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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:
- Erdafitinib (JNJ-42756493) - Metastatic (NCT02365597)
- BGJ398 - Non muscle invasive bladder cancer (NCT02657486)
- BGJ398 - Metastatic 2nd line (NCT02160041)
- AZD4547 alone or with durvalumab (BISCAY) - Metastatic 2nd or 3rd line (NCT02546661)
- Debio 1347- Metastatic after standard treatment (NCT01948297)
- Rogaratinib (BAY1163877) - Metastatic (NCT01976741)
- LY3076226 – Metastatic (NCT02529553)
- INCB054828 - Metastatic (NCT02872714)
- B-701 (FIERCE 21) - Metastatic (NCT02401542)
- B-701 with pembrolizumab (FIERCE 22) - Metastatic post-platinum (NCT03123055)
Written by: Evan Yu, MD
- Van Rhijn BWG, Montironi R, Zwarthoff EC, et al. Frequent FGFR3 mutations in urothelial papilloma. J Pathol 2002; 198:245-51.
- Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507:315-22.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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).
- 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).
- 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).
- 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.
- 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).