Platinum-based chemotherapy is the standard first-line treatment for patients with advanced and metastatic urothelial carcinoma (mUC).^1,2 However, over 50% of patients are ineligible for cisplatin treatment and those who receive chemotherapy typically progress within a few months.^1,2 As such, immune checkpoint inhibitors such as inhibitors of PD-1 and PD-L1 are often used in patients ineligible for cisplatin, as maintenance therapy after platinum-based chemotherapy, or in those with relapsed or refractory disease.^1,2 Nevertheless, response rates to such treatments have remained low.^1,2 Erdafitinib is a new treatment option recently approved by the United States Food and Drug Administration (FDA) for patients with locally advanced or mUC with selected genetic alterations whose disease has progressed on or after prior systemic therapy.^2,3 This approval was granted based on the clinical and overall survival benefit observed in cohort 1 of the phase 3 THOR study.^2,3

Alterations in the fibroblast growth factor receptor (FGFR) gene are observed in approximately 20% of advanced or mUC and may function as oncogenic drivers.¹ Erdafitinib is an oral selective pan-FGFR tyrosine kinase inhibitor previously shown in a phase 2, single-arm trial to benefit patients with FGFR-altered advanced urothelial cancer who had progression after platinum-containing chemotherapy.^1,2 The phase 3, confirmatory, randomized, open-label THOR study compared the use of erdafitinib with chemotherapy in surgically unresectable or mUC patients.¹

The THOR study population included 2 cohorts, both of which included patients with FGFR3/2 alterations (mutation/fusion), who were primarily evaluated on overall survival (OS) with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), and safety.^1,4 Cohort 1 assessed erdafitinib (n=136) vs. chemotherapy (n=130) in patients with FGFR­-altered mUC who progressed on or after ≥1 prior treatment that included programmed death-ligand 1 or programmed cell death protein-1 inhibitors [anti-PD-(L)1] in the first- or second-line setting.^1,4 Cohort 2 assessed erdafitinib (n=175) vs. pembrolizumab (n=176) in FGFR­-altered mUC patients who had progressed after 1 prior treatment not containing an anti-PD-(L)1 agent.⁴

The THOR cohort 1 study found a significantly longer median OS with erdafitinib over chemotherapy (12.1 months vs. 7.8 months; HR=0.64; 95% CI: 0.47-0.88; p=0.005), translating to a 36% risk reduction in death.¹ This OS benefit was consistently observed across subgroups, including FGFR alteration type, lines of prior treatment, presence of visceral metastasis, and chemotherapy drug.¹ The median PFS was also longer with erdafitinib than chemotherapy (5.6 months vs. 2.7 months; HR=0.58; 95% CI:0.44-0.78; p=0.0002).¹ The ORR was significantly higher as well (45.6% vs. 11.5%, relative risk=3.94, 95% CI:0.2.37-6.57; p<0.001).¹ The safety profiles were consistent with the known profiles of erdafitinib and chemotherapy.¹ The adverse events with erdafitinib were mostly manageable with dose modifications and supportive care.¹

In summary, the results of this study support the clinical efficacy of erdafitinib which landed its approval by the FDA as a treatment for patients with locally advanced or mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy.¹ These findings also support molecular testing for FGFR alterations in all patients with mUC to identify those with susceptible FGFR alterations most likely to benefit from this newly approved drug.¹