Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution.
Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf)DNA assessment.
FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n=5), AKT1 (n=1), and second-site FGFR3 mutations (n=2).
FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Sep 08 [Epub ahead of print]
Brendan J Guercio, Michal Sarfaty, Min Yuen Teo, Neha Ratna, Cihan Duzgol, Samuel A Funt, Chung-Han Lee, David H Aggen, Ashley M Regazzi, Ziyu Chen, Michael Lattanzi, Hikmat A Al-Ahmadie, A Rose Brannon, Ronak Shah, Carissa Chu, Andrew T Lenis, Eugene Pietzak, Bernard H Bochner, Michael F Berger, David B Solit, Jonathan E Rosenberg, Dean F Bajorin, Gopa Iyer
James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States., Sheba Medical Center, Ramat Gan, Israel., Memorial Sloan Kettering Cancer Center, New York, New York, United States., Memorial Sloan Kettering Cancer Center, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Columbia University Medical Center, New York, NY, United States., Texas Oncology, Austin, TX, United States., Memorial Sloan Kettering Cancer Center, NY, NY, United States., Memorial Sloan Kettering Cancer, New York, New York, United States.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37682528