Background: Pts with M/UR UC have poor prognoses. Programmed death (ligand)-1 (PD-[L]1) inhibitors have improved outcomes in some pts, but responses vary based on genotypic subtype. Fibroblast growth factor receptor gene alterations (FGFRalt) are present in 20% of pts with UC, and may reflect an immunologically “cold” tumor that does not respond well to immunotherapy (Siefker-Radtke ASCO GU 2018). In early phase 2 data, the pan-FGFR (1-4) inhibitor erdafitinib (ERDA, 8 mg/d continuous) demonstrated tolerability and a favorable 42% objective response rate (ORR) in pts with M/UR UC and FGFRalt; uptitration to 9 mg/d was feasible. Activity of single-agent ERDA will be compared with chemo or pembrolizumab in pts with M/UR UC in this randomized phase 3 study.
Trial design: Adult pts (ECOG performance status ≤ 2 and adequate bone marrow, liver, and renal function; no uncontrolled cardiovascular disease, known HIV, hepatitis B or C, or baseline phosphate persistently above the upper limit of normal allowed) with stage 4 M/UR UC and specific pathogenic FGFRalt (FGFR3 mutations or FGFR2/3 fusions) who have received 1 line of prior systemic therapy are eligible. Pts will be screened for FGFRalt and randomized 1:1 to cohort 1 or 2. In cohort 1 (n ≈280), pts with prior chemo and PD-(L)1 inhibitor (prior PD-[L]1 inhibitor alone allowed for cisplatin-ineligible pts) in combination or in maintenance setting will receive 8 mg/d continuous ERDA vs chemo (1:1) with docetaxel or vinflunine. In cohort 2, pts (n ≈350) with prior chemo but no prior PD-(L)1 inhibitor will receive 8 mg/d ERDA vs pembrolizumab (1:1). Uptitration of ERDA to 9 mg/d is recommended in pts with serum phosphate ≤ 9 mg/dL. Primary end point: overall survival. Secondary end points: progression-free survival, ORR, duration of response, pt-reported outcomes, safety, and pharmacokinetics. PD-L1 expression level per immunohistochemistry and UC subtype per RNA sequencing or other methods are exploratory end points. Pts are being enrolled at sites in 25 countries. For additional information on specific sites/countries: https://clinicaltrials.gov/ct2/show/NCT03390504.
Disclosures: YL: Consulting or advisory role, Janssen, Astellas, Roche, Ipsen, Sanofi, AstraZeneca, MSD, Seattle Genetics; Research funding, Sanofi, Janssen; Travel expenses: Roche, MSD, AstraZeneca. JPMR: None. AN: Consulting or advisory role, Merck, Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology; Travel expenses, Roche, Merck, Sharp & Dohme, Pierre Fabre; Research funding, Amgen, Merck, Sharp & Dohme, AstraZeneca. SHP: Consulting or advisory role, Lilly; Speaker’s bureau, Lilly. RH: Stock or other ownership interests, Cancer Centre London LLP; Consulting or advisory role, MSD, Roche, Bristol-Myers Squibb; Speaker’s bureau, Roche, Elekta; Research funding, MSD, Elekta; Travel expenses, Roche, MSD. EB: Stock and other ownership interests, Exelixis, Becton Dickinson, Calithera Biosciences, Gilead Sciences, McKesson, Medtronic; Consulting or advisory role, Janssen, Roche/Genentech, Bayer, Pfizer; Speaker’s bureau, Exelixis, Janssen; Research funding, Pfizer, Astellas Pharma; Travel expenses, Janssen, Exelixis, Pfizer. ASR: Consulting or advisory role, Janssen, Merck, NCCN, Eisai, Genentech, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, EMD Serono, Inovio Pharmaceuticals; Research funding, NIH, Michael and Sherry Sutton Fund for Urothelial Cancer, Janssen, Takeda; Patents, royalties, other intellectual property, Methods of characterizing and treating molecular subsets of muscle-invasive cancer. BZ, ASW, SL, TR, PDP: Employment, Janssen; Stock ownership, Johnson & Johnson.