TPS592 Background: Fibroblast growth factor receptor (FGFR) 3 gene alterations (GAs) are involved in UC pathogenesis. Pts with metastatic UC and FGFR3 GAs express low programmed cell death ligand 1 (PD-L1) levels; combination with FGFR inhibitors may confer added benefit via tumor-direct and immunomodulatory effects. Preliminary data from a phase 2 monotherapy trial of PEMI (INCB054828), a selective, potent, oral FGFR1–3 inhibitor, confirmed efficacy in previously treated relapsed/refractory pts with UC and FGFR3 GAs (NCT02872714). FIGHT-205, a randomized, open-label, phase 2 study, will assess efficacy and safety of PEMI + PEMBRO vs PEMI alone vs SOC (carboplatin [CARB] + gemcitabine [GEM] or PEMBRO alone) in CIS-ineligible metastatic/unresectable UC with FGFR3 mutation/rearrangement (NCT04003610). Methods: Eligible pts are adults with confirmed metastatic/unresectable UC; ≥1 measurable target lesion (per RECIST v1.1); platinum (PT)/CIS-ineligible; centrally confirmed FGFR3 mutation/rearrangement; ECOG PS ≤2. Exclusions include prior selective FGFR inhibitor, anti-PD-1/PD-L1/2, or co-inhibitory T-cell receptor directed agent; chemotherapy (except adjuvant, neoadjuvant); clinically significant corneal/retinal disorder; Ca/PO4 homeostasis disorder/systemic mineral imbalance with ectopic calcification; untreated CNS metastases. Pts will be randomized (1:1:1) to 3 groups: PEMI 13.5 mg QD (continuous, 21-d cycle) + PEMBRO 200 mg Q3W, PEMI alone (same dose), or SOC (GEM [1000 mg/m2 on D1 + D8] + CARB [AUC 5 (or 4.5) on D1 or D2] Q3W or PEMBRO [same dose] if PD-L1 score high/PT-ineligible). PEMI titration to 18 mg starting at cycle 2 is required for pts without hyperphosphatemia (serum PO4 >5.5 mg/dL) and grade ≥2 treatment-related AEs during cycle 1. Hyperphosphatemia will be managed by diet modifications, PO4 binders, diuretics, or dose adjustments. PEMI will continue until progression/unacceptable toxicity. Primary endpoint is progression-free survival. Secondary endpoints are overall survival, objective response rate, duration of response, safety, and quality of life. Clinical trial information: NCT04003610.