Prognostic Impact of Fibroblast Growth Factor Receptor (FGFR) Genomic Alterations and Outcomes in Patients with Metastatic Urothelial.

537 Background: FGFR mutations/translocations are druggable targets in metastatic urothelial cancer (mUC). However, the prognostic effect of these genomic alterations (GA) and their role in the response to conventional therapy remain poorly characterized. Methods: We undertook an observational retrospective study in four Academic Hospitals in Madrid, Spain. Clinical and molecular information of patients diagnosed of Urothelial Cancer (UC) between January 2010 and December 2020 was systematically reviewed. The objective of this work was to compare the outcome of mUC patients with GA in the FGFR 2-3 genes versus wild type tumors. Analyses for detection of FGFR translocations and mutations using DNA isolated from formalin-fixed and paraffinized tumor tissue samples consisted of either next-generation sequencing (Foundation One test; n = 68) or qualitative real-time polymerase chain reaction–based assays (n = 9) with TFGFR or QIAGEN therascreen® tests that evaluated somatic mutations within the FGFR2-3 gene: R248C, S249C, G370C and Y373C and fusions: FGFR3-TACC3v3, FGFR3-TACC3v1 and FGFR3-BAIAP2L1, FGFR2-BICC1 and FGFR2-CASP7. Overall response rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) were determined and Cox-regression analysis were performed to assess the prognostic impact of these alterations. Results: We identified 201 patients diagnosed with UC. Genomic profiling was available in 77 mUC with 28 patients harboring any FGFR GA. Regarding ORR to first line a trend towards a better outcome was identified in FGFR GA (mutation/translocation/fusion) vs wild type cases (57,7% vs 45,5%, p=0,46). However, median OS was significantly worse among FGFR GA (mutation/translocation) vs FGFR wt tumours (13.8 vs 26.2 months, p=0,021). Prognostic factors associated with an unfavorable outcome in multivariable analysis were visceral metastases (HR 7,29 95% CI 1.6-32,3), ECOG >1 (HR 7,03 95% CI 2,59-19,1), first line treatment with checkpoint inhibitors (HR 2,67; 95% CI 1,06-6,74) and the presence of FGFR GAs (HR 2,98, 95% CI 1.37-6.5). Conclusions: Despite a better response to first line treatment, overall FGFR GA showed to be an independent risk factor in mUC. Thus, this determination should be included in new prognostic models.[Table: see text]