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Ref Type Journal Article
PMID (36240478)
Authors Sternberg CN, Petrylak DP, Bellmunt J, Nishiyama H, Necchi A, Gurney H, Lee JL, van der Heijden MS, Rosenbaum E, Penel N, Pang ST, Li JR, García Del Muro X, Joly F, Pápai Z, Bao W, Ellinghaus P, Lu C, Sierecki M, Coppieters S, Nakajima K, Ishida TC, Quinn DI
Title FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 41 3 2023 Jan 20 629-639 J Clin Oncol
URL
Abstract Text Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy.FORT-1 (ClinicalTrials.gov identifier: NCT03410693) was a phase II/III, randomized, open-label trial. Patients with FGFR1/3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed.ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy.To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/3 mRNA overexpression may be better predictors of rogaratinib response.

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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 over exp transitional cell carcinoma no benefit Rogaratinib Phase II Actionable In a Phase II trial (FORT-1), Rogaratinib (BAY 1163877) treatment did not result in improved outcomes compared to chemotherapy in advanced or metastatic urothelial carcinoma patients with FGFR1 or FGFR3 overexpression, with similar median overall survival (8.3 mo vs 9.8 mo), median progression-free survival (2.7 mo vs. 3.2 mo), and objective response rate (20.7% (18/87) vs 19.3% (17/88)), failing to meet the predetermined criteria for continuation to Phase III (PMID: 36240478; NCT03410693). 36240478
FGFR1 over exp transitional cell carcinoma no benefit Rogaratinib Phase II Actionable In a Phase II trial (FORT-1), Rogaratinib (BAY 1163877) treatment did not result in improved outcomes compared to chemotherapy in advanced or metastatic urothelial carcinoma patients with FGFR1 or FGFR3 overexpression, with similar median overall survival (8.3 mo vs 9.8 mo), median progression-free survival (2.7 mo vs. 3.2 mo), and objective response rate (20.7% (18/87) vs 19.3% (17/88)), failing to meet the predetermined criteria for continuation to Phase III (PMID: 36240478; NCT03410693). 36240478
FGFR3 act mut FGFR3 over exp transitional cell carcinoma predicted - sensitive Rogaratinib Phase II Actionable In a Phase II trial (FORT-1), Rogaratinib (BAY 1163877) treatment resulted in a higher objective response rate of 52.4% (11/21) compared to 26.7% (4/15) with chemotherapy in advanced or metastatic urothelial carcinoma patients with FGFR3 overexpression and an FGFR3 alteration (including FGFR3 G370C, FGFR3 R248C, FGFR3 S249C, FGFR3 Y373C, FGFR3-TACC3v1, and FGFR3-TACC3v3) (PMID: 36240478; NCT03410693). 36240478