MSK-ACCESS for the detection of fibroblast growth factor receptor-3 (FGFR3) mutations in plasma cell-free (cf)DNA of metastatic urothelial carcinoma (mUC) patients (pts) pre- and on erdafitinib (erda) therapy.

Abstract

e17034 Background: The pan-FGFR inhibitor erda was recently FDA-approved for pretreated mUC pts harboring FGFR2/3 alterations. We explored concordance of FGFR3 mutation profiles between the primary tumor and cfDNA using the MSK-ACCESS platform. We also correlated changes in FGFR3 cfDNA mutant allele fraction (MAF) with response to drug. Methods: Plasma samples were collected from mUC pts started on erda at baseline, on treatment (tx), and at progression. Demographic and clinical characteristics were obtained. Baseline tumors were sequenced with MSK-IMPACT (ref) and plasma samples were sequenced using MSK-ACCESS, a cfDNA platform that sequences 129 genes using unique molecular indexes to generate > 15,000x coverage and detection of somatic mutations down to 0.1% MAF. Results: Between 08/2019-1/2020, 11 pts received erda 8mg daily. Of these, 3 pts increased dose to 9mg daily based on phosphorus level, 4 required dose reductions and 6 dose interruptions. In 5 pts, erda was discontinued for disease progression. FGFR3 S249C was the most frequent alteration detected (64%) followed by Y373C (18%), R248C and S371C (both 9%). Pre-treatment plasma FGFR3 profiles were concordant with tissue in 91% (10/11) of pts and additional FGFR3 mutations were detected in 3 cases (27%, Table), including 1 pt with an FGFR3-TACC3 fusion and hotspot mutations only in cfDNA. In 2 responding pts, the mutant allele was undetectable on erda. Conclusions: A high degree of concordance between primary tumor and cfDNA FGFR3 mutation detection was observed. FGFR3 mutations exclusive to cfDNA were found in a subset of pts. Further pt accrual and follow-up are ongoing to assess for correlations between erda response and tx-related changes in cfDNA MAF, and to assess whether cfDNA can identify resistance mechanisms. [Table: see text]