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

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, 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

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.

Conflict of interest statement

Jae-Lyun Lee

Stock and Other Ownership Interests: Myovant Sciences, Johnson & Johnson/Janssen, Amgen, Merck, BeiGene, Innovent Biologics, Black Diamond Therapeutics, Karyopharm Therapeutics, Zymeworks

Honoraria: Bristol Myers Squibb, Astellas Pharma, Pfizer, AstraZeneca, MSD

Consulting or Advisory Role: Pfizer, BMS Korea, GI Innovation, MSD, Merck, AstraZeneca, Sanofi, Oscotec

Research Funding: Pfizer (Inst), Janssen (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), MSD (Inst), Bayer Schering Pharma (Inst), Seattle Genetics (Inst), GI Innovation (Inst), Amgen (Inst)

Tatiane Cristine Ishida

Employment: Bayer

Hiroyuki Nishiyama

Consulting or Advisory Role: MSD, Chugai Pharma, Bayer Yakuhin, Janssen, Lilly

Speakers' Bureau: MSD, Chugai Pharma, Astellas Pharma

Research Funding: Astellas Pharma (Inst), Ono Pharmaceutical (Inst), Takeda (Inst), Bayer Yakuhin (Inst)

Sabine Coppieters

Employment: Bayer, Argenx

Stock and Other Ownership Interests: Bayer, Argenx

Michiel S. van der Heijden

Stock and Other Ownership Interests: Gilead Sciences

Consulting or Advisory Role: Roche/Genentech (Inst), Astellas Pharma (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), MSD Oncology (Inst), Seattle Genetics (Inst), Janssen (Inst), Pfizer (Inst)

Research Funding: Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Roche (Inst), AstraZeneca (Inst), Seattle Genetics (Inst), 4SC (Inst)

Travel, Accommodations, Expenses: Novartis, Astellas Pharma, MSD Oncology, Roche

Weichao Bao

Stock and Other Ownership Interests: Bayer (Inst)

David I. Quinn

Employment: AbbVie

Honoraria: Bayer, Pfizer, Genentech/Roche, Merck Sharp & Dohme, Bristol Myers Squibb, Exelixis, Seattle Genetics, Myovant Sciences, AVEO, Clinigen Group

Consulting or Advisory Role: Pfizer, Bristol Myers Squibb, Genentech/Roche, Merck Sharp & Dohme, Bayer, Exelixis, Eisai, US Biotest, Seattle Genetics, Myovant Sciences, AVEO, Clinigen Group

Research Funding: Genentech/Roche (Inst), Merck (Inst), Pfizer (Inst)

Travel, Accommodations, Expenses: Bayer, Exelixis

Uncompensated Relationships: Eisai, US Biotest

Howard Gurney

Consulting or Advisory Role: Bristol Myers Squibb, Ipsen, Merck Sharp & Dohme, AstraZeneca, Janssen-Cilag, Pfizer, Roche, Merck Serono, Astellas Pharma

Speakers' Bureau: Merck Serono

Travel, Accommodations, Expenses: AstraZeneca

Florence Joly

Consulting or Advisory Role: AstraZeneca, Janssen, Ipsen, Pfizer, MSD Oncology, Bristol Myers Squibb, GlaxoSmithKline, Astellas Pharma, Clovis Oncology, Amgen, Seattle Genetics, Bayer

Travel, Accommodations, Expenses: Janssen, AstraZeneca, Ipsen, GlaxoSmithKline, BMS

Keiko Nakajima

Employment: Bayer, Daiichi Sankyo/Astra Zeneca

Stock and Other Ownership Interests: Bayer, Daiichi Sankyo/Astra Zeneca

Joaquim Bellmunt

Stock and Other Ownership Interests: Rainier Therapeutics

Honoraria: UpToDate

Consulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers Squibb

Research Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)

Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen

Mitchell Sierecki

Employment: Gilead Sciences, Bayer HealthCare Pharmacuticals

Leadership: Gilead Sciences, Bayer HealthCare Pharmacuticals

Travel, Accommodations, Expenses: Gilead Sciences

Andrea Necchi

Employment: Bayer

Stock and Other Ownership Interests: Bayer

Honoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol Myers Squibb

Consulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, Ferring

Research Funding: Merck Sharp & Dohme (Inst), AstraZeneca (Inst), Ipsen, Seattle Genetics (Inst)

Travel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen, Rainier Therapeutics

Other Relationship: Bayer

Xavier García del Muro

Consulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, Roche, Lilly, PharmaMar, EUSA Pharma, GlaxoSmithKline, Merck, Eisai

Speakers' Bureau: Pfizer, Bristol Myers Squibb, Astellas Pharma, Eisai

Research Funding: AstraZeneca

Travel, Accommodations, Expenses: Pfizer, Roche

Cora N. Sternberg

Consulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine, Bristol Myers Squibb/Medarex, IMPAC Medical Systems

Eli Rosenbaum

Stock and Other Ownership Interests: Brainsway, Conergent

Consulting or Advisory Role: MSD Oncology, Teva, Astellas Pharma, Bayer, Janssen

Speakers' Bureau: MSD Oncology

Peter Ellinghaus

Employment: Bayer

Leadership: Bayer

Stock and Other Ownership Interests: Bayer

Daniel P. Petrylak

Stock and Other Ownership Interests: Bellicum Pharmaceuticals, TYME

Consulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Urogen pharma, Advanced Accelerator Applications, Ipsen, Bicycle Therapeutics, Mirati Therapeutics, Monopteros Therapeutics, Regeneron, Gilead Sciences

Research Funding: Progenics (Inst), Sanofi (Inst), Endocyte (Inst), Genentech (Inst), Merck (Inst), Astellas Medivation (Inst), Novartis (Inst), AstraZeneca (Inst), Bayer (Inst), Lilly (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Pfizer (Inst), Roche (Inst), Seattle Genetics (Inst), Clovis Oncology (Inst), Bristol Myers Squibb (Inst), Advanced Accelerator Applications (Inst), Agensys (Inst), BioXCel Therapeutics (Inst), Eisai (Inst), Mirati Therapeutics (Inst), Replimune (Inst), Medivation (Inst), Gilead Sciences (Inst)

Expert Testimony: Celgene, Sanofi

Nicolas Penel

Research Funding: Bayer (Inst)

Travel, Accommodations, Expenses: Astellas Pharma, Janssen-Cilag

Other Relationship: PharmaMar

Chengxing Lu

Employment: Bayer, Biogen, AstraZeneca

Stock and Other Ownership Interests: Bayer, Biogen, AstraZeneca

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Kaplan-Meier curves of (A) OS and (B) PFS (full analysis set). Median (95% CI) from Kaplan-Meier estimates; P value is taken from stratified log-rank test; HR (95% CI) on the basis of stratified Cox proportional hazards model. HR, hazard ratio; NE, not evaluable; OS, overall survival; PFS, progression-free survival.

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