Abstract 1161: EZH2 inhibitor tazemetostat demonstrates activity in preclinical models of Bruton's tyrosine kinase inhibitor-resistant relapsed/refractory mantle cell lymphoma

Abstract

Tazemetostat (EZM6438) is a potent, orally bioavailable small molecule inhibitor of EZH2, the enzymatic subunit of the polycomb repressive complex 2, which has been approved for treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma. EZH2 has been shown to play a key role in B-cell maturation and multiple B-cell malignancies are dependent on EZH2 for survival. Mantle cell lymphoma (MCL) is a rare subtype of mature B cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1, which plays a significant role in tumor cell proliferation via cell cycle dysregulation, chromosomal instability, and epigenetic regulation. This disease most often presents at an advanced stage and while initial responses occur, most cases relapse to frontline therapy, including Bruton's Tyrosine Kinase (BTK) inhibitors. The rate of intrinsic and acquired resistance to these treatments results in a high unmet medical need. We previously reported that treatment with EZH2 inhibitors, as monotherapy or in combination with BTK inhibitors, elicited in vitro anti-proliferative activity and in vivo tumor growth inhibition in MCL models, demonstrating that EZH2 may be a promising therapeutic target in this indication. To extend our previous in vitro combination studies, we demonstrated that the recently approved BTK inhibitor, zanubrutinib synergized with tazemetostat and demonstrated that tazemetostat resensitized a subset of cell lines intrinsically resistant to BTK inhibitors. In vivo studies confirmed these findings, showing a significant tumor growth delay when tazemetostat was combined with zanubrutinib in the MCL MINO cell line-derived murine xenograft model compared to the single agent treatments. To understand if EZH2 inhibition offered potential therapeutic benefit to the MCL BTK inhibitor-resistant population, we generated in vitro MCL models of acquired resistance to the BTK inhibitors ibrutinib and zanubrutinib. These cell lines retained the in vitro sensitivity to tazemetostat observed in the parental cell line, suggesting a potential therapeutic option for tazemetostat in the setting of acquired resistance to BTK inhibitors. Additionally, we showed that tazemetostat induced anti-proliferative effects ex vivo in samples derived from MCL patients that were relapsed or refractory to one or more current standard of care agents, including the BTK inhibitor ibrutinib. Subsequent studies aim to identify the mechanisms of growth inhibition driven by tazemetostat in MCL models sensitive and resistant to BTK inhibitors. In summary, these data suggest that tazemetostat treatment (alone or in combination with a BTK inhibitor) could be a potential therapeutic option in the treatment of the MCL patient population that is relapsed/refractory to BTK inhibitor therapy. Citation Format: Jeffrey A. Keats, Arleide Lee, Jeremy C. Cunniff, Weiqing Chen, Revonda Mehovic, Vania Estanek, Crag Markwood, Cuyue Tang, Daniel T. Dransfield, Veronica Gibaja, Alejandra Raimondi. EZH2 inhibitor tazemetostat demonstrates activity in preclinical models of Bruton's tyrosine kinase inhibitor-resistant relapsed/refractory mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1161.

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

“…Moreover, the loss of FGFR1 abrogated EZH2 expression, improved survival in vivo [ 141 , 142 ], and provided an alternative therapeutic strategy for targeting R/R MCL. EZH2 inhibitor tazemetostat in combination with zanubrutinib or ibrutinib in an ibrutinib/zanubrutinib-resistant MCL model showed synergistic activity in the MCL xenograft model [ 143 ].…”