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Ref Type Journal Article
PMID (37682528)
Authors Guercio BJ, Sarfaty M, Teo MY, Ratna N, Duzgol C, Funt SA, Lee CH, Aggen DH, Regazzi AM, Chen Z, Lattanzi M, Al-Ahmadie HA, Brannon AR, Shah R, Chu C, Lenis AT, Pietzak E, Bochner BH, Berger MF, Solit DB, Rosenberg JE, Bajorin DF, Iyer G
Title Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 R255W missense unknown FGFR2 R255W lies within the extracellular domain of the Fgfr2 protein ( R255W has been identified in sequencing studies (PMID: 37964396, PMID: 37682528), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Nov 2023).
FGFR3 H673Y missense unknown FGFR3 H673Y lies within the protein kinase domain of the Fgfr3 protein ( H673Y has been identified in sequencing studies (PMID: 37682528), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Nov 2023).
FGFR3 K649_K650delinsIE indel unknown FGFR3 K649_K650delinsIE results in the deletion of two amino acids in the protein kinase domain of the Fgfr3 protein from amino acids 649 to 650, combined with the insertion of an isoleucine (I) and glutamic acid (E) at the same site ( K649_K650delinsIE has been identified in sequencing studies (PMID: 37682528), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Nov 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 R255W FGFR3 S249C FGFR3 V553M FGFR3 K650M transitional cell carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 V553M, FGFR3 K650M, and FGFR2 R255W, along with AKT1 E17K, was identified on post-progression biopsy in a patient with urothelial carcinoma harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) (PMID: 37682528). 37682528