Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant activity in patients (pts) with advanced or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al 2018]. Given the distinct biologic characteristics of upper tract UC (UTUC) and urothelial carcinoma of the bladder (UCB), we sought to determine if infigratinib had varying activity in these settings. Methods: Eligible pts had mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy, unless contraindicated. Pts received infigratinib 125 mg orally daily (3 wks on/1 wk off). Overall response rate (ORR: CR+PR) and disease control rate (DCR; CR+PR+SD) were characterized in UCB and UTUC pts. Comprehensive genomic profiling was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA). Blood was collected for cell-free (cf)DNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer. Results: 67 pts were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. ORR was 25.4% and DCR was 64.2%. In the 8 pts with UTUC, 1 CR and 3 PRs were observed (ORR 50%); the remainder had a best response of SD (DCR 100%). UTUC pts were predominantly 2^nd line (62.5%), with only 2 (25%) showing response to previous treatment. In pts with UCB, 13 PRs were observed (ORR 22%), and 22 pts had a best response of SD (DCR 59.3%). Notable differences in genomic alterations between cohorts included a higher frequency of FGFR3-TACC3 fusions (12.5% vs 5.8%) and FGFR3 R248C mutations (50% vs 11.5%), and a lower frequency of FGFR3 S249C mutations (25% vs 59.6%) in UTUC vs UCB. Consistent with previous reports [Sfakianos et al 2016], UTUC pts had a differential frequency of alterations in HRAS, CDKN2B and ARID1A. Sufficient cfDNA yield was obtained in UTUC and UCB pts and a comprehensive comparison of these data will be presented. Conclusions: Differences in cumulative genomic profile were observed between UCB and UTUC in this FGFR3-restricted experience, underscoring the distinct biology of these diseases. Results with infigratinib in UTUC support a planned phase III adjuvant study predominantly in this population. Clinical trial information: NCT01004224