Abstract C071: Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies
Authors: Ji Tao , Lihou Christine , Asatiani Ekaterine , Féliz Luis , Overholt Heather , Landman Robert , Chen Xuejun , Yeleswaram Swamy 
Published: March 2020

Pemigatinib is a potent inhibitor of fibroblast growth factor receptors (FGFR) 1, 2, and 3 with selectivity against other kinases and is currently being studied in solid tumors expressing FGFR translocations and/or mutations. A first-in-man phase 1 study (FIGHT-101) was conducted in patients with solid tumors who are refractory to approved treatments, to establish the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pemigatinib. The study was conducted in 3 parts to allow dose escalation, dose expansion, and food-effect and combination treatments, respectively. Both intermittent (2 wks on/1 wk off) and continuous daily dosing were evaluated. A total of 116 patients have received monotherapy and 44 received combination therapy, as of February 19, 2019. Serial blood samples were collected to enable PK/PD analyses, and plasma samples were assayed for pemigatinib by a validated LC-MS/MS method with a linear validated range of 1 to 1000 nM in human plasma. With multiple-dose administration in the fasted state, pemigatinib plasma concentrations attained peak values (Cmax) typically at 1–2 hours (median Tmax) post-dose, and subsequently exhibited a bi-exponential decay, with a steady-state geometric mean terminal-phase disposition half-life (t½) of approximately 15 hours that was not dose-dependent. The geometric mean accumulation ratio was approximately 1.6 for area under the curve from time 0 to 24 hours (AUC0-24). Within the dose range of 1 to 20 mg once daily (QD), increases in the pemigatinib steady-state Cmax and AUC0-24 were proportional to dose; that is, pemigatinib exhibited linear PK over the dose range studied. Pemigatinib exhibited a low steady-state oral clearance with geometric mean of 9.88–11.7 L/h and moderate volume of distribution with geometric mean of 173–244 L. At the recommended part 2 dose of 13.5 mg QD, the geometric mean (CV%) of t½, steady-state Cmax, and AUC0-24 were 15.4 h (51.6%), 236 nM (56.4%), and 2620 h*nM (54.1%), respectively. The PK parameters of pemigatinib following combination therapy were similar to that of monotherapy. Administration of a standardized high-fat and high-calorie breakfast prolonged the median pemigatinib Tmax to 4 hours, decreased the geometric mean steady-state Cmax by 18%, and increased the geometric mean steady-state AUC0-24 by 11%. The 90% CI of geometric mean ratio for steady-state Cmax and AUC0-24 were (0.648–1.03) and (0.935–1.31), respectively. The effect of food on pemigatinib plasma exposures was considered as modest and not clinically meaningful. Therefore, pemigatinib can be administered without regard to food. The geometric mean fraction of pemigatinib excreted in urine was 1.19% (range, 0.226–7.24%) with a geometric mean renal clearance of 0.133 L/h based on exploratory urine excretion data, indicating minor contribution from renal clearance towards total systemic clearance. Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition. The increase in serum phosphorus observed after treatment with pemigatinib was exposure-dependent and followed a sigmoidal relationship. In conclusion, pemigatinib exhibits rapid absorption, linear PK, and a t½ consistent with QD dosing. Pemigatinib is predominantly cleared by metabolism and there are no active metabolites.

Citation Format: Tao Ji, Christine Lihou, Ekaterine Asatiani, Luis Féliz, Heather Overholt, Robert Landman, Xuejun Chen, Swamy Yeleswaram. Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C071. doi:10.1158/1535-7163.TARG-19-C071