FGFR3 alteration sites and response rate to FGFR inhibitors in urothelial carcinoma.

Dysregulation of fibroblast growth factor receptor (FGFR) signaling contributes to tumorigenesis and FGFRs have been clinically approved as treatment targets for FGFR inhibitor (FGFRi) in urothelial carcinoma (UC). The present study aimed to explore the correlations between different FGFR3 alteration sites and response to FGFRi. We involved a total of 1045 FGF/FGFR-altered UC patients treated with FGFRi, among whom 54.93 % carried FGFR3 mutations and 15.22 % carried FGFR3 fusions. Erdafitinib (47.37 %) was the most frequently used FGFRi drug in clinical studies. The objective response rate was 31.29 % in all participants. Higher frequencies of FGFR3-TACC3 fusion were positively correlated with elevated treatment response rates, particularly in complete response (coefficient=0.762, P = 0.028) and disease control (coefficient=0.786, P = 0.036), whereas FGFR3 S249C mutation showed a negative correlation with response. Similar results were identified in subgroup analyses. In conclusion, UC patients with FGFR3 fusions, especially FGFR3-TACC3 fusions, may benefit more from FGFRi than those with FGFR3 mutations, which highlighted the importance of FGFR3 alteration site test in determining the efficacy of FGFRi-based therapy and enhanced the patient benefit for FGF/FGFR-altered UC. Future studies with larger sample size and individual patient data are needed to confirm these findings and explore the underlying mechanisms of the differential response to FGFRi.