Abstract 783: Ponatinib demonstrates antitumor activity in RET- and FGFR-driven patient-derived xenografts

Abstract

Abstract Background: Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI) approved for patients (pts) with refractory or T315I+ chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. We have previously shown that ponatinib also inhibits oncogenic variants of KIT, RET, and FGFR in vitro. Moreover, ponatinib induced complete regression of KIT-mutant tumors in a gastrointestinal stromal tumor (GIST) patient-derived xenograft (PDX), a finding consistent with the preliminary evidence of efficacy observed in pts with refractory GIST (NCT01874665). In this study, we evaluated ponatinib in a panel of PDXs harboring oncogenic variants of RET and FGFR. Methods: The efficacy of ponatinib (20 mg/kg once-daily oral dosing) was compared to that of vehicle in 10 PDXs derived from a variety of tumor types containing oncogenic RET or FGFR fusions, high-level FGFR amplification (amp), or no known oncogenic drivers (WT; Table 1). Chemotherapeutic comparators (cisplatin or 5-fluorouracil) were included in 6 models. To confirm target modulation, levels of RET or FGFR phosphorylation in tumors were analyzed 6 hrs post dosing. Results: Ponatinib induced tumor regression or ∼80% tumor growth inhibition (TGI) in the 4 RET fusion PDXs, and 62-98% TGI in the 3 FGFR PDXs (Table 1). Complete abrogation of target phosphorylation due to ponatinib treatment was verified in the 3 models examined. The efficacy of ponatinib exceeded that of the chemotherapy comparator in RET-driven but not WT PDXs, further suggesting this efficacy was driven primarily through inhibition of the driver oncogene. Conclusion: Ponatinib demonstrates marked efficacy across several PDX models with either RET fusion-, FGFR2/3 fusion-, or FGFR2 amp-driven cancers, in a target dependent manner. These results provide additional support for evaluating ponatinib in pts with cancers positive for these aberrations; such trials are planned or ongoing (NCT01813734, NCT02265341, NCT01935336, and NCT02272998). Table 1: Ponatinib's efficacy in PDX tumor modelsCancer TypeTargetTumor growth inhibition (%)Tumor regression (%)CRCCCDC6-RET-78CRCNCOA4-RET79-NSCLCKIF5B-RET80-NSCLCKIF5B-RET-12NSCLCMCU-FGFR290-GliomaTACC3-FGFR362-GastricFGFR2 amp98-CRCWT (control)41-CRCWT (control)24-NSCLCWT (control)51- Citation Format: Joseph M. Gozgit, Youngchul Song, Victor M. Rivera. Ponatinib demonstrates antitumor activity in RET- and FGFR-driven patient-derived xenografts. [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 783. doi:10.1158/1538-7445.AM2015-783