Introduction

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.

Background

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.

Hepatotoxicity

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.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

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.

Outcome and Management

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.

Drug Class: Antineoplastic Agents