FORAGER-2: A randomized phase 3 study evaluating the efficacy and safety of vepugratinib combined with enfortumab vedotin and pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma with an FGFR3 genetic alteration.

Abstract

TPS895 Background: Treatment with enfortumab vedotin (EV)/pembrolizumab (P) has significantly improved clinical outcomes for untreated locally advanced or metastatic urothelial cancers (LA/mUCs). However, with a median progression-free survival (PFS) of only ~12 months, most patients (pts) will still progress and succumb to their disease. Activating alterations in fibroblast growth factor receptor 3 (FGFR3) occur in 15-20% mUC. Vepugratinib is an oral, highly potent, isoform-selective FGFR3 inhibitor, designed to limit off-target toxicity associated with pan FGFR inhibitors. The FORAGER-1 phase 1 study (NCT05614739) demonstrated promising efficacy in pts with previously treated FGFR3-altered mUC (Drakaki, ESMO 2025). The favorable safety profile observed at the selected monotherapy dose, 200 mg BID, supports combining vepugratinib with other agents. Preclinical studies in FGFR3-altered mUC demonstrate vepugratinib induces upregulation of cell-surface NECTIN-4 and enhanced antitumor activity when given in combination with EV/P (Goetz, AACR-NCI-EORTC, 2025), providing a strong biological rationale for combination with EV/P. FORAGER-2 (NCT07218380) is a randomized, double-blind, placebo-controlled phase 3 study evaluating the addition of vepugratinib to EV/P in pts with previously untreated LA/mUC harboring an FGFR3 genetic alteration. Methods: Approximately 450 pts with untreated, histologically confirmed LA/mUC with an activating FGFR3 mutation or fusion determined via local molecular testing (tissue or blood), will be randomized in a 1:1 ratio to receive EV/P + vepugratinib or EV/P + placebo. Pts may receive 1 cycle of standard of care EV/P before study enrollment for cases where immediate treatment is clinically indicated while awaiting FGFR3 test results. Treatment will continue until radiographic progression or unacceptable toxicity. Pts will be stratified at baseline by Eastern Cooperative Oncology Group performance status score, presence of liver or bone metastases, and geographical region. The primary endpoint is PFS assessed by blinded independent central review. Key secondary endpoints include overall survival, investigator-assessed PFS, objective response rate, duration of response, PFS2, safety, and patient-reported outcomes such as health-related quality of life. The randomized portion of FORAGER-2 will be preceded by a single-arm safety lead-in. Enrollment is ongoing and will be opened in approximately 19 countries. Clinical trial information: NCT07218380 .