On January 23, 2020, tazemetostat was granted accelerated approval for the treatment of adults and pediatric patients aged 16 and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.^1,2

Supporting Efficacy Data

Approval was based on the finding of durable responses in a single-arm cohort (cohort 5) of the multicenter EZH-202 trial (ClinicalTrials.gov identifier NCT02601950).² In the cohort, 62 patients received oral tazemetostat at 800 mg twice daily until disease progression or unacceptable toxicity. Patients were required to have integrase interactor 1 (INI1) loss, as detected by local tests, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

The median age of patients was 34 years (range = 16–79 years), 63% were male, 76% were white and 11% were Asian, 44% had proximal disease, 92% had an ECOG performance status of 0 or 1, 77% had prior surgery, and 61% had prior systemic chemotherapy.

The overall response rate on blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, v1.1, was 15% (95% confidence interval [CI] = 7%–26%), with 1.6% of patients having a complete response. Responses ranged from 3.7 to more than 24.5 months, with 67% of responders having a response lasting at least 6 months.

How It Works

Tazemetostat is an inhibitor of the methyltransferase EZH2 and some EZH2 gain-of-function mutations, including Y646X and A687V. Tazemetostat also inhibits EZH1. The best-characterized function of EZH2 is as the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzing mono-, di-, and trimethylation of lysine 27 of histone H3. Trimethylation of histone H3 leads to transcriptional repression. SWI/SNF complexes can antagonize PRC2 function in the regulation of the expression of certain genes. Preclinical and in vivo models with loss or dysfunction of certain SWI/SNF complex members—eg, integrase interactor 1 (INI1/SNF5/SMARCB1/BAF47) and SMARCA4 and SMARCA2—can lead to aberrant EZH2 activity or expression and a resulting oncogenic dependence on EZH2.

How It is Used

The recommended dosage of tazemetostat in the current indication is 800 mg orally twice daily until disease progression or unacceptable toxicity.

For adverse reactions, the dose may be reduced stepwise to 600 mg twice daily and then to 400 mg twice daily. The drug should be discontinued if 400 mg twice daily cannot be tolerated.

Product labeling provides instructions on dose modification, including interruption, reduction, and discontinuation, for adverse reactions consisting of neutropenia, thrombocytopenia, anemia, and other grade 3 and 4 adverse reactions.

Coadministration of tazemetostat with strong or moderate CYP3A inhibitors should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the tazemetostat dose should be reduced from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg once daily plus 200 mg once daily, or from 400 mg twice daily to 200 mg twice daily. After discontinuation of the moderate CYP3A inhibitor for three elimination half-lives, the tazemetostat dose used prior to initiating the CYP3A inhibitor can be resumed.

Concomitant use of tazemetostat with strong or moderate CYP3A inducers should be avoided.

Safety Profile

Among the 62 patients in cohort 5 of the EZH-202 trial, 44% were exposed to tazemetostat for at least 6 months and 24% for more than 1 year. The most common adverse events of any grade (incidence ≥ 20%) were pain (52%), fatigue (47%), nausea (36%), decreased appetite (26%), vomiting (24%), and constipation (21%). The most common grade 3 or 4 adverse events included pain (7%), decreased appetite (5%), dyspnea (5%), and hemorrhage (5%). The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin (15%) and decreased lymphocytes (13%).

Serious adverse events occurred in 37% of patients, with those occurring in at least 3% consisting of hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress. Adverse events led to dose interruptions in 34% of patients, with the most common causes (≥ 3%) being hemorrhage, increased alanine aminotransferase, and increased aspartate aminotransferase. Adverse events led to dose reduction in one patient (decreased appetite) and to permanent treatment discontinuation in one patient (altered mood).

Among 668 adults who received tazemetostat at 800 mg twice daily in clinical trials, myelodysplastic syndromes or acute myeloid leukemia occurred in 0.6%. One pediatric patient developed T-cell lymphoblastic lymphoma.

Tazemetostat has warnings/precautions for secondary malignancies and embryofetal toxicity. Tazemetostat increases the risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndromes, and acute myeloid leukemia. Patients should be advised not to breastfeed while receiving tazemetostat. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves tazemetostat for advanced epithelioid sarcoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tazemetostat-advanced-epithelioid-sarcoma. Accessed February 19, 2020.

2. Tazverik (tazemetostat) for oral use prescribing information, Epizyme, Inc., January 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211723s000lbl.pdf. Accessed February 19, 2020.