ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following prior therapies for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs).

Abstract

770 Background: Erdafitinib (E), a pan-FGFR inhibitor, is approved for FGFR3-altered mUC after prior therapy. Enfortumab Vedotin (EV) is active as monotherapy post-platinum and in combination with pembrolizumab (EVP) as 1 st line therapy in mUC. Retrospective studies suggest EV activity is maintained in FGFR 3/2-altered disease. Since EV and E have different mechanisms of activity and toxicities are mostly non-overlapping, we evaluated the feasibility, safety, pharmacokinetics (PK), and antitumor activity of E+EV in this population. Methods: Single arm, multicenter Phase Ib with 3+3 dose-escalation and expansion study of E at 8 mg daily orally + EV on days 1,8, and 15 every 4 weeks in FGFR3/2 altered mUC patients who progressed on prior therapies. EV dose level 1 (DL1) was 1 mg/kg, escalation dose was 1.25 mg/kg (DL2), and reduction was allowed to 0.75 mg/kg (DL -1). Primary objective: determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV with fixed dose of E. Secondary objectives: objective response rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and PK. Results: Fifteen patients were enrolled and completed the dose limiting toxicity (DLT) period (1st cycle). Median age was 69 years and 13 (87%) were male. In dose-escalation, 6 patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The MTD and RP2D of EV was 1.25 mg/kg with E at 8 mg/day; an additional 6 patients were treated at RP2D. Common all-grade treatment-related adverse events (TRAEs) included hyperphosphatemia, AST increase, mucositis, diarrhea, fatigue, peripheral neuropathy, dry mouth, palmar–plantar erythrodysesthesia (PPE) and hypercalcemia. Grade 3–4 TRAEs were UTI 27%, PPE 20%, anemia 13%, lymphopenia 13%, vomiting 13%, Stevens–Johnson syndrome 7%, and hyponatremia 7%; there were no grade 5 events. PK: E Ctrough 1320±421 ng/mL. For the EV payload (MMAE), exposures aligned with monotherapy references—DL1: Ctrough 0.6±0.3, Cmax 3.9±0.9 ng/mL; DL2: Ctrough 0.9±0.6, Cmax 5.5±2.3 ng/mL. Objective responses were observed in 14 of 15 patients (93.3%, 95% CI: 68.1-99.8%), including 12 partial responses, 2 complete responses, and 1 stable disease. The median OS was 26.4 months (95% CI 12.1-NR); median PFS was 11.1 months (95% CI: 7.6-NR) with median follow up of 27.2 months (95% CI 18.6- NR). The median DOR was 8.25 months (range 1.7-24.2) among responders. Conclusions: E+EV was feasible, tolerable, and showed high anti-tumor activity in FGFR3/2-altered mUC. The magnitude of response in this small cohort supports a biologic rationale for dual targeting of FGFR3 signaling and NECTIN-4–mediated antibody drug conjugate with further prospective evaluation of EVP and FGFR3-selective inhibitors in larger biomarker-defined studies. Clinical trial information: NCT04963153 .