Targeting the FGFR Pathway in Urothelial Carcinoma: The Future is Now - Beyond the Abstract

Cancer genomics is rapidly advancing in the field of oncology, including metastatic urothelial cancer (mUC), which has seen the first accelerated approval of a targeted therapy in April 2019. Erdafitinib (Balversa) targets the FGFR pathway, which is an oncogenic driver pathway in 75%, 20%, and 10-15% of low grade non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), and mUC respectively. FGFR alterations also have a location predisposition in the upper tract(1,2,3).


In this review, we describe the pre-clinical and clinical evidence supporting the use of FGFR inhibition in mUC. To date, erdafitinib (Balversa) remains the only FGFR inhibitor that is FDA approved for treating mUC with susceptible FGFR alterations (FGFR3 mutations: R248C, S249C, G370C, Y373C or FGFR2/3 fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7) after progression on platinum-based chemotherapy(4,5). As erdafitinib is a new drug being adopted into practice, we outline clinical management of treatment, including optimal methods for FGFR testing, dose escalation protocols, drug interactions, and monitoring and managing toxicities, specifically ocular and serum phosphate abnormalities.

We summarize the future of FGFR inhibition, including the shift towards combination strategies and moving FGFR inhibition to an earlier setting. Prominent trials such as NORSE (NCT03473743) and FORT-2 (NCT NCT03473756) have shown promising results for combination regimens, and ongoing studies, such as PROOF-302, are evaluating FGFR inhibition in the adjuvant space(6,7,8). Lastly, we address foreseeable challenges, including sequencing of erdafitinib in the treatment algorithm, discovering biomarkers to predict response and resistance, and developing novel testing strategies for FGFR alterations, such as urine cell-free DNA (cf-DNA) or plasma circulating tumour DNA (ctDNA).

All in all, the approval of erdafitinib marks an exciting era in bladder cancer. We are hopeful that prospective clinical trials will address our current challenges to improve uptake of FGFR inhibitors in the future.

Written by: Jenny Peng & Di Maria Jiang, MD, FRCPC

Princess Margaret Cancer Centre, University Health Network, Toronto, ON

References:

  1. Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019 Feb 26;16(2):105–22.
  2. Lenis AT, Lec PM, Chamie K, MSHS M. Bladder Cancer. JAMA. 2020 Nov 17;324(19):1980.
  3. Nauseef JT, Villamar DM, Lebenthal J, Vlachostergios PJ, Tagawa ST. An evaluation of the efficacy and safety of erdafitinib for the treatment of bladder cancer. Expert Opin Pharmacother. 2020 May 23;21(8):863–70.
  4. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338–48.
  5. Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248–58.
  6. The Phase 2 NORSE Trial Discussion: Erdafitinib or Erdafitinib Plus Cetrelimab for Patients With Metastatic or Locally Advanced Urothelial Carcinoma and FGFR Alterations [Internet]. UROToday; Sept 16 - 21 2021 [cited June 18 2022]. Available from: https://www.urotoday.com/conference-highlights/esmo-2021/esmo-2021-bladder-cancer/132175-esmo-2021-invited-discussant-the-phase-2-norse-trial.html.
  7. Safety and efficacy of rogaratinib in combination with atezolizumab in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression in the phase Ib/II FORT-2 study. J Clin Oncol. 2021 May 20;39(15_suppl):4521–4521.
  8. Study of Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations [Internet]. Clinicaltrials.gov; Dec 13 2019 [cited June 18 2022]. Available from: https://clinicaltrials.gov/ct2/show/NCT04197986.

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