Abstract LB-C12: Derazantinib (DZB): A dual FGFR/CSF1R-inhibitor active in PDX-models of urothelial cancer
Authors: McSheehy Paul , Bachmann Felix , Forster-Gross Nicole , Lecoultre Marc , Shemerly Mahmoud El , Roceri Mila , Reinelt Stefan , Kellenberger Laurenz , Walker Paul R , Lane Heidi 
Published: March 2020

Abstract
Background: DZB is an oral small-molecule Fibroblast Growth Factor Receptor 1/2/3 inhibitor (FGFRi) with clinically relevant activity in FGFR2-fusion cholangiocarcinoma. Extensive kinase profiling identified Colony-Stimulating Factor 1 receptor (CSF1R) as an additional anti-cancer target for DZB. CSF1R plays a role in the maintenance of tumor-promoting M2-macrophages; inhibition facilitates repolarization to M1-type thus restoring tumor T cell activity. Screening of urothelial cancer (UC) models both in vitro and in vivo has provided information on potential response biomarkers additional to FGFR genetic aberrations. Methods: Kinase assays used a radiometric assay and anti-proliferative activity was assessed using crystal-violet (72h incubation). Bone-marrow derived mouse macrophages were CSF1 starved (12h), pre-incubated with DZB/BLZ945 (30/10m) and stimulated with 0.3 μM CSF1 (3m). CSF1R phosphorylation (pCSF1R) was analyzed by immunoblotting. Compound docking experiments used MOE software and public X-ray structures. DZB was tested at MTD (75 mg/kg, po, qd) in UC-CDX (8 mice/group) and -PDX (3 mice/group) models with FGFR-mutations and/or differing FGFR copy-number (CN)/RNA-seq expression levels. Efficacy and tolerability were quantified at the 3-week endpoint as a dT/C (treated/control). Results: Comparative kinase IC50s showed that DZB had 1:1 nM activity against FGFR1/2/3 and CSF1R, a potency not observed for other clinically relevant FGFRi’s. Structural analyses suggested a different size of the inhibitor binding-site of FGFR- and CSF1R-structures, with DZB efficiently occupying the smaller CSF1R kinase sub-pocket. Indeed, DZB reduced ligand-stimulated pCSF1R in mouse macrophages in a concentration-dependent manner, with a maximal effect similar to the selective CSF1R inhibitor BLZ945. Based on an in vitro anti-proliferative screen across 14 UC-lines, DZB had a mean GI50 of 1.7±0.2 μM (range 0.4-3.4 μM). The most sensitive lines were RT4 and RT112/84, both of which had FGFR3-TACC3 fusions, a known oncogenic-driver. In mice bearing s.c. RT4 tumors, DZB induced tumor-stasis (dT/C&lt;0.1) and was well tolerated (dT/C&gt;1.0) but no response was observed in the RT112/84 model suggesting that not only FGFR mutations contribute to DZB response. An unbiased UC-PDX screen indicated efficacy in 4/17 models (dT/C≤0.4; median=0.81) with DZB-response significantly positively-associated with high FGFR expression. The most sensitive tumor had high FGFR2 RNA-expression yet low CN. Data will be presented from confirmatory efficacy experiments and bioinformatic analyses. Conclusion: DZB is a potent FGFRi and CSF1R inhibitor. Screens in UC models indicate that DZB efficacy is driven by FGFR mutation and expression and, potentially, CSF1R modulation. A clinical trial is ongoing in UC patients (NCT04045613) to assess DZB monotherapy, and combination with the PD-L1 antibody atezolizumab.
Citation Format: Paul McSheehy, Felix Bachmann, Nicole Forster-Gross, Marc Lecoultre, Mahmoud El Shemerly, Mila Roceri, Stefan Reinelt, Laurenz Kellenberger, Paul R Walker, Heidi Lane. Derazantinib (DZB): A dual FGFR/CSF1R-inhibitor active in PDX-models of urothelial cancer [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 LB-C12. doi:10.1158/1535-7163.TARG-19-LB-C12