Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.

Autor:	Guercio BJ; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York., Sarfaty M; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Teo MY; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Ratna N; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Duzgol C; Commonwealth Radiology Associates, Andover, Massachusetts., Funt SA; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Lee CH; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Aggen DH; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Regazzi AM; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Chen Z; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Lattanzi M; Texas Oncology, Austin, Texas., Al-Ahmadie HA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Brannon AR; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Shah R; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Chu C; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Lenis AT; Department of Urology, Columbia University Irving Medical Center, New York, New York., Pietzak E; Weill Cornell Medical College, New York, New York.; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Bochner BH; Weill Cornell Medical College, New York, New York.; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Berger MF; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Solit DB; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Rosenberg JE; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Bajorin DF; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Iyer G; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Nov 14; Vol. 29 (22), pp. 4586-4595.
DOI:	10.1158/1078-0432.CCR-23-1283
Abstrakt:	Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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