2503 - Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Patients (pts) With Metastatic or Surgically Unresectable (M/UR) Urothelial Carcinoma (UC) and Selected FGFR Gene Alterations (FGFRalt): the Phase 3 THOR Study

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. 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.

Clinical trial identification

NCT03390504.

Legal entity responsible for the study

Janssen Research & Development.

Funding

Janssen Research & Development.

Editorial Acknowledgement

Editorial assistance was provided by Tamara Fink, PhD, of PAREXEL (Hackensack, NJ, USA), with funding from Janssen Global Services, LLC (Raritan, NJ, USA).

Disclosure

Y. Loriot: Consulting/advisory role: Janssen, Astellas, Roche, Ipsen, Sanofi, AstraZeneca, MSD, Seattle Genetics; Research funding: Sanofi, Janssen; Travel expenses: Roche, MSD, AstraZeneca. A. Necchi: Consulting/advisory capacity: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology; Travel expenses: Roche, Merck Sharp & Dohme, Pierre Fabre; Research funding: Amgen, Merck Sharp & Dohme, AstraZeneca. S.H. Park: Consulting/advisory role and in Speaker's bureaus: Eli Lilly. R.A. Huddart: Consulting/advisory role: MSD, Roche, Bristol-Myers Squibb; Stock or other ownership interests: Cancer Centre London, LLP; Speaker's bureaus: Roche, Elekta; Research funding: MSD, Elekta; Travel expenses: Roche, MSD. E. Burgess: Consulting/advisory role: Janssen, Roche/Genentech, Bayer, Pfizer; Stock or other interests: Exelixis, Becton Dickinson, Calithera Biosciences, Gilead Sciences, McKesson, Medtronic; Speaker's bureaus: Janssen, Exelixis; Research funding: Pfizer, Astellas; Travel expenses: Janssen, Exelixis, Pfizer. B. Zhong, A. Santiago-Walker, S. Little, T. Roccia, P. De Porre: Employed by Janssen Research & Development; Stock in Johnson & Johnson. A.O. Siefker-Radtke: Consulting/advisory role: Janssen, Merck, NCCN, Eisai, Genentech, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, EMD Serono, Inovio Pharmaceuticals; Research funding: Janssen, NIH, the Michael and Sherry Sutton Fund for Urothelial Cancer, Takeda; Patents, royalties or other intellectual property titled, "Methods of characterizing and treating molecular subsets of muscle-invasive cancer”.