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)

Abstract

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.

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK‐rearranged non–small cell lung cancer

“…This combination treatment was tolerable for the mice and induced marked shrinkage of H3122 LR3 tumor (Figure 4C). In addition to FGFR abnormalities described above, recent studies revealed that FGFR fusion proteins can induce resistance to EGFR TKIs 46,47 . Therefore, we analyzed the existence of FGFR3 fusion protein in H3122 LR3 cells, but no FGFR3 fusion proteins were detected.…”

“…In addition to FGFR abnormalities described above, recent studies revealed that FGFR fusion proteins can induce resistance to EGFR TKIs. 46 , 47 Therefore, we analyzed the existence of FGFR3 fusion protein in H3122 LR3 cells, but no FGFR3 fusion proteins were detected. However, this result does not preclude the possibility that FGFR3 fusion can induce resistance to ALK TKIs.…”

New clinical trial design in precision medicine: discovery, development and direction

“…The high expression/fusion of FGFR1 increases tumorigenicity and resistance to EGFR-TKI in EGFR mutant lung adenocarcinoma cells, which can be reversed by the dual inhibition of EGFR and FGFR. 270 , 271 The combination of EGFR and FGFR inhibitors reverses EGFR resistance mediated by downstream PIK3CA activation in skin squamous cell carcinoma. 272 Interactively, EGFR-dependent signal transduction induces resistance to FGFR inhibitors in head and neck squamous cell carcinoma cells with high expression of FGFR1 and cholangiocarcinoma cells with FGFR2 fusion.…”

Oncogenic alterations in advanced NSCLC: a molecular super-highway

“…FGFR3-TACC3 fusions account for over 91% of them, while fusions co-occurred with EGFR mutations in roughly 24% of cases. Among 3 patients with FGFR3-TACC3 fusions as resistance mechanisms to EGFR TKIs, two were treated with an EGFR TKI with the FGFR TKI, erdafitinib, with a 6 and 13 month response [ 264 ]. These results highlight the complexity of FGFR alterations.…”