FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC)

fusions have been reported infrequently in aNSCLC, including as a rare, acquired resistance mechanism following treatment with EGFR TKIs. Data regarding their prevalence and therapeutic implications are limited. The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and fusions; fusion prevalence with and without a co-existing mutation was assessed. The ED of Tel-Aviv Sourasky Medical Center (TASMC, June 2020-June 2021) was evaluated for cases of aNSCLC and de novo fusions. Patients with mutant aNSCLC progressing on EGFR TKIs and developing an fusion were selected from the ED of Davidoff Cancer Center (DCC) and Oncology Department, Bnei-Zion hospital (BZ) (April 2014-April 2021). Clinicopathological characteristics, systemic therapies, and outcomes were assessed. In the GH ED ( = 57,445), the prevalence of and fusions were 0.02% and 0.26%, respectively. fusion predominated (91.5%). In 23.8% of cases, fusions co-existed with sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent fusions and sensitizing mutations, 41.0% also included resistant mutations. In TASMC ( = 161), 1 case of de novo fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with fusions following progression on EGFR TKIs, two received EGFR TKI plus erdafitinib, an FGFR TKI, with clinical benefit duration of 13.0 and 6.0 months, respectively. Over 23% of fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.