Fibroblast growth factor receptor (FGFR) signaling is deregulated in urothelial carcinomas (UC). Rogaratinib is an oral inhibitor of FGFRs 1-4 with demonstrated antitumor activity in bladder cancer xenograft models. We report the results from a rogaratinib phase I trial expansion cohort in UC patients selected based on FGFR1-3 mRNA tumor overexpression and/or presence of activating mutations in the FGFR3 gene.
Patients with locally advanced or metastatic UC who have progressed or ineligible for standard therapy were screened for high FGFR1-3 mRNA expression levels by RNA in situ hybridization (RNAscope®) and Nanostring® assays utilizing fresh or archival FFPE tumor specimens. FGFR3-activating mutations were evaluated by a PCR based assay (Qiagen). Patients were treated with rogaratinib 800mg BID on a continuous regimen. Tumor response was assessed by RECIST, v1.1. Adverse events were classified using CTCAE v4.03 criteria.
Biopsies from a total of 109 patients with advanced UC were screened, with 42.3% found to be FGFR positive; of which 87% due to FGFR3 mRNA overexpression, 4% FGFR1, and 9% mixed FGFR isoform mRNA expression. Co-ocurrence of FGFR3-activating mutations and high FGFR3 mRNA expression was seen in 8% of patients. Among 20 patients with UC treated with rogaratinib, 16 (75%) had tumor shrinkage in target lesions with 9 (45%) showing tumor shrinkage of more than 20%, and 6 (30%) having a partial response (PR). Disease control rate (CR+PR+SD>12w) was 75%. Three patients with a PR had elevated tumor FGFR3 mRNA levels without corresponding genomic alterations. The most frequent AEs were hyperphosphatemia and diarrhea.
Selection of UC patients for treatment with rogaratinib based on FGFR1-3 mRNA expression levels in archival tissue was feasible and identified patients benefitting from treatment without having aberrations of FGFR-encoding genes. Rogaratinib has a favorable safety profile and showed anti-tumor activity in biomarker-selected UC patients which warrants further clinical development.
Clinical trial identification
Legal entity responsible for the study
M. Schuler: Consultant: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Novartis, Roche; Honoraria: Alexion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Novartis Research: Boehringer Ingelheim, Bristol Myers-Squibb, Novar. S. Bender, M. Ocker, H. Nogai, A. Wagner, P. Ellinghaus: Employment: Bayer AG. S. Ince: Employment: Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest.