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.

Abstract

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 (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.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 41 Issue 3 Pg. 629-639 (01 20 2023) ISSN: 1527-7755 [Electronic] United States
• PMID: 36240478 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• DNA
• FGFR1 protein, human
• Platinum
• Receptor, Fibroblast Growth Factor, Type 1
• RNA, Messenger
• Rogaratinib

Topics

• Humans
• Antineoplastic Agents (adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Carcinoma, Transitional Cell (drug therapy)
• DNA (therapeutic use)
• Platinum (therapeutic use)
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, therapeutic use)
• RNA, Messenger
• Urinary Bladder Neoplasms (pathology)