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

Purpose: 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.

Methods: FORT-1 ( 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.

Results: 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.

Conclusion: 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.

Cora N Sternberg, Daniel P Petrylak, Joaquim Bellmunt, Hiroyuki Nishiyama, Andrea Necchi, Howard Gurney, Jae-Lyun Lee, Michiel S van der Heijden, Eli Rosenbaum, Nicolas Penel, See-Tong Pang, Jian-Ri Li, Xavier García Del Muro, Florence Joly, Zsuzsanna Pápai, Weichao Bao, Peter Ellinghaus, Chengxing Lu, Mitchell Sierecki, Sabine Coppieters, Keiko Nakajima, Tatiane Cristine Ishida, David I Quinn

Englander Institute for Precision Medicine, Weill Cornell Medicine, Sandra and Edward Meyer Cancer Center, New York, NY. Yale Cancer Center, New Haven, CT. Beth Israel Deaconess Medical Center and PSMAR-IMIM Lab, Boston, MA. Harvard Medical School, Boston, MA. Department of Urology, University of Tsukuba, Tsukuba, Japan. Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy. Clinical Trials Unit FMHS, Macquarie University, Sydney, New South Wales, Australia. University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Medical Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel. Lille University and Department of Medical Oncology, Centre Oscar Lambret, Lille, France. Division of Urology, Department of Surgery, Linkou Chang Gung Memorial Hospital, Linkou, Taiwan. Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan. Department of Medical Oncology, University of Barcelona, Idibell Institute of Research, Institut Català d'Oncologia Hospitalet, Barcelona, Spain. Clinical Research Department, Centre François Baclesse, Caen, France. Oncology Department, Medical Centre, Hungarian Defence Forces, Budapest, Hungary. Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ. Bayer AG, Wuppertal, Germany. Bayer AG, Diegem, Belgium. Division of Oncology, Department of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA.

Source: Cora N. Sternberg, Daniel P. Petrylak, Joaquim Bellmunt et al. 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 of Clinical Oncology. 2022. doi: 10.1200/JCO.21.02303.

Read an Expert Commentary by Bishoy Faltas, MD