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FGFR Inhibition in Urothelial Carcinoma
Roger Li1, Joshua Linscott2, James W F Catto3
1Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Background And Objective:
The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain.
Methods:
Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer". An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review.
Key Findings And Limitations:
Somatic FGFR3 alterations are found in up to 70% of low-grade non-muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC.
Conclusions And Clinical Implications:
With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.
Insights
The 2024 FDA approval of erdafitinib marks a new era for targeted bladder cancer therapy. FGFR inhibitors show promise for treating urothelial carcinoma, with ongoing research into early-stage applications.
Area of Science:
- Fibroblast Growth Factor Receptor (FGFR) pathway alterations in oncogenesis.
- FGFR3 alterations in bladder cancer, including prevalence and prognostic significance.
Background:
- The 2024 FDA approval of erdafitinib for metastatic urothelial carcinoma (mUC) with FGFR3 alterations.
- FGFR pathway alterations drive oncogenesis in bladder cancer, leading to cellular proliferation.
Purpose of the Study:
- To review the effects of FGFR pathway alterations in bladder cancer.
- To summarize clinical data supporting FGFR inhibitors in mUC management.
- To discuss remaining challenges and future directions for FGFR inhibition in bladder cancer therapy.
Main Methods:
- Systematic literature search of PubMed and MEDLINE (1995-2024) for FGFR inhibitors in urothelial cancer.
- Keywords used: "FGFR" and "bladder cancer".
- Collaborative narrative review synthesized by an international expert panel.
Main Results:
- Somatic FGFR3 alterations found in up to 70% of low-grade non-muscle-invasive bladder cancers.
- FGFR3 alterations activate downstream signaling, promoting cellular proliferation.
- FGFR3-altered tumors may have a non-inflamed microenvironment, with no apparent impact on immunotherapy response.
- Pan-FGFR inhibitors investigated in mUC; intravesical delivery systems show potential for early-stage UC.
Conclusions:
- FGFR inhibition is poised to transform bladder cancer treatment.
- Advancements in understanding bladder cancer biology, diagnostics, and drug delivery will drive precision medicine.
- FGFR inhibition is expected to lead advancements in precision treatment for bladder cancer.
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