789P - Pharmacokinetics (PK) of the pan-FGFR inhibitor erdafitinib in urothelial carcinoma

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Urothelial Cancers
Presenter Josep Tabernero
Citation Annals of Oncology (2016) 27 (6): 266-295. 10.1093/annonc/mdw373
Authors J. Tabernero1, J.R. Infante2, A. Mita3, C. Keung4, D. Skee4, H. Xie5, T. Parekh6, P. De Porre7, F.R. Luo8, J. Soria9
  • 1Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 2Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville/US
  • 3Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, CA 90048 - Los Angeles/US
  • 4Clinical Pharmacology, Janssen Research and Development, Raritan/US
  • 5Experimental Medicine, Janssen Research and Development, Spring House/US
  • 6Cdtl Oncology, Janssen Research and Development, Raritan/US
  • 7Clinical Oncology, Janssen Research and Development, Beerse/BE
  • 8Experimental Medicine, Janssen Research and Development, Raritan/US
  • 9Department Of Medicine Ditep, Gustave Roussy Cancer Campus and University Paris-Sud, 94805 - Villejuif/FR

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.

Total Erdafitinib Concentrations* at Steady State by Sevelamer Use - Any Tumor Type, Mean (Coefficient of Variance %)

Dose N Cmax, ng/mL AUC24, ng•h/mL
9 mg continuous (without sevelamer) 6 1,140 (44.8) 21,900 (44.8)
10 mg intermittent 15
With sevelamer 11 1,850 (34.7) 34,300 (50.6)
Without sevelamer 4 1,520 (25.1) 31,500 (30.4)
12 mg intermittent 14
With sevelamer 9 1,950 (60.6) 34,000 (50.2)
Without sevelamer 5 2,160 (60.2) 31,900 (115.7)

* Approximately 0.3% of total erdafitinib is unbound in plasma.

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.

Clinical trial identification

NCT01703481

Legal entity responsible for the study

Janssen Research & Development, LLC

Funding

Janssen Research & Development, LLC

Disclosure

J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda and Taiho. A. Mita: Speakers' Bureau: Genentech. C. Keung, D. Skee, H. Xie, T. Parekh, P. De Porre, F.R. Luo: Employee of Janssen Research & Development and Johnson & Johnson stock holder. J-C. Soria: Honoraria: Johnson and Johnson. All other authors have declared no conflicts of interest.