Abstract 531: Activity of the selective FGFR 1, 2 and 3 inhibitor INCB054828 in genetically-defined models of triple-negative breast cancer
Authors: Liu Phillip C.C. , Lehmann Brian D. , Ruggeri Bruce , DiMatteo Darlise , Schafer Johanna M. , Lu Jin , Lee Sang Hyun , Lin Luping , Burn Timothy C. , Diamond Melody , Volgina Alla , Wu Liangxing , Hollis Gregory , Huber Reid , Pietenpol Jennifer A. , Scherle Peggy 
Published: July 2017

Activation of the Fibroblast Growth Factor (FGF)-FGF Receptor (FGFR) signaling axis occurs in many human cancers. In preclinical models, cell lines with genetic aberrations in FGF/FGFR genes are preferentially inhibited by compounds that selectively target the FGFR kinase. INCB54828 is a potent, selective, and reversible inhibitor of FGFR1, 2 and 3 that is currently in Phase 2 clinical trials for advanced malignancies characterized by FGF-FGFR alterations. In this study, we investigated the efficacy of INCB054828 in models of triple-negative breast cancer (TNBC).

FGFR1 and FGFR2 are amplified in approximately 4% and 5% of TNBC, respectively, and oncogenic fusion proteins including FGFR3-TACC3 have also been identified in some TNBC specimens. To profile the activity of INCB054828, we screened a panel of diverse TNBC cell lines that are representative of each of the four subtypes of TNBC. Three human TNBC lines MFM223, SUM185 and SUM52PE were highly sensitive to INCB054828 in viability assays. Each of these responsive cell lines has a known alteration in FGFR, whereas TNBC lines lacking any aberrations in FGF/FGFR genes were refractory to growth inhibition. Inhibition of cell viability was associated with suppression of growth promoting pathways including Ras-MAPK. To confirm this association in vivo, four PDX models of TNBC were tested: two chemo-refractory models with FGFR1 amplification (CNV = 4 and 6) and two without any known FGF/FGFR alterations. Both of the models with FGFR1 copy number gain showed a response to INCB054828 as monotherapy with 36 and 78% tumor growth inhibition that was statistically significant vs vehicle control (P&lt;0.05 and p&lt;0.001, respectively). At the maximally efficacious dose of 1 mg/kg daily, neither PDX model lacking FGF/FGFR alteration responded to the treatment. Finally to assess the effect of the microenvironment on drug sensitivity, mouse 4T1 breast cancer cells were orthotopically implanted into the mammary fat pad; under these conditions, 4T1 tumors retained sensitivity to a standard dose of INCB054828. In summary these results demonstrate that the FGFR1/2/3 inhibitor INCB054828 is highly active against models of TNBC with genetic alterations in FGFR genes, and confirms the importance of patient stratification strategies for clinical trials with FGFR targeted therapies.

Citation Format: Phillip C.C. Liu, Brian D. Lehmann, Bruce Ruggeri, Darlise DiMatteo, Johanna M. Schafer, Jin Lu, Sang Hyun Lee, Luping Lin, Timothy C. Burn, Melody Diamond, Alla Volgina, Liangxing Wu, Gregory Hollis, Reid Huber, Jennifer A. Pietenpol, Peggy Scherle. Activity of the selective FGFR 1, 2 and 3 inhibitor INCB054828 in genetically-defined models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 531. doi:10.1158/1538-7445.AM2017-531