Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors

Abstract

Inhibitors of fibroblast growth factor receptor (FGFR) represent an outstanding treatment approach for selected patients with urothelial cancer (UC). These agents are changing the clinical approach to a subgroup of UC, the luminal-papillary subtype, characterized by FGFR mutations, fusions, or amplification. In this review, we provide an overview of the results of recent clinical trials on FGFR tyrosine kinase inhibitors (TKIs) currently in clinical development for the treatment of UC: erdafitinib, rogaratinib, infigratinib, and the monoclonal antibody vofatamab. The Food and Drug Administration recently granted accelerated approval to erdafitinib for patients with advanced UC with alterations of FGFR2 or FGFR3 after progression on platinum-based chemotherapy. We also look at future therapeutic options of combination regimens with immune-checkpoint inhibitors as strategies for improving the antitumor effects of this class of drug, and for preventing or delaying the development of resistance.

Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype

“…The FGFR3 oncogenic pathway is associated with a non-T-cell-inflamed cancer phenotype, characterized by reduced CD8+ T cells, chemokines, and interferons, resulting in resistance to immune checkpoint inhibitors [20]. However, combination therapies of FGFR inhibitors with immune checkpoint inhibitors give hope for enhanced therapeutic effects, by the modulation of the tumor micro-environment, inducing a T-cell-inflamed phenotype, which may result in a response to immune checkpoint inhibitors [20,21]. The first results regarding combination therapies were presented from a phase II study on the human anti-FGFR3 monoclonal antibody vofatamab in combination with pembrolizumab, with responses in both FGFR3 wild type and FGFR3-mutated patients, and an overall response rate of 36% [21].…”

“…However, combination therapies of FGFR inhibitors with immune checkpoint inhibitors give hope for enhanced therapeutic effects, by the modulation of the tumor micro-environment, inducing a T-cell-inflamed phenotype, which may result in a response to immune checkpoint inhibitors [20,21]. The first results regarding combination therapies were presented from a phase II study on the human anti-FGFR3 monoclonal antibody vofatamab in combination with pembrolizumab, with responses in both FGFR3 wild type and FGFR3-mutated patients, and an overall response rate of 36% [21]. Further trials with FGFRand immune checkpoint inhibitor combination therapies are currently recruiting [21].…”

Epidemiology of Bladder Cancer

“…Among somatic mutations, growth factor receptor FGFR has been implicated in up to 20% of recurrent bladder cancer patients, leading to the approval of the tyrosine kinase inhibitor erdafitinib as a later line therapy [28]. As in many neoplasms, p53 mutations are implicated in bladder cancer carcinogenesis and may even have prognostic value [29,30].…”

Traditional Classification and Novel Subtyping Systems for Bladder Cancer

“…FGFR3 is one of the most common amplification mutation genes in luminal subtypes, and targeted FGFR has become a promising treatment. FGFR1-4 alterations UC patients respond well to the FGFR inhibitors erdafitinib and rogaratinib (52,53), and these drugs are undergoing UC II/III clinical trials. Similarly, PIK3CA is also a common activated mutant gene, and targeting the PI3K pathway has achieved a good therapeutic effect in vivo and in vitro preclinical BC treatment (54).…”