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

• Main Authors: Diego Enrico, MD, Ludovic Lacroix, PharmD, PhD, Jeanne Chen, MD, Etienne Rouleau, PharmD, PhD, Jean-Yves Scoazec, MD, PhD, Yohann Loriot, MD, PhD, Lambros Tselikas, MD, Cécile Jovelet, PharmD, PhD, David Planchard, MD, PhD, Anas Gazzah, MD, Laura Mezquita, MD, PhD, Maud Ngo-Camus, MSc, Stefan Michiels, PhD, Christophe Massard, MD, PhD, Gonzalo Recondo, MD, PhD, Francesco Facchinetti, MD, Jordi Remon, MD, Jean-Charles Soria, MD, PhD, Fabrice André, MD, PhD, Gilles Vassal, MD, PhD, Luc Friboulet, PhD, Benjamin Besse, MD, PhD
• Format: Article
• Language: English
• Published: Elsevier 2020-06-01
• Series: JTO Clinical and Research Reports
• Subjects: EGFR resistance; Oncogene fusions; NSCLC; EGFR tyrosine kinase inhibitors
• Online Access: http://www.sciencedirect.com/science/article/pii/S2666364320300230

Introduction: Despite initial benefit, virtually all patients suffering from EGFR-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 EGFR-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 EGFR-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 (EIF4G2-GAB1) 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 (FGFR3-TACC3) (n = 2), kinesin family member 5B–Ret proto-oncogene (KIF5B-RET) (n = 1), striatin–anaplastic lymphoma kinase (STRN-ALK) (n = 1), and zinc finger DHHC-Type palmitoyltransferase 20–Thr790Met (ZDHHC20-BRAF) (n = 1) transcripts. Out of two patients that received osimertinib at first-line, one acquired an FGFR3-TACC3 fusion at progression. In all patients, fusions co-occurred with the original activating EGFR 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.