The FDA has granted accelerated approval to tazemetostat (TazverikTM, Epizyme) for the treatment of adult and pediatric patients aged 16 or older with unresectable locally advanced or metastatic epithelioid sarcoma.
Epithelioid sarcoma, which often occurs in young adults and comprises less than 1% of all soft tissue sarcomas, carries a high risk of local and regional spread, and it metastasizes in approximately 30% to 50% of cases. Tazemetostat, a first-in-class selective enhancer of zeste homologue-2 (EZH2) inhibitor, is the first approved drug to specifically target this rare sarcoma subtype. Over 90% of epithelioid sarcoma tumors lack INI1 expression, which is important to epigenetic regulation. Because INI1 is not functioning in these cases, EZH2, another epigenetic modifier, is able to become an oncogenic driver within the tumor cells.
The approval was based on an open-label, multicenter phase 2 trial (NCT02601950), in which 62 patients with INI1-negative epithelioid sarcoma were treated with tazemetostat 800 mg twice daily. Tazemetostat produced partial responses in 13% of patients and a complete response in 1 patient (1.6%), for an objective response rate of 15%. It produced a disease control rate of 26%. The duration of response ranged from over 7.1 weeks to over 103.0 weeks, with the median not reached; 67% of responders had a response lasting at least six months. The median overall survival for all 62 patients on the trial was 82.4 weeks.
During the trial, adverse events of any attribution that occurred in at least 10% of patients included fatigue (39%), nausea (35%), and cancer pain (32%). Treatment-related adverse events of grade 3 or higher were reported in 16% of patients; those affecting at least 2 patients in the trial included anemia (6%) and decreased weight (3%). No drug-related deaths occurred, and only 1 patient discontinued treatment.
Tazemetostat increases the risk of developing several secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia. Women of reproductive potential should be advised to use effective contraception during treatment with tazemetostat and for six months following the final dose, and men with a female partner of reproductive potential should use effective contraception during treatment and for three months after the final dose. Tazemetostat is contraindicated in women who are pregnant or breastfeeding.
"In the largest prospective clinical trial of epithelioid sarcoma to date, tazemetostat achieved disease control in 26% of patients with advanced epithelioid sarcoma who entered this study," concluded the investigators in the abstract from their presentation at the 2019 ASCO Annual Meeting, led by first author Silvia Stacchiotti, MD, a medical oncologist with the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy. "Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety, with few patients with treatment-related adverse events [of] grade ≥3."
The recommended dose of tazemetostat is 800 mg twice daily, taken orally with or without food.
For More Information
Clinicaltrials.gov (2019). A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adult subjects with INI1-negative tumors or relapsed/refractory synovial sarcoma. NLM identifier: NCT02601950.
Stacchiotti S, Schoffski P, Jones R, et al (2019). Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950). J Clin Oncol (ASCO Annual Meeting Abstracts), 37(suppl_15). Abstract 11003. DOI:10.1200/JCO.2019.37.15_suppl.11003
US Food and Drug Administration (2020). FDA approves tazemetostat for advanced epithelioid sarcoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tazemetostat-advanced-epithelioid-sarcoma
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