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Fibroblast Growth Factor Receptors, a New Hope for Patients with Urothelial Carcinomas

The fibroblast growth factor receptor (FGFR) family has functional roles in regulation of cell proliferation, differentiation, migration, angiogenesis and tumorigenesis.  Activating point mutations of FGFR3 are common (~86%) in low grade and stage bladder tumors.1  However, The Cancer Genome Atlas Research Network identified only 12% of muscle invasive bladder cancers with FGFR3 mutations.2  FGFR3 mutations are also very common in upper tract urothelial tumors, especially of the ureter.3  FGFR1 has been less intensively studied, but increased expression at both the mRNA and protein level is present in a large proportion of bladder tumors.4  Expression of FGFR1 tends to be high in bladder cancer cell lines with a mesenchymal phenotype, suggesting a role in invasion and metastasis.5 

Initial efforts to inhibit FGFRs in clinical trials have been attempted with multi-kinase inhibitors.  Dovitinib was tested in a phase 2 trial of advanced urothelial bladder cancer patients who received prior combination platinum chemotherapy.  No responses were seen in the FGFR3 mutated population while only one response was seen in the wild-type population.6  Hence, the trial was terminated at the end of stage 1 for lack of efficacy.  Similarly, a phase 2 trial in the BCG unresponsive population harboring either FGFR3 mutation or over expression was closed early with limited activity and significant toxicity due to cessation of clinical development.7  Pazopanib has provided an exceptionally durable response for a patient known to harbor both the FGFR3 S249C activating mutation and amplification.8 

Selective FGFR targeting inhibitors may offer more promise with less non-specific toxicity.  However, FGFR-selective agents offer a different toxicity profile, including hyperphosphatemia, tissue calcification, nail and hair changes, mucositis, retinal detachment and arthralgias.9  Although these FGFR-specific toxicities have been seen with Erdafitinib (JNJ-42756493), 3 urothelial carcinoma patients had durable responses, one with FGFR3 translocation and another with FGFR2 truncation.  BGJ398 has also reported phase 1 results with partial responses in 3 of 8 patients and stable disease in another 3 patients, all with FGFR3 mutation.10  AZD4547 has shown activity in urothelial bladder cancer in a trial where FGFR alteration was required.  Specifically, 2 of 3 patients showed a durable response, both harboring high FGFR1 and FGFR3 expression with one with an additional mutation in the ligand-binding domain of FGFR3.11  Phase 1 results from the Debio 1347 trial included 5 patient responses of 56 total, and one responding patient had urothelial carcinoma with a FGFR3 fusion.12  The trial will continue to enroll to disease specific cohorts now.  In patients with high FGFR1-3 tumor mRNA levels, Rogaratinib (BAY 1163877) showed the highest response rates in the bladder cancer expansion cohort, with 3 partial responses out of 8 patients.13  TAS-120 is another highly selective FGFR inhibitor that enrolled 8 bladder cancer patients in an initial clinical trial without detecting a measurable response.14 

Another strategy to target FGFR is with monoclonal antibodies.  The FGFR3-specific monoclonal antibody, MFGR1877S underwent phase 1 testing in patients with multiple advanced solid tumors and myeloma.  Ten bladder cancer patients were enrolled and 5 had long-term stable disease.15  B-701 is another monoclonal antibody that blocks both the wild type and activated mutant FGFR3 receptor.  Early testing with B-701 has been in urothelial bladder cancer patients who had disease progression on or after 1-2 lines of prior chemotherapy, excluding taxanes.  Treatment is in combination with docetaxel and an early abstract revealed 17 evaluable patients, 1 with a complete response and 2 with partial responses.16  The disease control rate was 58%.  Five patients had FGFR3 mutation and that included 1 complete and 1 partial responder, with an 80% disease control rate.  This trial is still ongoing and another trial in combination with pembrolizumab for the metastatic or locally-advanced post-platinum population has also been initiated. 

Next steps in clinical development of the above promising agents and other ongoing FGFR targeting trials for urothelial carcinoma are listed below:


Written by: Evan Yu, MD


References

  1. Van Rhijn BWG, Montironi R, Zwarthoff EC, et al.  Frequent FGFR3 mutations in urothelial papilloma.  J Pathol 2002; 198:245-51. 
  2. Cancer Genome Atlas Research Network.  Comprehensive molecular characterization of urothelial bladder carcinoma.  Nature 2014; 507:315-22.
  3. Van Oers JMM, Zwarthoff EC, Rehman I, et al.  FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumors.  Eur Urol 2009; 55:650-8.
  4. Tomlinson DC, Lamont FR, Shnyder SD, Knowles MA.  Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer.  Cancer Res 2009; 69:4613-20.
  5. Tomlinson DC, Baxter EW, Loadman PM, et al.  FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCgamma/COX-2-mediated mechanisms.  PLoS ONE 2012; 7:e38972.
  6. Milowsky MI, Dittrich C, Duran I, et al.  Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma.  Eur J Cancer 2014; 50:3145-52.
  7. Hahn NM, Bivalacqua TJ, Ross AE, et al.  A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: Hoosier Cancer Research Network Trial HCRN 12-157.  Clin Cancer Res 2017; 23:3003-11.
  8. Palma N, Morris JC, Ali SM, et al.  Exceptional response to pazopanib in a patient with FGFR3 activating mutation and amplification.  Eur Urol 2015; 68:168-70.
  9. Tabernero J, Bahleda R, Dienstmann R, et al.  Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.  J Clin Oncol 2015; 33:3401-8.
  10. Nogova L, Sequist LV, Garcia MP, et al.  Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: Results of a global phase I, dose-escalation and dose-expansion study.  J Clin Oncol 2017; 35:157-65.
  11.  Kilgour E, Ferry D, Saggese M, et al.  Exploratory biomarker analysis of a Phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors.  J Clin Oncol 2014; 32 (suppl; abstr 11010).
  12. Voss MH, Hierro C, Heist RS, et al.  Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase 1 dose-escalation study in patients with FGFR genomically activated advanced solid tumors.  J Clin Oncol 2017; 35 (suppl; abstr 2500).
  13. Joerger M, Soo R, Cho BC, et al.  Phase I study of the pan-fibroblast growth factor receptor (FGFR) inhibitor BAY 1163877 with expansion cohorts for subjects based on tumor FGFR mRNA expression levels.  Ann Oncol 2016; 27:1-36 (abstr 360O).
  14. Kuboki Y, Matsubara N, Bando H, et al.  First-in-human study of TAS-120, a highly selective covalent oral fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors.  Ann Oncol 2017; 28 (suppl_5; abstr 372PD).
  15. O’Donnell P, Goldman JW, Gordon MS, et al.  A phase I dose-escalation study of MFGR1877S, a human monoclonal anti-fibroblast growth factor receptor 3 (FGFR3) antibody, in patients with advanced solid tumors.  Eur J Cancer 2012; 48 (Suppl. 6):191-2.
  16. Bellmunt J, Pal SK, Picus J, et al.  Safety and efficacy of docetaxel + B-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma.  J Clin Oncol 2017; 35 (suppl; abstr 4540).