FGFR-Altered Urothelial Carcinoma in the EV–Pembrolizumab Era: Rationale and Emerging Data for Upfront Triplet Strategies

Urothelial cancer (UC) is a common malignancy with a significant incidence worldwide, particularly in Europe and North America. Approximately 5% of patients have de novo metastatic disease at the time of initial diagnosis. The combination of Enfortumab vedotin and Pembrolizumab recently transformed the first-line treatment landscape, providing better clinical outcomes and greater tolerability compared to traditional cisplatin-based therapies. However, alterations in fibroblast growth factor receptor (FGFR) signaling may diminish the effectiveness of Immune Checkpoint Inhibitors (ICIs), underscoring the need for novel combination therapies. This review examines emerging evidence supporting combination strategies incorporating pan-FGFR tyrosine kinase inhibitors in FGFR-altered urothelial carcinoma, focusing on their potential integration with first-line doublet regimens. Ongoing and future clinical studies will be essential to define the clinical value of these combinations and to advance precision immunotherapy strategies guided by genomic alterations, to improve outcomes for patients with UC.