Abstract LB-232: Derazantinib (ARQ 087) pharmacodynamics: Alterations in FGF19/21/23 and phosphate in patients with cholangiocarcinoma
Authors: Hall Terence , Mazzaferro Vincenzo , El-Rayes Bassel , Cotsoglou Christian , Harris William P. , Damjanov Nevana , Masi Gianluca , Rimassa Lorenza , Personeni Nicola , Zagonel Vittorina , Papadopoulos Kyriakos P. , Bhoori Sherrie , Droz-Dit-Busset Michele , Shaib Walid , Lamar Maria , Kazakin Julia , Schwartz Brian , Wang Yunxia , Savage Ronald E. 
Published: August 2018

Abstract
Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in cell proliferation, cell differentiation, cell migration, cell survival, protein synthesis, and angiogenesis. The FGFR family consist of four genes encoding tyrosine kinase receptors (FGFR1, FGFR2, FGFR3, and FGFR4). Dysregulation of FGFR signaling has been implicated in a number of developmental syndromes as well as cancers, e.g., intrahepatic cholangiocarcinoma (iCCA), squamous non-small cell lung cancer, small cell lung cancer, gastric, liver, breast, ovarian, endometrial, and bladder carcinomas, fueling significant interest in FGFRs as targets for therapeutic intervention. In human cancers, FGFRs have been found to be dysregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. Members of the FGF19 ligand subfamily, FGFs 19, 21 and 23, are involved in the regulation of bile acid synthesis, glucose and lipid metabolism, and phosphate homeostasis, respectively. Unlike other FGFR ligands that act locally, the FGF19 subfamily circulate throughout the body, and can act as endocrine hormones at organs distant from their site of synthesis. The wide circulation of FGFs 19, 21, 23 makes them excellent potential biomarkers for FGFR inhibition.
Study Design: 29 patients (18 women, 11 men, median age 58.7 years, all white) with FGFR2 gene positive fusion iCCA were enrolled and treated with derazantinib (dose range 300-400mg QD) at eight sites in the United States and Italy between August 2014 and October 2017 as part of clinical trial ARQ 087-101 [NCT01752920]. Patients' plasma samples were collected (on Day 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2-6) and analyzed for levels of FGF & phosphate. FGF levels were quantified using commercially available ELISA kits for FGF-19 and 21 (R&D Systems, Minneapolis, MN), and FGF-23 (EMD-Millipore, Billerica, MA).
Results: Preliminary data analysis showed clear increase in mean FGF19, 23, and phosphate levels in iCCa patients treated with derazantinib. On Cycle 2 Day 1, phosphate levels on average increased by 40% over baseline. FGF19 and FGF23 increased by 300% and 140%, respectively. Final results and any additional findings will be presented at the meeting.
Conclusions: The changes in FGF19, FGF23, and phosphate observed during treatment suggest that at the recommended phase II dose of derazantinib (300 mg QD), clinical signs of target engagement are detectable. Additional data to demonstrate potential correlation between FGFs/phosphate levels and clinical outcomes, including response and toxicity will be presented. DeLIVERr, a pivotal study of derazantinib in patients with FGFR2 gene fusion positive iCCA is ongoing (NCT03230318).
Citation Format: Terence Hall, Vincenzo Mazzaferro, Bassel El-Rayes, Christian Cotsoglou, William P. Harris, Nevana Damjanov, Gianluca Masi, Lorenza Rimassa, Nicola Personeni, Vittorina Zagonel, Kyriakos P. Papadopoulos, Sherrie Bhoori, Michele Droz-Dit-Busset, Walid Shaib, Maria Lamar, Julia Kazakin, Brian Schwartz, Yunxia Wang, Ronald E. Savage. Derazantinib (ARQ 087) pharmacodynamics: Alterations in FGF19/21/23 and phosphate in patients with cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-232.