Erdafitinib for the treatment of urothelial cancer

ABSTRACT

Introduction: Fibroblast growth-factor receptor (FGFR) inhibition is a promising strategy of treatment in urothelial cancer (UC). FGFR3 mutations or fusions (mut/fus) are common in luminal-1 UC subtype, which exhibits poor responses to immunotherapy. Erdafitinib is a potent and selective pan-FGFR tyrosine kinase inhibitor. Based on the results of the phase 2 BLC2001 trial (NCT02365597), in which erdafitinib showed an overall response rate of 40% in metastatic UC with FGFR3 mut/fus, it is the first approved targeted therapy in metastatic UC.

Areas covered: This review covers the preclinical and clinical evidence for erdafitinib, summarizes the results of other FGFR inhibitors tested in UC and explores future perspectives of FGFR inhibition in UC.

Expert opinion: In the era of precision medicine, erdafitinib approval marks a step forward in UC. Erdafitinib qualifies as a compelling comparator in the salvage therapy setting. Special attention must be paid to typical adverse class-effects of FGFR inhibitors. In the near future, in order to achieve an optimal selection of molecularly-altered tumors, it will be important to assess the performance of different diagnostic tools and to investigate the role of liquid biopsy. Combinations with immunotherapy represent a novel therapeutic opportunity being tested in ongoing trials.

KEYWORDS:

• Erdafitinib
• urothelial carcinoma
• targeted therapy
• systemic therapy
• FGFR3 alterations

Article highlights

• Fibroblast growth-factor receptor (FGFR) alterations can be found in up to 70% of low-grade and in approximately 20% of muscle-invasive or metastatic urothelial bladder carcinoma (UC)

• FGFR alterations are enriched in luminal-1 UC subtype, which is endowed with predicted poor responsiveness to immune-checkpoint inhibition

• Erdafitinib is a potent and selective pan-FGFR tyrosine kinase inhibitor (TKI)

• Erdafitinib showed an objective response-rate (ORR) of 40% in metastatic UC with selected FGFR3 mutations or fusions (mut/fus)

• Special attention must be paid to typical side effects that are class-effects of FGFR inhibitors (i.e. hyperphosphatemia, nail and skin alterations, eye disorders)

• Appropriate selection of patients, identification of responding and non-responding UC and the characterization of tumor biology underlying response/resistance will be major challenges in the near future

• Preliminary clinical trial data supports the development of FGFR inhibitors in combination with checkpoint inhibitors in UC

• The investigation of FGFR inhibitors in earlier disease stages (e.g., non muscle-invasive bladder UC) may be limited by their long-term toxicity and quality of life concerns

Declaration of interest

Andrea Necchi has served as a consultant and advisor for Merck, Incyte, Astra Zeneca, Roche, Rainier Therapeutics, Clovis Oncology, Bristol-Myers Squibb, Bayer, Basilea Pharmaceutica. Andrea Necchi has received research grants from Astra Zeneca, Ipsen, Merck and Incyte. Andrea Necchi’s spouse has stock ownership in Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.