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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK594408_"><span class="title" itemprop="name">Tazemetostat</span></h1><p class="fm-aai"><a href="#_NBK594408_pubdet_">Publication Details</a></p></div></div><div class="body-content whole_rhythm" itemprop="text"><div id="Tazemetostat.OVERVIEW"><h2 id="_Tazemetostat_OVERVIEW_">OVERVIEW</h2><div id="Tazemetostat.Introduction"><h3>Introduction</h3><p>Tazemetostat is a methyltransferase inhibitor and antineoplastic agent used in the therapy of advanced epithelioid sarcoma. Tazemetostat is associated with a moderate rate of transient serum enzyme elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury with jaundice.</p></div><div id="Tazemetostat.Background"><h3>Background</h3><p>Tazemetostat (taz’ met o stat) is a small molecule inhibitor of the histone methyltransferase, enhancer of zest homolog 2 (EZH2), an enzyme that can be overexpressed as a result of gene mutations in certain cancers. In early clinical studies tazemetostat was found to have activity in vitro and in vivo against epithelioid sarcoma, a rare malignant soft tissue sarcoma that has a poor prognosis and is often resistant to other antineoplastic agents. In preregistration open-label trials, tazemetostat therapy was associated with an objective response rate of only 13%. Nevertheless, tazemetostat was given accelerated approval in the United States in 2020 as therapy of adults and children (16 years of age or older) with metastatic or advanced unresectable epithelioid sarcoma. Confirmatory trials were required for its continued approval, and subsequently higher rates of response have been reported in treatment of patients with epithelioid sarcoma as well as other tumors with confirmed mutations in EZH2 or in its pathway of activation. Tazemetostat is available in tablets of 200 mg under the brand name Tazverik. The recommended dose is 800 mg (4 tablets) twice daily in 28-day cycles until unacceptable toxicity or disease progression. Adverse events are common and can include pain, fatigue, nausea, vomiting, constipation, diarrhea, decreased appetite, weight loss, anemia, lymphopenia, alopecia, cough, dyspnea, and headache. Rare but potentially severe adverse events include secondary malignancies including lymphoma, leukemia and myelodysplastic syndromes, and embryo-fetal toxicity.</p></div><div id="Tazemetostat.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>In clinical trials, serum ALT elevations occurred in 14% and AST elevations in 18% of patients on tazemetostat therapy and rose to more than 5 times ULN in 3.5%. Nevertheless, there were no instances of clinically apparent liver injury with symptoms or jaundice in several multicenter open-label trials of tazemetostat. Despite the frequency of adverse events during tazemetostat therapy, discontinuations due to adverse events are uncommon. Clinical experience with tazemetostat, however, is limited and the frequency of de novo serum enzyme elevations during treatment raises the issue of its potential for causing hepatotoxicity.</p><p>Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).</p></div><div id="Tazemetostat.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>Tazemetostat is metabolized in the liver, largely via CYP 3A4 and is likely to be susceptible to drug-drug interactions with moderate or strong inducers or inhibitors of CYP 3A4 which should be avoided during therapy. The cause of the serum aminotransferase elevations during tazemetostat therapy is unknown but may relate to the inhibition of EZH2 methyltransferase or to the production of a toxic or immunogenic metabolite.</p></div><div id="Tazemetostat.Outcome_and_Management"><h3>Outcome and Management</h3><p>The serum enzyme elevations during tazemetostat therapy are mostly mild-to-moderate in severity but elevations above 5 times the ULN should trigger a search for other causes and, if none are found, to use dose modification or transient discontinuation until they fall into the normal or near normal range. Tazemetostat has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between tazemetostat and other agents used for soft tissue sarcoma such as doxorubicin or pazopanib.</p><p>Drug Class: <a href="/books/n/livertox/AntineoplasticAgents/?report=reader">Antineoplastic Agents</a></p></div></div><div id="Tazemetostat.PRODUCT_INFORMATION"><h2 id="_Tazemetostat_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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</p><p>Tazemetostat – Tazverik®</p><p>
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<b>DRUG CLASS</b>
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</p><p>Antineoplastic Agents</p><p>
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<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Tazemetostat" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
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</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="Tazemetostat.CHEMICAL_FORMULA_AND_STRUCT"><h2 id="_Tazemetostat_CHEMICAL_FORMULA_AND_STRUCT_">CHEMICAL FORMULA AND STRUCTURE</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figTazemetostatTc"><a href="/books/NBK594408/table/Tazemetostat.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figTazemetostatTc" rid-ob="figobTazemetostatTc"><img class="small-thumb" src="/books/NBK594408/table/Tazemetostat.Tc/?report=thumb" src-large="/books/NBK594408/table/Tazemetostat.Tc/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="Tazemetostat.Tc"><a href="/books/NBK594408/table/Tazemetostat.Tc/?report=objectonly" target="object" rid-ob="figobTazemetostatTc">Table</a></h4></div></div></div><div id="Tazemetostat.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Tazemetostat_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 04 August 2023</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Tazemetostat.REF.fda">FDA. <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211723Orig1s000MultidisciplineR.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.accessdata<wbr style="display:inline-block"></wbr>​.fda.gov/drugsatfda_docs<wbr style="display:inline-block"></wbr>​/nda/2020/211723Orig1s000MultidisciplineR.pdf</a><div><i>(FDA website including product label and multidiscipline review of data submitted by the sponsor in support of the approval of tazemetostat, mentions that in a safety cohort of 62 treated subjects ALT elevations arose 14% and were above 5 times the upper limit of normal (ULN) in 3.5% while AST elevations arose in 18% and were above 5 times ULN in 3.5%. Nevertheless, there were no hepatic serious adverse events or deaths from liver failure, and the FDA reviewer concluded that “the overall safety profile of tazemetostat is acceptable for treatment of a serious and life-threatening condition”).</i></div></div></li><li><div class="bk_ref" id="Tazemetostat.REF.morschhauser.2020.1433">Morschhauser
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F, Tilly
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H, Chaidos
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A, McKay
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P, Phillips
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T, Assouline
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S, Batlevi
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CL, et al.
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Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.
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Lancet Oncol
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2020;21:1433-1442. [<a href="/pmc/articles/PMC8427481/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8427481</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33035457" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33035457</span></a>]<div><i>(Among 99 adults with relapsed or refractory follicular lymphoma treated with tazemetostat [800 mg twice daily], the overall objective response rate was 69% in patients with the EZH2 mutant and 35% in those with wild type EZH2, and adverse events were frequent [99%] and were scored as serious in 27%, most frequently nausea, diarrhea, alopecia, cough and fatigue; ALT elevations which were above 5 times ULN arose in one patient but were not associated with symptoms or jaundice and resolved despite continuing therapy; there were no treatment related deaths).</i></div></div></li><li><div class="bk_ref" id="Tazemetostat.REF.gounder.2020.1423">Gounder
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M, Schöffski
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P, Jones
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RL, Agulnik
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M, Cote
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GM, Villalobos
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VM, Attia
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S, et al.
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Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.
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Lancet Oncol.
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2020;21:1423-1432. [<a href="https://pubmed.ncbi.nlm.nih.gov/33035459" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33035459</span></a>]<div><i>(Among 62 patients with advanced epithelioid sarcoma treated with tazemetostat [800 mg twice daily in 28-day cycles until disease progression], 9 [15%] had an objective response with a median follow up of 14 months, and while adverse events were frequent, ALT elevations arose in only 3 patients [5%], treatment related serious adverse events were uncommon [3%], and there were no treatment related deaths).</i></div></div></li><li><div class="bk_ref" id="Tazemetostat.REF.izutsu.2021.3627">Izutsu
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K, Ando
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K, Nishikori
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M, Shibayama
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H, Teshima
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T, Kuroda
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J, Kato
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K, et al.
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Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan.
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Cancer Sci.
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2021;112:3627-3635. [<a href="/pmc/articles/PMC8409398/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8409398</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34159682" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34159682</span></a>]<div><i>(Among 20 Japanese patients with relapsed or refractory B-cell lymphoma harboring EZH2 mutations who were treated with tazemetostat, the objective response rate was 80% and complete response rate 50%, and while all patients had at least one adverse event, there were only 3 treatment related serious adverse events, none of which were liver related, and only 2 subjects had ALT elevations, both of which were transient and less than 5 times ULN).</i></div></div></li><li><div class="bk_ref" id="Tazemetostat.REF.zauderer.2022.758">Zauderer
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MG, Szlosarek
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PW, Le Moulec
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S, Popat
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S, Taylor
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P, Planchard
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D, Scherpereel
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A, et al.
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EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study.
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Lancet Oncol.
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2022;23:758-767. [<a href="https://pubmed.ncbi.nlm.nih.gov/35588752" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35588752</span></a>]<div><i>(Among 74 adults with refractory or relapsed malignant pleural mesothelioma and a BAP-1 mutation treated with tazemetostat, the disease control rate at 12 weeks was 54% but there were no complete responses and only one ongoing partial response, and while adverse events were common [99%] and serious adverse events arose in 34%, there was no mention of ALT elevations or treatment related hepatic adverse events).</i></div></div></li></ul></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK594408_pubdet_">Publication Details</h2><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">August 4, 2023</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="https://www.niddk.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute of Diabetes and Digestive and Kidney Diseases</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Tazemetostat. [Updated 2023 Aug 4].<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/livertox/Taxanes/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/livertox/Tebentafusp/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobTazemetostatTc"><div id="Tazemetostat.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK594408/table/Tazemetostat.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Tazemetostat.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_Tazemetostat.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Tazemetostat.Tc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_Tazemetostat.Tc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Tazemetostat.Tc_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Tazemetostat.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tazemetostat</td><td headers="hd_h_Tazemetostat.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/249820378" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1403254-99-8</a>
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</td><td headers="hd_h_Tazemetostat.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C34-H44-N4-O4</td><td headers="hd_h_Tazemetostat.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/249820378" title="View this structure in PubChem" class="img_link" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem"><img src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&sid=249820378" alt="image 249820378 in the ncbi pubchem database" /></a>
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