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.
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.
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.
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.
European urology. 2024 Sep 30 [Epub ahead of print]
Roger Li, Joshua Linscott, James W F Catto, Siamak Daneshmand, Bishoy M Faltas, Ashish M Kamat, Joshua J Meeks, Andrea Necchi, Benjamin Pradere, Jeffrey S Ross, Michiel S van der Heijden, Bas W G van Rhijn, Yohann Loriot
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Electronic address: ., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Department of Urology, University of Sheffield, Sheffield, UK., Department of Urology, Keck School of Medicine of USC, Los Angeles, CA, USA., Department of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA., Department of Urology, MD Anderson Cancer Center, Houston, TX, USA., Department of Urology and Biochemistry, Northwestern University, Chicago, IL, USA., Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Department of Urology, UROSUD, La Croix du Sud Hospital, Quint Fonsegrives, France., Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY, USA; Office of the CEO, Foundation Medicine, Boston, MA, USA., Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Department of Surgical Oncology (Urology), Netherlands Cancer Institute, Amsterdam, The Netherlands., Département de Médecine Oncologique, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.