Urothelial carcinoma: the development of FGFR inhibitors in combination with immune checkpoint inhibitors

Introduction: The recent approval of erdafitinib and the emergence of other potent and selective fibroblast growth factor receptor (FGFR) inhibitors (FGFRi’s) are shifting the treatment paradigm for patients with advanced urothelial carcinoma (UC) harboring FGFR3 alterations. Whether such therapies can, and should, be combined with immune checkpoint inhibitors (ICI’s) is an area of major research interest. Areas covered: Herein, we review the FGFR signaling pathway and impact of altered FGFR signaling on UC tumorigenesis, the clinical development of FGFRi’s, the rationale for FGFRi-ICI combinations, current trials, and future directions. Expert opinion: FGFR3 altered UCs are not less responsive to ICI’s compared with FGFR3 wild-type (WT) tumors. However, FGFR3 altered tumors may exhibit distinct immunobiology compared with WT tumors that could potentially be exploited therapeutically. Given these considerations along with the clinical non-cross resistance of these therapeutic classes, clinical investigation of regimens combining FGFR3i and ICI is warranted.