Tazemetostat as a treatment for epithelioid sarcoma

ABSTRACT

Introduction

Epithelioid Sarcomas is a rare aggressive subtype of soft tissue sarcomas that is most prevalent in young adult males. It is locally invasive and frequently metastasizes to regional lymph nodes and distant organ sites. Complete surgical resection is curative in early-stage disease; however, there remains a high recurrence rate and distant metastatic risk. Outcomes remain poor in patients that develop metastatic disease. These tumors are characterized by loss of INI-1/SMARCB1 expression, which opposes the enzymatic function of EZH2, a critical component of epigenetic regulation. Tazemetostat is a highly selective, orally available EZH2 inhibitor. The recommended dose of Tazemetostat is 800 mg twice daily for patients aged 16 years or older with advanced or metastatic epithelioid sarcomas not eligible for complete surgical resection.

Areas covered

Clinical studies investigating Tazemetostat in epithelioid sarcomas.

Expert opinion

Approval of the Tazemetostat New Drug Application represents the first FDA approval for the treatment of advanced epithelioid sarcomas. It is the first epigenetic therapy approved for solid tumors. The approval encourages investigation in epigenetic regulation as a targetable therapy in other tumor types. Clinical issues remaining post-approval include efficacy of Tazemetostat in combination with other approved agents, and follow up to assess the long-term safety risks.

KEYWORDS:

• Epithelioid sarcomas
• EZH2 inhibitor
• INI-1 deficiency
• soft tissue sarcomas
• tazmetostat

Article Highlights

• Epithelioid sarcoma is a rare and aggressive sub-type of soft tissue sarcoma characterized by loss of INI-1/SMARCB1 expression, which opposes the enzymatic function of zest-homolog 2 (EZH2)

• EZH2 is an epigenetic regulator critical in controlling normal gene expression with aberrant activity described in a number of malignancies

• Tazemetostat (Tazverik, Epizyme, inc) is an orally available inhibitor of EZH2 now FDA approved for the treatment of locally advanced or metastatic epithelioid sarcoma

• The phase II EZH202 clinical trial show clinical benefit of tazemetostat with durable responses and an overall tolerable safety profile leading to drug approval

Box 1. Drug summary box.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.