Abstract 3410: Identifying potential mechanisms of resistance to erdafitinib (erda) via longitudinal analysis of circulating tumor (ct)-DNA of patients (pts) with advanced/metastatic urothelial cancer (mUC)
Authors: Guercio Brendan J. , Sarfaty Michal , Teo Min Yuen , Funt Samuel A. , Lee Chung-Han , Aggen David H. , Ratna Neha , Regazzi Ashley M. , Chen Ziyu , Lattanzi Michael , Al-Ahmadie Hikmat A. , Brannon A. Rose , Berger Michael F. , Solit David B. , Rosenberg Jonathan E. , Bajorin Dean F. , Iyer Gopa 
Published: June 2022

Abstract
Background: The fibroblast growth factor receptor (FGFR) inhibitor erda is the only FDA-approved targeted treatment (tx) for mUC with FGFR2/3 alterations (alt). Median progression-free survival on erda is 5.5 months and mechanisms of resistance remain poorly characterized. Analysis of ctDNA offers an opportunity to longitudinally and non-invasively assess for mechanisms of resistance.
Methods: Plasma was collected from mUC pts on erda at baseline, on-tx, and at disease progression (PD). Clinical characteristics were recorded. Pre-tx tumors were sequenced with MSK-IMPACT and plasma samples with MSK-ACCESS, a cell-free DNA assay sequencing 129 genes with unique molecular indexes to generate &gt;15,000x coverage for detection of mutations to an allele frequency of 0.1%.
Results: Between 8/2019-9/2021, 18 pts received erda. Median progression-free survival was 4.2 months, range 1.4-10.8. Tx was discontinued in 14 pts for PD, 3 for toxicity, and 1 death unrelated to erda/PD. During tx, several pts acquired new alts in ctDNA compared to pre-tx tumor/ctDNA, most commonly in TP53 (n = 5) and FGFR3 (n = 4) (Table 1). Of 9 newly acquired FGFR2/3 alts observed in ctDNA on-tx, 3 were hotspots. Several acquired FGFR3 alts have been shown to impact binding of erda to FGFR3 in vitro (Table 1). Of 5 pts with primary refractoriness to erda, 3 had baseline activating alts of signaling downstream or parallel to FGFR, including alts of PIK3CA (n = 1), TSC1 (n = 1), and HER2 (n = 2). Of 3 pts with TP53 alts in baseline ctDNA, 2 had PD as best response to erda.
Conclusions: Pts with mUC treated with erda demonstrated on-tx acquisition of ctDNA alts of FGFR2/3 and TP53 and activating alts downstream or parallel to FGFR signaling. Most pts with TP53 alts in baseline ctDNA were refractory to erda. Acquired FGFR2/3 alts on erda may drive resistance through interference with drug-target binding.
Case # Pre-tx FGFR2/3 alts Alts acquired on erda related to TP53 and FGFR signaling 1 FGFR3 Y373C TP53 K132M; TP53 R158L 2 FGFR3 S371C; FGFR3 R399C; FGFR3 R248C; FGFR3 S249C; FGFR3-TACC3 fusion FGFR3 R669G&; FGFR3 V553M&; FGFR3 N540S&; FGFR3 H673Y; FGFR3 K649_K650delinsIE; TP53 S241C; BRAF-CLIP2 fusion 3 FGFR3 S249C TP53 E287Q 4 FGFR3 S249C FGFR3 V553M&; FGFR3 K650M; FGFR2 R255W; AKT1 E17K 5 FGFR3 S249C FGFR3 R248C 6 FGFR3 S249C TP53 I195T 7 FGFR3 Y373C TP53 R248W; TP53 S241Y 8 FGFR3 S249C; FGFR3 L645V FGFR3 S424C & Alts likely to impact erda binding to FGFR3.
Citation Format: Brendan J. Guercio, Michal Sarfaty, Min Yuen Teo, Samuel A. Funt, Chung-Han Lee, David H. Aggen, Neha Ratna, Ashley M. Regazzi, Ziyu Chen, Michael Lattanzi, Hikmat A. Al-Ahmadie, A. Rose Brannon, Michael F. Berger, David B. Solit, Jonathan E. Rosenberg, Dean F. Bajorin, Gopa Iyer. Identifying potential mechanisms of resistance to erdafitinib (erda) via longitudinal analysis of circulating tumor (ct)-DNA of patients (pts) with advanced/metastatic urothelial cancer (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3410.