IDENTIFYING EGFR EXON 20 INSERTION MUTATIONS (EX20INS) IN NON-SMALL CELL LUNG CANCER (NSCLC): A NEW TARGETED THERAPY PERSPECTIVE

EGFR tyrosine kinase inhibitors (TKIs) highlited the beginning of the precision therapy era for NSCLC. In this context, the ex20ins is the third most common EGFR mutation founded. Patients with EGFR ex20ins mutations have not demonstrated the same sensitivity to TKIs (eg. gefitinib and erlotinib) as canonical activating EGFR mutations (eg. exon 19 deletion and L858R), and have generally a poor prognosis. On the other hand, some emerging therapies targeting EGFR ex20ins, as the monoclonal bispecific anti-EGFR-MET antibody, have been recently approved by the U.S. Food and Drug Administration and European Medicines Agency. Furthermore, the enlarged of next-generation sequencing (NGS) in clinical practice improved the knowledge of uncommon mutations. Here, we describe the molecular features of EGFR mutations samples (n=5820 brazilian patients with NSCLC, of which 33,8% had EGFR mutation-positive). DNA was extracted with the QiaSymphony platform. Hotspot regions were amplified with customized panel (Thermo Fisher), and submitted to NGS using the Ion S5 System. The generated sequences were aligned against the hg19 reference and processed in the bioinformatics pipeline (Ion Torrent/Ion Reporter). The frequency of the ex20ins mutation was 2,11% among all patients with NSCLC and 6% among those with EGFR mutations . Other driver mutations showed the following frequencys: 40% in 19 exon deletion, 32% in L858R, and others common mutations ranged from 2-4% (E709X, G719X, T790M, S768I, L861Q). EGFR ex20ins presented highest frequencies than reviously reported for Asia Pacific region (0,1%–4% all NSCLC cases and 1%–5% of mutated EGFR) and the US (0,5%–2,6% and 5%–12%). This may be due to ethnicity, or due to the variation in the genotyping method used, with less sensitivity of complex insertions. Among all ex20ins mutations, we observed a high heterogeneity of in-frame insertions (between 1–4 amino acids), with 23 rare mutations identified, harboring p.A767_V769dup (14,8%), p.A768_V770dup and p.M767_A768insSVD (11,3%), p.N771_H773dup, p.H773_V774insHPH and p.M766_A767insASV (7%). In this study we demonstrate a growing ex20ins incidence, denoting that this mutation would be increasingly clinically relevant. It’s a promise for future therapeutic options that will be effective for patients with NSCLC.