Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which showed meaningful clinical benefit in cholangiocarcinoma patients (pts) with FGFR2-driven (fusions, mutations or amplifications) tumors (NCT03230318). The current study explored the activity of DZB in patients with mUC and FGFR1-3 GA (NCT04045613). Methods: Eligible pts with advanced mUC and ≥1 prior lines of standard treatment and FGFR1/2/3 mutations/short variants and rearrangements/fusions confirmed by central/local NGS testing received DZB 300 mg QD (N = 32) or 200 mg BID (N = 17). Primary efficacy endpoint was objective response rate (ORR) by central radiology review per RECIST v1.1. Key secondary efficacy endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events were assessed according to NCI CTCAE v5.0. Results: From 01/2020 to 01/2022, 282 pts were screened and 49 pts were included in the study and received DZB. The median age was 67 years, 30.6% of pts were female, 94% had an ECOG 0/1, 75.5% had ≥2 prior treatment lines, 77.6% had received prior immune-checkpoint inhibitors. At data cutoff (30-Aug-2022), all pts had discontinued treatment. Confirmed ORR was 8.2% (95% CI 2.2, 19.6) based on 4 PRs (all with FGFR3 S249C mutation/FGFR3 TACC3 fusion) and the DCR was 28.6% (95%CI: 16.6, 43.3). PFS ranged 0.3-8.8 months, and OS ranged 0.3-21.4 months. Median duration of response was 6.9 months, and longest time on treatment was 18 months. Most common all-grade treatment-emergent adverse events were transaminase increased (40.8%), nausea (38.8%), fatigue (32.7%) and decreased appetite (30.6%). Drug-related retinal events (12.2%), nail toxicities (6.1%), stomatitis (4.1%) and palmar-plantar erythrodysesthesia (PPE) (0%) were infrequent. Safety and efficacy results were similar in patients receiving 300 mg QD or 200 mg BID. Conclusions: Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613.