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)

Background. FGFR1/2/3 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. Methods. The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and FGFR2/3 fusions; FGFR2/3 fusion prevalence with and without a co-existing EGFR 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 FGFR1/2/3 fusions. Patients with EGFR mutant aNSCLC progressing on EGFR TKIs and developing an FGFR1/2/3 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. Results. In the GH ED (n = 57,445), the prevalence of FGFR2 and FGFR3 fusions were 0.02% and 0.26%, respectively. FGFR3-TACC3 fusion predominated (91.5%). In 23.8% of cases, FGFR2/3 fusions co-existed with EGFR sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent FGFR fusions and EGFR sensitizing mutations, 41.0% also included EGFR resistant mutations. In TASMC (n = 161), 1 case of de novo FGFR3-TACC3 fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with FGFR3-TACC3 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. Conclusions. Over 23% of FGFR2/3 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