Emerging agents for the treatment of metastatic urothelial cancer

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

“…Recently, the efficacy of immunotherapy using immune checkpoint inhibitors (ICIs) has been investigated in patients with a/m UBC [1,4,5,7,8]. Anti-programmed death-1 (PD-1) agents pembrolizumab and nivolumab, as well as anti-programmed death ligand-1 (PD-L1) agents avelumab and atezolizumab, have been approved by the USA Food and Drug Administration (FDA) for treating a/m UBC patients who do not respond to platinumbased chemotherapy and have demonstrated durable clinical benefits with reduced toxicity.…”

“…However, only a subset of patients may respond to ICIs (objective response rate (ORR): 15-21%), and treatment options are limited for patients who do not respond to ICIs. For such patients, antibody-drug conjugates (ADCs) and targeted therapies/anti-angiogenesis agents, which are still under clinical trials, remain the only viable treatment strategies, while taxane-based or vinflunine chemotherapy has modest results but is still used in clinical practice [2,4,5,8].…”

“…Multi-platform, high-throughput next-generation sequencing (NGS) technology has enabled comprehensive assessment of the UBC landscape and significantly improved our understanding of its complex pathology, ushering in a new era of precision oncology [2,4,5,[8][9][10]. Advances in genomic profiling, the development of targeted therapies, and the resurgence of ICI have led to the molecular subclassification of a/m UBC, and efforts are underway to define therapeutic strategies and associated predictive biomarkers.…”

“…Receptor tyrosine kinases (RTKs), which transduce extracellular signals to a variety of intracellular signaling cascades [11,12], are classified into the epidermal growth factor receptor (EGFR) group (EGFR, HER2, MET, and RYK, among others), the fibroblast growth factor receptor (FGFR) group (FGFRs, colony-stimulating factor 1 receptor (CSF-1R) and vascular endothelial growth factor (VEGF) R2, among others. ), the insulin receptor (INSR) group (INSR, insulin-like growth factor 1 receptor (IGF1R), ALK, and ROS1, among others), the RAR-related orphan receptor (ROR) group (ROR1, ROR2, DDR2, and NTRK1, among others), and the EPH receptor (EPH) group (EPHA1, EPHB1, and PTK7, among others) [8,[11][12][13][14][15][16]. The human FGFR family includes four highly conserved RTKs: FGFR1, FGFR2, FGFR3, and FGFR4, which are encoded by distinct genes.…”

“…Gain-of-function coding mutations, gene fusion, and gene amplification are three major classes of FGFR alterations associated with the luminal-papillary subtype of a/m UBC [4,5,8,15,17,18]. In spite of the general association between FGFR alterations and favorable characteristics in NMI-UBC, there is no evidence to suggest that FGFR gene alterations correlate with a less aggressive phenotype once urothelial carcinoma advances.…”