Abstract A137: Initial testing (Stage 1) of EPZ-6438 (tazemetostat), a novel EZH2 inhibitor, by the pediatric preclinical testing program (PPTP)

Abstract

Abstract Background: EZH2 is the functional histone methyltransferase component of the multiprotein complex known as Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes mono-, di- and tri-methylation of H3K27. Activating mutations in EZH2 produce altered substrate specificity, and mutant EZH2 acts in concert with wild-type EZH2 to produce increased H3K27 tri-methylation, abnormal repression of PRC2 targets, and tumorigenesis. Rhabdoid tumors are associated with loss of SMARCB1, a component of the SWI/SNF chromatin remodeling complex. Tumorigenesis in SMARCB1 deficient mice is blocked by inactivation of EZH2 (Cancer Cell 2010;18:316-28), and an EZH2 inhibitor induced regression in a rhabdoid tumor xenograft (PNAS 2013;110:7922-7). EPZ-6438 is a potent, specific and SAM-competitive EZH2 inhibitor that demonstrates favorable pharmacological properties and in vivo activity in multiple xenograft tumor models following oral dosing. It has entered clinical evaluation, and objective responses were noted in patients with NHL and rhabdoid tumor with twice daily oral dosing during phase 1 dose escalation studies. The aim of this preclinical study was to assess the antitumor activity of EPZ-6438 against pediatric solid tumor models with a focus on rhabdoid tumors of the kidney and CNS. Procedures: EPZ-6438 was evaluated using a dose of 400 mg/kg (mono-HBr salt, 350 mg/kg of active compound) administered twice-daily by oral gavage for 28 days. Standard PPTP measures of in vivo antitumor activity were utilized. Results: EPZ-6438 induced significant differences in event-free survival (EFS) distribution compared to control in 9 of 30 (30%) xenografts studied, with significant differences observed in 5 of 7 (71%) rhabdoid tumor xenograft lines compared to 4 of 23 (17%) non-rhabdoid lines (χ2 test p = 0.006). For the EFS T/C activity measure, intermediate activity requires an EFS T/C value > 2.0, and high activity additionally requires a reduction in final tumor volume compared to starting tumor volume. EPZ-6438 demonstrated intermediate or high EFS T/C activity in 2 of 26 (8%) and 1 of 26 (4%) xenografts evaluable for this measure, respectively. Intermediate/high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (3 of 5 rhabdoid tumor lines versus 0 of 21 non-rhabdoid tumor lines, χ2 test p<0.001). For the objective response metric, 1 of 7 rhabdoid tumor xenografts (G401) showed stable disease. PD2 (Progressive Disease 2) response indicates progressive disease with growth delay (EFS T/C >1.5) and was observed in an additional 5 of 7 rhabdoid tumor xenografts, but in only 3 of 23 non-rhabdoid tumor xenografts. For two rhabdoid tumors (G401 and KT-16), delayed reductions in tumor size to EPZ-6438 were noted following 1-2 weeks of tumor growth. Pharmacodynamic evaluation of H3K27 methylation status in treated and control tumors is ongoing. Conclusions: EPZ-6438 showed antitumor activity against rhabdoid tumor models, but showed no consistent activity against any other histology. The pattern of delayed tumor response observed for two rhabdoid tumor xenografts will need to be considered when developing clinical trials for EPZ-6438. Further preclinical testing using rhabdoid tumor lines and evaluating EPZ-6438 in combination with other anticancer agents may provide guidance for its pediatric clinical development. Citation Format: Raushan Kurmasheva, Kat Cosmopoulos, Melissa Sammons, Edward Favours, Jianwrong Wu, Peter Houghton, Malcolm Smith. Initial testing (Stage 1) of EPZ-6438 (tazemetostat), a novel EZH2 inhibitor, by the pediatric preclinical testing program (PPTP). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A137.