fusions during EGFR-TKI treatment included RET (n = 6, 37.5%), ALK (n = 5, 31.3%), NTRK1 (n = 4, 25.0%), ROS1 (n = 1, 6.3%) and FGFR3 (n = 1, 6.3%). All the RET and EML4-ALK fusions were uncommon variants non-KIF5B-RET and E2:A20 (V5), respectively. Interestingly, RET fusion occurred only after osimertinib treatment, and contributed to drug resistance in 50.0% (6/12) of patients treated with osimertinib, indicating that fusions had different prevalence when functioned as resistance mechanisms to EGFR-TKI. Moreover, we found that in all patients developing drug resistance to EGFR-TKIs due to fusion emergence (n=16), those had treatment history of third-generation EGFR-TKI accounted for 75.0% (n=12). We extended the current knowledge of resistance mechanisms to EGFR-TKIs in non-small cell lung cancer. Detection of RTK fusions should be included in genomic profiling panels to uncover potential resistance mechanism of EGFR-TKI which might inform therapeutic strategies such as combination therapy approaches to circumvent tumorigenesis.