Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.

Tazemetostat 是一种新型口服选择性 zeste 同源物增强子 2 (EZH2) 抑制剂，于 2020 年获得美国食品药品监督管理局 (FDA) 批准用于晚期上皮样肉瘤或复发/难治性 (R/R) EZH2 突变患者滤泡性淋巴瘤。这些适应症已获得 FDA 根据 2 期临床试验的客观缓解率和缓解持续时间加速批准。 Tazemetostat 与 S-腺苷甲硫氨酸 (SAM) 辅因子竞争抑制 EZH2，降低组蛋白 3 (H3K27me3) 的三甲基化赖氨酸 (H3K27me3) 的水平，被认为是药效学标志物。他泽美司他具有口服生物利用度，其特点是吸收快，暴露量与剂量成比例，不受与食物或胃酸减少剂合用的影响。它高度分布在组织中，但进入中枢神经系统的机会有限。他泽美司他在肝脏中被CYP3A代谢为3种主要无活性代谢物（M1、M3和M5），半衰期短，主要通过粪便排泄。中度 CYP3A 抑制剂（如氟康唑）显示出药物间相互作用，导致 FDA 建议减少 50% 的剂量，同时研究他泽美司他与强效抑制剂/诱导剂的联合用药正在进行中。不建议根据肾或肝功能障碍调整剂量。总体而言，他泽美司他是 FDA 批准用于癌症治疗的首个 EZH2 抑制剂。目前的临床研究正在评估多种恶性肿瘤患者的联合疗法。