Long-term survival is poor for patients with locally advanced or metastatic urothelial carcinoma (UC) receiving chemotherapy and/or immunotherapy following progression with platinum-containing chemotherapy. Genetic alterations of fibroblast growth factor receptors (FGFR) have been shown to play a role in UC development and progression. Non-genetic and epigenetic activation of FGFR gene expression have also been described. Rogaratinib, an oral pan-FGFR 1-3 inhibitor, has shown promising activity and a manageable safety profile in a phase I study in patients with UC who were selected based on FGFR1-3 mRNA overexpression and/or activating mutations in the FGFR3 gene.
This is a randomized, open-label, phase 2/3 study to evaluate the efficacy and safety of rogaratinib compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic UC who have received prior platinum-containing chemotherapy. The primary objective is to show superiority of rogaratinib over chemotherapy in prolonging overall survival (OS) of UC patients with FGFR-positive tumors. Secondary objectives include: objective response rate (ORR), progression-free survival, disease control rate, duration of response, and safety. Testing for FGFR1 and 3 mRNA over expression will be conducted centrally using an RNA in situ hybridization (RNA-ISH) in archival samples. Eligible patients will be randomized 1:1 to rogaratinib (800 mg po bid) or iv chemotherapy Q3W (docetaxel 75 mg/m2; paclitaxel 175 mg/m2; or 320 mg/m2 vinflunine). Randomization will be stratified according to PIK3CA and/or RAS activating mutations, prior immunotherapy, and modified 4-factor Bellmunt risk score. The objective for the phase 2 part of the study is ORR. A total of 116 patients in PIK3CA and RAS WT patients will be enrolled to the phase 2 part of the study to rule out a low difference in ORR between rogaratinib and chemotherapy as futility. The phase 3 portion of the study is powered to detect an increase in median OS in PIK3CA and RAS WT patients. Total patient enrollment expected to be approximately 400 patients.
Clinical trial identification
Legal entity responsible for the study
K. Nakajima, C. Lu, A. Holynskyj: Bayer employment. All other authors have declared no conflicts of interest.