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 III 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.