Abstract 784: Nonclinical activity of the FGFR, VEGFR and PDGFR inhibitor lucitanib in FGFR3 translocated tumor models

Abstract

Abstract Lucitanib (S 80881, E-3810, CO-3810) is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR1-3), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFRα-ß). A Phase 1/2 clinical study (Soria et al., 2014, Ann. Oncol. 25(11):2244-51) showed compelling activity of lucitanib in solid tumors and, in particular, a 50% (6 of 12 patients) RECIST partial response rate in breast cancer patients with FGF-aberrant (FGFR1 and/or FGF3/4/19 gene amplified) tumors. On-going clinical studies are further defining the activity of lucitanib in breast (NCT02053636; NCT02202746) and lung cancer (NCT02109016). FGFR gene translocations (fusions; e.g. FGFR3-TACC3) resulting in constitutively active FGFR signaling and tumor proliferation are observed in a wide variety of cancers (Stransky et al., 2014; Nat. Comm. (5):5006), and inhibition of FGFR signaling in FGFR translocated tumors with lucitanib may be a potential new therapeutic strategy. We evaluated the nonclinical activity of lucitanib in FGFR3 translocated models with the hypothesis that the combined blockade of FGFR and VEGFR signaling would be more effective than targeting each receptor tyrosine kinase independently. The in vitro activity of lucitanib was first evaluated in a panel of bladder carcinoma cell lines (n = 8) with and without FGFR3 translocation. Lucitanib preferentially inhibited the growth of cell lines with FGFR3 translocations in 2D and 3D cell culture, with GI50 values of 80-120 nM in a 72-hour cell viability assay, coincident with a reduction in phosphorylated FGFR3 with an IC50 of ∼60 nM. Minimal activity was observed in five wild-type FGFR3 cell lines (GI50 > 5 μM) with the exception of the JMSU1 bladder cell line that is reported to be dependent on FGFR1 signaling for proliferation (Tomlinson et al., 2009, Cancer Res. 69(11):4613-20). The anti-tumor activity of lucitanib dosed orally at 20 mg/kg/day was evaluated in three bladder carcinoma cell-line derived xenografts with FGFR3 translocation (RT112/84, RT4 and SW780) and a patient-derived xenograft (PDX) model of glioblastoma (BN2289; Crown Bioscience) harboring a FGFR3-TACC3 fusion. Administration of lucitanib resulted in significant (p<0.0001) tumor growth inhibition and, in some cases, tumor regression. The anti-tumor activity of lucitanib in these xenograft models was greater than that observed with either sunitinib (VEGFR/PDGFR inhibitor; 40 mg/kg/day) or BGJ398 (FGFR1-4 inhibitor; 20 mg/kg/day). Together, these results provide a strong nonclinical rationale for further exploration of lucitanib in tumors with FGFR translocations in clinical studies. Citation Format: Minh Nguyen, Kevin K. Lin, Mike F. Burbridge, Andrew D. Simmons, Thomas C. Harding. Nonclinical activity of the FGFR, VEGFR and PDGFR inhibitor lucitanib in FGFR3 translocated tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 784. doi:10.1158/1538-7445.AM2015-784