Pharmacokinetics (PK) of the pan-FGFR inhibitor erdafitinib in urothelial carcinoma

Abstract

Background: Erdafitinib (JNJ‐42756493) potently inhibits cell proliferation in FGFR pathway‐activated cancer cell lines. The targeted therapeutic range for unbound plasma erdafitinib is >0.5 to 2.4 ng/mL based on efficacious concentrations in preclinical tumor models. This analysis examined the PK of erdafitinib in the targeted population of patients with urothelial carcinoma and FGFR aberrations. Methods: The first‐in‐human, open‐label, multicenter, phase 1 study included patients with advanced or refractory solid tumors or lymphoma and FGFR aberrations. Patients received erdafitinib 0.5‐12 mg once daily (QD) continuously (C) or erdafitinib 10 or 12 mg 7d on/7d off intermittently (I) in 28d cycles. A phosphate binder (sevelamer) could be used to manage elevated phosphate. This analysis focused on PK for 9 mg C, 10 mg I, and 12 mg I. Blood samples for PK were obtained at steady state on Cycle 1 Day 8 (9 mg C) or Cycle 1 Day 7 (10 or 12 mg I) and analyzed for total erdafitinib, of which ~0.3% is unbound. Results: Among 28 patients with urothelial carcinoma, 5 received erdafitinib 9 mg C, 10 mg I, or 12 mg I and provided extensive PK samples at steady state. Maximum concentration (Cmax) for total erdafitinib was 1,130 to 2,690 ng/mL and area under the 24‐hour concentration‐time curve (AUC24h) was 19,900 to 52,600 ng?h/mL. Phosphate concentration, a pharmacodynamics biomarker, increased when erdafitinib concentrations increased and returned toward baseline when erdafitinib was stopped. Among patients with any tumor type and PK data at steady state, total drug concentrations were similar with or without concurrent sevelamer use (Table). Anti‐tumor efficacy and safety are reported separately. Conclusions: Exposure for the pan‐FGFR inhibitor erdafitinib at 9 mg C, 10mg I, and 12 mg I achieved or exceeded the targeted therapeutic range in patients with urothelial carcinoma and FGFR aberrations. Concurrent use of a phosphate binder did not affect erdafitinib PK. (Table Presented).