e16519 Background: The pan-FGFR inhibitor erdafitinib (erda) is FDA-approved for pretreated mUC pts harboring FGFR2/3 alterations. We explored concordance of FGFR3 alt profiles between primary tumor and cfDNA using the next generation sequencing assay MSK-ACCESS. We also correlated changes in FGFR3 cfDNA mutant allele fraction (MAF) with response to erda. Methods: After consent on an approved biomarker protocol, plasma samples were collected from mUC pts on erda at baseline, on treatment (tx), and at progression along with patient clinical characteristics. Baseline tumors were sequenced with MSK-IMPACT and plasma samples sequenced with MSK-ACCESS, a cfDNA platform that sequences select exons and introns of 129 genes and uses unique molecular indexes to detect somatic mutations down to 0.1% MAF. Results: Between 8/2019-12/2020, 18 pts started erda 8mg daily and had plasma drawn for MSK-ACCESS. Three pts increased to 9mg daily, 7 required dose reductions and 10 had dose interruptions. Treatment was discontinued in 13 pts for disease progression and 3 for toxicity. Median PFS was 3.7 months. FGFR3 S249C was the most frequent alt detected (11/18, 61%), then Y373C (3/18, 16%), and R248C (2/18, 11%) (Table). FGFR3 alt were detected in 15/18 (83%) baseline plasma samples, all of which were of the same alt as tumor tissues. In 3 samples, additional FGFR3 alt were detected, including 1 pt with an FGFR3-TACC3 fusion and hotspot mutations found only in cfDNA. FGFR3 MAF decreased in 7 of 9 pts on erda, 2 of whom declined to undetectable levels. Conclusions: A high degree of concordance of FGFR3 alt was observed between primary tumors and cfDNA. Most erda responders displayed reduction of FGFR3 cfDNA MAF. FGFR3 alts exclusive to cfDNA were found in a small subset of pts. Further pt accrual and follow-up are ongoing to assess for correlations between erda response/progression and changes in FGFR3 cfDNA MAF, and to assess whether cfDNA can identify resistance mechanisms.[Table: see text]