Epithelioid sarcoma is associated with a high rate of recurrence and local and distant metastases that usually spread via the lymphatic system.2 In a 2006 review of patients with epithelioid sarcoma, the rate of distant metastases was 43% in patients receiving curative-intent intervention and 57% in an overall population of patients with epithelioid sarcoma; moreover, the lung was the most common site of metastatic disease.4
The standard treatment for epithelioid sarcoma is surgical resection to remove the tumor and the surrounding tissue; however, in some cases, chemotherapy and radiation therapy are used.1,3
More than 90% of epithelioid sarcomas show a complete absence of INI1 expression, a component of epigenetic regulation.5 The loss of function of INI1 triggers the activation of the EZH2 gene, which is involved in the enzyme histone methyltransferase that is overexpressed or mutated in various cancer cells and is implicated in tumor-cell proliferation.6,7 Recently, an oral inhibitor of the methyltransferase EZH2 became the first treatment to receive approval specifically for patients with epithelioid sarcoma.8
FDA Approved Tazemetostat for Epithelioid Sarcoma
On January 23, 2020, tazemetostat (Tazverik; Epizyme), a methyltransferase inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of adults and young patients aged ≥16 years with metastatic or locally advanced epithelioid sarcoma who are not candidates for complete resection.8 Tazemetostat was granted accelerated approval and was designated as an orphan drug by the FDA.8
“Epithelioid sarcoma accounts for less than one percent of all soft tissue sarcomas,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease. When we brought Tazverik’s application to the Oncologic Drugs Advisory Committee last month, the committee voted unanimously that the benefits of the drug outweighed the risks,” Dr Pazdur commented on the approval of tazemetostat for this indication.8
In addition, in June 2020, tazemetostat received an accelerated FDA approval and an orphan drug designation for the treatment of adults with relapsed or refractory follicular lymphoma and EZH2 mutation, as detected by an FDA-approved test, in patients who received at least 2 systemic therapies and for those who have no satisfactory alternative therapeutic options.9
Mechanism of Action
The methyltransferase EZH2 is an oncogene driver in tumor cells.7,10 Tazemetostat is a small-molecule inhibitor of EZH2 with potential antineoplastic activity.7 Through selective inhibition of either wild-type EZH2 or EZH2 mutation, tazemetostat blocks the methylation of histone H3 lysine 27, thereby altering gene-expression patterns that are linked to cancer pathways. This disruption of gene-expression patterns results in reduced tumor-cell proliferation of tumor cells with EZH2 mutation.7,10 Tazemetostat has also demonstrated antitumor activity in a xenograft model of B-cell lymphomas with or without EZH2 gain-of-function mutations.10
Dosing and Administration
The recommended dose of tazemetostat is 800 mg administered orally twice daily. Tazemetostat is available as a 200-mg tablet.10
Tazemetostat can be taken with or without food; the tablets should be swallowed whole and should not be cut, crushed, or chewed.10
Pivotal Clinical Trial: EZH-202
The efficacy of tazemetostat was evaluated in the EZH-202 study, an open-label, multicenter, phase 2 clinical trial that included 62 patients (median age, 34 years; range, 16-79 years) with confirmed metastatic or locally advanced epithelioid sarcoma; most of the patients were male (63%), white (76%), and had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (92%).6,10
Eligible patients were required to have INI1 loss, as detected by an FDA-approved test, and a performance status of 0 to 2, as defined by the ECOG performance score. Overall, 77% of patients had previous surgery, and 61% received previous systemic chemotherapy. Patients received tazemetostat 800 mg orally twice daily until disease progression or unacceptable toxicity. The median follow-up duration in this study was 14 months (range, 0.4-31 months).10
The overall response rate in patients who received tazemetostat treatment was 15%; moreover, 67% of patients who achieved a response sustained the response for ≥6 months (Table).10
The most common (≥20%) adverse reactions associated with tazemetostat in patients with epithelioid sarcoma are pain (52%), fatigue (47%), nausea (36%), decreased appetite (26%), vomiting (24%), and constipation (21%).10
Serious adverse reactions were reported in 37% of patients with epithelioid sarcoma who received tazemetostat, and 1 (2%) patient permanently discontinued treatment as a result of an adverse reaction (altered mood).10
The coadministration of tazemetostat with a strong or moderate cytochrome P450 3A (CYP3A) inhibitor increases the plasma concentrations of tazemetostat, which can increase the incidence or severity of adverse reactions. Strong or moderate CYP3A inhibitors should not be coadministered with tazemetostat.10
When tazemetostat is coadministered with a strong or moderate CYP3A inducer, the plasma concentrations and efficacy of tazemetostat may be decreased. Moderate and strong CYP3A inducers should not be coadministered with tazemetostat.10
Coadministration of tazemetostat with CYP3A substrates, including hormonal contraceptives, may reduce the concentrations and efficacy of CYP3A substrates.10
Tazemetostat has no contraindications.
Use in Specific Populations
No data are available on the presence of tazemetostat in human milk, or on its effects on the breastfed child or milk production. Women should not breastfeed during treatment and for 1 week after the final dose of tazemetostat.10
Clinical studies of tazemetostat did not include enough patients aged ≥65 years to establish whether they have a different treatment response compared with younger patients.10
No dose adjustment of tazemetostat is required for patients with mild-to-severe renal impairment or end-stage renal disease, or for patients with mild hepatic impairment. Tazemetostat was not studied in patients with moderate or severe hepatic impairment.10
Warnings and Precautions
Treatment with tazemetostat can increase the risk for secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia. Patients who are receiving tazemetostat should be monitored long-term for secondary malignancies.10
When administered to pregnant women, tazemetostat can cause fetal harm. Pregnant women should be advised of the potential risk; women of reproductive potential should use effective nonhormonal contraception during treatment and for 6 months after the final dose of tazemetostat.10
The FDA approval of tazemetostat, an oral methyltransferase inhibitor, provides the first pharmacologic treatment option specifically for patients with epithelioid sarcoma, a rare form of soft-tissue cancer with a high rate of metastases and recurrence. In addition, later in 2020, the FDA approved tazemetostat for the treatment of patients with relapsed or refractory follicular lymphoma.
In the EZH-202 pivotal clinical trial, tazemetostat demonstrated a 15% overall response rate in patients with epithelioid sarcoma. Moreover, 67% of patients who responded to treatment with tazemetostat sustained their response for ≥6 months in that study.
- National Center for Advancing Translational Sciences. Epithelioid sarcoma. Genetic and Rare Diseases Information Center. Updated May 7, 2020. https://rarediseases.info.nih.gov/diseases/10181/epithelioid-sarcoma. Accessed July 9, 2020.
- Jawad MU, Extein J, Min ES, Scully SP. Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res. 2009;467:2939-2948.
- Hosseinzadeh P, Cheung F. Epithelioid sarcoma. Electronic Sarcoma Update Newsletter. December 2009;6. Accessed July 13, 2020.
- de Visscher SAHJ, van Ginkel RJ, Wobbes T, et al. Epithelioid sarcoma: still an only surgically curable disease. Cancer. 2006;107:606-612.
- Hornick JL, Dal Cin P, Fletcher CDM. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33:542-550.
- Stacchiotti S, Schoffski P, Jones R, et al. Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950). J Clin Oncol. 2019;37(15_suppl):Abstract 11003.
- National Cancer Institute. Tazemetostat hydrobromide. NCI Drug Dictionary. www.cancer.gov/publications/dictionaries/cancer-drug/def/tazemetostat. Accessed July 9, 2020.
- US Food and Drug Administration. FDA approves first treatment option specifically for patients with epithelioid sarcoma, a rare soft tissue cancer. January 23, 2020. www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-option-specifically-patients-epithelioid-sarcoma-rare-soft-tissue. Accessed July 7, 2020.
- US Food and Drug Administration. FDA granted accelerated approval to tazemetostat for follicular lymphoma. June 18, 2020. www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma. Accessed July 8, 2020.
- Tazverik (tazemetostat) tablets, for oral use [prescribing information]. Cambridge, MA: Epizyme; June 2020.