Tazemetostat (EPZ-6438) is a potent, selective, orally bioavailable small molecule inhibitor of EZH2, the enzymatic subunit of the polycomb repressive complex 2, which is currently being evaluated in multiple phase II clinical trials for the treatment of non-Hodgkin lymphoma, mesothelioma and molecularly defined solid tumors. Objective clinical responses have been observed in phase II studies of tazemetostat, including patients with B-cell lymphomas.
EZH2 has been shown to play a key role in the maturation of B-cells and, consistent with this phenomenon, multiple B-cell malignancies are dependent on EZH2 for survival. In preclinical studies in mantle cell lymphoma (MCL), a disease arising from mantle zone cells surrounding germinal centers, treatment with EZH2 inhibitors, in in vitro and in vivo models demonstrated antiproliferative activity, suggesting EZH2 may be a promising therapeutic target for MCL.
MCL is a distinct B-cell non-Hodgkin lymphoma characterized by the chromosomal translocation t(11;14) that leads to overexpression of cyclin D1. The disease most often presents at an advanced stage, and while initial responses occur, nearly all cases relapse or become resistant to frontline therapy and progress with poor prognosis. Novel targeted therapies are currently entering the clinic in combination with standard of care treatments, but heterogeneous response rates and durations of response show that there remains an unmet medical need in this population.
The most widely used MCL treatment regimens include combinations of two or more Standard of Care (SOC) agents. In order to support potential future clinical investigations with tazemetostat we established in vitro assays to assess its combinatorial activity with 24 traditional and emerging therapies across seven MCL cell lines. All compounds were evaluated for their single agent activity in order to determine the appropriate starting doses to investigate synergy. We then looked at both a seven-day pretreatment with tazemetostat alone followed by a four-day cotreatment with combination partner as well as a seven-day cotreatment including both drugs simultaneously. Synergy status was determined via Loewe, BLISS and additional mathematical models. Robust synergy was observed with glucocorticoid receptor agonists, immunomodulatory drugs, venetoclax and a variety of B-cell receptor pathway modulators in both dosing regimens. In addition, we show that EPZ011989 (an EZH2 tool compound) induces tumor growth inhibition in a MCL xenograft model, and has combination benefit with ibrutinib.
Preclinical data suggest that the sensitivity to tazemetostat as a single agent in MCL cell lines can be greatly enhanced in combination with new and emerging therapies. These combination approaches may be worthy of exploration in the clinic for the treatment of MCL.
Citation Format: Tami L. Hood, Kat Cosmopoulos, Allison Drew, Kelli Armstrong, Jennifer Johnson, Smith Jesse, Alejandra Raimondi. Opportunity for therapeutic expansion in mantle cell lymphoma: Tazemetostat combination synergy status in preclinical MCL models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 808.