Background
Phase III, open-label RCT. 266 patients with advanced urothelial carcinoma with FGFR2/3 alterations (mutations or fusions) who had received prior platinum-based chemotherapy AND a PD-1/PD-L1 checkpoint inhibitor. Erdafitinib (pan-FGFR inhibitor) compared to investigator's choice chemotherapy (docetaxel or vinflunine), making THOR the first phase III trial of FGFR-targeted therapy in UC. Note: n=180 in HemeOncBuddy DB is the earlier phase 2 erdafitinib trial (BLC2001, Loriot Y NEJM 2019).
Interventions and follow up
Arm A: Erdafitinib 8mg/day orally (up-titrated to 9mg if tolerated after cycle 1)
Arm B: Investigator's choice: docetaxel 75mg/m² IV q3wk OR vinflunine 320mg/m² IV q3wk
Primary endpoint: OS
mFollow up: 15.9 mo
Arm B: Investigator's choice: docetaxel 75mg/m² IV q3wk OR vinflunine 320mg/m² IV q3wk
Primary endpoint: OS
mFollow up: 15.9 mo
Results
OS: 12.1 vs 7.8 mo, HR 0.64, P=.005
PFS: 5.6 vs 5.9 mo, HR 0.86, P=.19 — not significant
ORR: 45.6% vs 11.5%
DCR: 73.7% vs 48.7%
PFS: 5.6 vs 5.9 mo, HR 0.86, P=.19 — not significant
ORR: 45.6% vs 11.5%
DCR: 73.7% vs 48.7%
Adverse events
Overall grade ≥3: 45.7% vs 46.5% (similar)
Ocular: central serous retinopathy (any grade) 23.5% vs 1.5% — FGFR class effect; dry eye (any grade) 28.7% vs 2.3%
Metabolic: hyperphosphatemia (any grade) 77.2% vs 8.5% — requires dietary phosphate restriction
Mucosal: stomatitis grade ≥3 7.4% vs 4.6%
Dermatologic: nail toxicity grade ≥3 3.7% vs 0%
Discontinuation: 14.1% vs 12.3%
Ocular: central serous retinopathy (any grade) 23.5% vs 1.5% — FGFR class effect; dry eye (any grade) 28.7% vs 2.3%
Metabolic: hyperphosphatemia (any grade) 77.2% vs 8.5% — requires dietary phosphate restriction
Mucosal: stomatitis grade ≥3 7.4% vs 4.6%
Dermatologic: nail toxicity grade ≥3 3.7% vs 0%
Discontinuation: 14.1% vs 12.3%
Conclusions
Erdafitinib significantly improved OS versus chemotherapy in FGFR2/3-altered mUC after prior platinum + IO therapy, despite not meeting the PFS primary endpoint (OS was co-primary). The OS benefit (HR 0.64) with a 4.3-month absolute gain establishes erdafitinib as the standard for FGFR-altered post-platinum/IO UC.
Key Limitations
Key Limitations: PFS was not significantly improved despite OS benefit — an unusual dissociation, possibly due to post-progression survival differences, crossover, or tumor heterogeneity. Central serous retinopathy (23.5% any grade) is an ocular toxicity requiring baseline and monitoring ophthalmologic evaluation. Hyperphosphatemia is ubiquitous and requires low-phosphate diet and potentially phosphate binders. FGFR alterations were required (present in ~15–20% of mUC patients), necessitating routine molecular testing. EV (sacituzumab govitecan, TROPHY-U-01) and ADC options are emerging in this same line.
Clinical Context
FDA approved erdafitinib for FGFR-altered mUC post-platinum in 2019 (phase 2, conditional) and full approval was supported by THOR in 2024. FGFR2/3 testing by ctDNA or tumor tissue is now essential in mUC workup. For FGFR-altered patients, erdafitinib competes with sacituzumab govitecan (TROPHY-U-01) and EV (EV-301) in later lines; sequencing depends on prior therapies. EV-302 era patients who received EV+pembro first-line represent a newly emerging population requiring FGFR-aware subsequent line planning.
References
References: Loriot Y et al, NEJM 2023 | Loriot Y et al, NEJM 2019 (phase 2)