Abstract B151: In FGFR2 driven tumors, preclinical pharmacokinetics (PK), pharmacodynamics (PD) and efficacy translate into clinical activity of ARQ 087
Authors: Hall Terence G. , Savage Ronald E. , Schwartz Brian , Yu Yi , Wang Yunxia , Kazakin Julia , Abbadessa Giovanni , Tolcher Anthony W. , Papadopoulos Kyriakos P. , Shaib Walid , el-Rayes Bassel 
Published: May 2016

Abstract
Background: ARQ 087 is a potent FGFR1-3 tyrosine kinase inhibitor which is currently in a Phase 1/2 clinical study in patients with FGFR-driven solid tumors. We present a comparison of preclinical-clinical PK, PD, and efficacy data.
Methods: In vitro proliferation studies were conducted in FGFR2 driven cell lines (Ba/F3 transfected, SNU-16, NCI-H716, AN3CA). In vivo studies were conducted in BaF3/FGFR2, SNU-16, ANC3A, and NCI-H716 xenograft models. Approximately 5×10^6 cells implanted subcutaneously and allowed to grow to an appropriate size (200-400mg) before initiating treatment with ARQ 087 (25-150 mg/kg QD). Treatment periods were from 10-21 days (model dependent), and ARQ 087 was generally well tolerated with minimal weight-loss. Levels of pFGFR, and other downstream markers of FGFR pathway inhibition, were tracked in cells and tumors to determine the effects of ARQ 087 on FGFR pathway activity.
Patients with solid tumors were enrolled in the ARQ 087-101 trial (NCT01752920) at 20-425 mg QD, and plasma was collected on cycle 1 day 1, 8, 22, and day 1 and 15 of subsequent cycles for PK and PD (FGF levels). Human and mouse plasma samples, were quantified for ARQ 087 levels.
Results: ARQ 087 is a potent inhibitor of cell lines with FGFR2 genetic alterations with IC50 values as low as 40 nM. In FGFR2 driven cell lines ARQ 087 inhibited pFGFR as well and downstream signaling proteins. SNU-16 xenograft models showed 69-99-% tumor growth inhibition (TGI), with plasma Cmax values of 1.2-4.9 μM. BaF3/FGFR2 xenografts had a TGI of up to 94% with plasma Cmax of 2.8-7.7 μM. AN3CA xenografts showed TGI 054% and a Cmax of 0.1-3.1 μM. In the dose escalation phase of ARQ 087-101 mean plasma Cmax concentrations at steady state were 2 μM at the MTD (400 mg QD). The recommended phase 2 dose for ARQ 087 is 300 mg QD, which provides comparable plasma concentrations. Two cholangiocarcinoma patients with FGFR2 translocations were treated at 400mg QD. A RECIST partial response (-34% in tumor size) was observed in a patient with an FGFR2-BICC1 fusion, whose steady state ARQ 087 Cmax level was 1.7 μM. A minor tumor response (-26%) was seen in a patient with an FGFR2-KIAA1217 fusion, and a steady state ARQ 087 Cmax was 1.5 μM. Finally, patients treated with ARQ 087 showed changes in circulating FGFs 19/21/23, which supports the monitoring of these FGFs as biomarkers for target engagement.
Conclusions: In our studies with ARQ 087, FGFR2 dysregulation correlates with efficacy. The translation of results from FGFR2 preclinical models into clinical efficacy in patients with FGFR2 fusion driven cholangiocarcinoma is encouraging and is currently evaluated in the ongoing clinical trial.
Citation Format: Terence G. Hall, Ronald E. Savage, Brian Schwartz, Yi Yu, Yunxia Wang, Julia Kazakin, Giovanni Abbadessa, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Walid Shaib, Bassel el-Rayes. In FGFR2 driven tumors, preclinical pharmacokinetics (PK), pharmacodynamics (PD) and efficacy translate into clinical activity of ARQ 087. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B151.