IBCN 2023: Added Value of ctDNA Testing For Identifying FGFR3 Alterations In Metastatic Urothelial Cancer Eligible For Erdafitinib Treatment

(UroToday.com) Fibroblast growth factor receptor (FGFR) inhibitors (e.g., erdafitinib) are increasingly important in the management of FGFR-altered metastatic urothelial carcinoma (mUC). Archival tissue testing for specific FGFR alterations is now implemented as a companion diagnostic but somatic FGFR status may change during disease progression and also after erdafitinib exposure. This ongoing study aims to evaluate the role of cell-free DNA (cfDNA) compared to tissue testing for FGFR alteration detection and to evaluate genomic mechanisms of erdafitinib resistance.

Patients with progressing mUC undergoing archival tissue testing for FGFR alterations were eligible. Blood plasma cfDNA and matched leukocyte DNA were subjected to deep-targeted sequencing with a custom panel covering the most relevant urothelial cancer (UC)--specific gene loci. To evaluate the feasibility of a rapid and low-cost alternative to our deep-targeted sequencing approach, we designed a quantitative (q)PCR assay covering the most frequent FGFR3 mutations and applied it to cfDNA.

A total of 163 patients have enrolled, with matched tissue and cfDNA results available for 77 patients. 58 of these 77 cfDNA screening samples had detected circulating tumor DNA (ctDNA) and could be evaluated for FGFR alterations. The concordance for FGFR status between evaluable ctDNA and tissue samples was 89%. Overall, 9% of tissue-negative patients were cfDNA-positive for FGFR alterations linked to the erdafitinib label, indicating that additional qualifying patients can be identified using cfDNA testing. Our rapid cfDNA qPCR assay demonstrated high concordance (92%) with targeted sequencing, correctly assigning FGFR3 status for all evaluable hotspot mutations. Among the patients providing cfDNA samples at progression on erdafitinib, we identified two patients with multiple new FGFR3 variants supporting polyclonal resistance.

In summary, this study suggests that cfDNA is a valuable adjunct to tissue-based assays for detecting FGFR alterations to identify patients eligible for FGFR inhibitor therapy and to monitor for resistance mechanisms.

Presented by: David C. Müller, MD, Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network (IBCN) Annual Meeting, September 29-30, 2023, Montreal, Canada