Oncogenic Fusions May Be Frequently Present at Resistance of EGFR Tyrosine Kinase Inhibitors in Patients With NSCLC: A Brief Report.

Introduction: Despite initial benefit, virtually all patients suffering from -mutant NSCLC experience acquired resistance to tyrosine kinase inhibitors (TKIs), driven by multiple mechanisms. Recent reports have identified oncogenic kinase fusions as off-target resistance mechanisms; however, these alterations have been rarely investigated at EGFR TKIs progression.

Methods: Patients with -mutated metastatic NSCLC (N = 62) with tissue and plasma biopsies at EGFR TKI progression between January 2015 and June 2019, at a French hospital and optionally before progression, were identified from the prospective MATCH-R study (NCT02517892). Postprogression biopsy samples were analyzed for gene fusions using targeted gene panel sequencing, whole-exome sequencing, RNA sequencing, and comparative genomic hybridization array.

Results: Six gene fusions were detected in tumor progression biopsies under an EGFR TKI from 62 consecutive patients (9.7%) with -mutated advanced NSCLC. Among 31 patients progressing to first- or second-generation EGFR TKIs, one (3%) had an Eukaryotic translation initiation factor 4 gamma 2-GRB2 associated binding protein 1 () fusion. Among 31 patients progressing to the third-generation osimertinib, five (16%) presented oncogene fusions of fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 () (n = 2), kinesin family member 5B-Ret proto-oncogene () (n = 1), striatin-anaplastic lymphoma kinase () (n = 1), and zinc finger DHHC-Type palmitoyltransferase 20-Thr790Met () (n = 1) transcripts. Out of two patients that received osimertinib at first-line, one acquired an fusion at progression. In all patients, fusions co-occurred with the original activating mutation; however, among four patients with an acquired T790M mutation, three (75%) lost the T790M mutation.

Conclusions: Oncogenic fusions at the time of EGFR TKI resistance were identified at a relatively high frequency, mainly after the third-generation TKI osimertinib. Patients progressing to EGFR TKIs may have a new opportunity for targeted therapy when oncogenic fusions are identified.