Targetable Pathways in Advanced Bladder Cancer: FGFR Signaling

Bladder cancer is the 10th most commonly diagnosed cancer in the world, accounting for around 573,000 new cases and 213,000 deaths in 2020. The current standard treatment for locally advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. The significant progress being made in the genomic and molecular understandings of bladder cancer has uncovered the genetic alterations and signaling pathways that drive bladder cancer progression. These developments have led to a dramatic increase in the evaluation of molecular agents targeting at these alterations. One example is Erdafitinib, a first-in-class FGFR inhibitor being approved as second-line treatment for locally advanced or metastatic urothelial carcinoma with FGFR mutations. Immunotherapy has also been approved as second-line treatment for advanced and metastatic bladder cancer. Preclinical studies suggest targeted therapy combined with immunotherapy has the potential to markedly improve patient outcome. Given the prevalence of FGFR alternations in bladder cancer, here we review recent preclinical and clinical studies on FGFR inhibitors and analyze possible drug resistance mechanisms to these agents. We also discuss FGFR inhibitors in combination with other therapies and its potential to improve outcome.