Reference Detail

Ref Type

Journal Article

PMID

(27932416)

Authors

Hahn NM, Bivalacqua TJ, Ross AE, Netto GJ, Baras A, Park JC, Chapman C, Masterson TA, Koch MO, Bihrle R, Foster RS, Gardner TA, Cheng L, Jones DR, McElyea K, Sandusky GE, Breen T, Liu Z, Albany C, Moore ML, Loman RL, Reed A, Turner SA, De Abreu FB, Gallagher T, Tsongalis GJ, Plimack ER, Greenberg RE, Geynisman DM

Title

A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	12	2017 Jun 15	3003-3011	Clin Cancer Res

URL

Abstract Text

Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non-muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate.Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut-, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. Six-month CR rate was 8% (0% in IHC+ Mut-; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment.Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003-11. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 S249C	bladder urothelial carcinoma	sensitive	Dovitinib	Case Reports/Case Series	Actionable	In a Phase II trial, Dovitinib (TKI258) treatment resulted in complete response in a patient with BCG-unresponsive, non-muscle-invasive, urothelial carcinoma of the bladder harboring FGFR3 S249C (PMID: 27932416).	27932416
FGFR3 mutant	bladder urothelial carcinoma	sensitive	Dovitinib	Phase II	Actionable	In a Phase II trial, Dovitinib (TKI258) treatment resulted in complete response in 33% (1/3) of patients with BCG-unresponsive, non-muscle-invasive, urothelial carcinoma of the bladder harboring FGFR3 mutations (PMID: 27932416).	27932416