A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adults: Epithelioid sarcoma cohort (NCT02601950)

Abstract

Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma with current treatments for metastatic disease having limited activity in terms of durable clinical benefit and significant toxicities. Loss of INI1, a subunit of the SWI/SWF complex and a negative regulator of EZH2, occurs in over 90% of ES tumors and is a characteristic diagnostic feature of ES. EZH2, a methyltransferase in PRC2, is a known oncogenic driver. In INI1 deficient preclinical models, EZH2 inhibition reprograms pathways related to abnormal cell growth, leading to cell death or differentiation and subsequent tumor control and regression. Tazemetostat, a potent, selective, orally available inhibitor of EZH2, has shown clinical activity in malignant rhabdoid tumor and ES patients (pts) in phase 1. We report interim phase 2 safety and efficacy of tazemetostat in pts with ES. Method(s): This was a phase 2, multicenter, open-label, single arm study of tazemetostat (800 mg PO BID) in adults with advanced disease whose tumors harbor INI1 loss (7 different tumor type cohorts). For the ES cohort, the primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included disease control rate (DCR; confirmed CR or PR of any duration or SD lasting >=32 weeks), safety/tolerability, and duration of response. Result(s): As of April 6, 2018, in 62 ES pts (63%male, median age 34 years,median of 1 prior systemic therapy), there were 8 confirmed PRs with anORR of 13%andDCR of 26%. Additionally, 35 pts had a best response of SD with 7 pts ongoing. Individual PR durations (weeks) were: 8+, 8+, 24+, 24, 32+, 40, 41, and70+(+ indicates ongoing response). No pts discontinued due to adverse events (AEs); 2 pts had dose reductions due to AEs. AEs (any grade) included fatigue (39%), nausea (32%), and cancer pain (31%). Treatmentrelated AEs>=Grade 3 reported in>=2 pts were anemia (5%) and decreased weight (3%). Conclusion(s): In this study, the largest prospective clinical trial of ES to date, tazemetostat showed promising single agent activity, resulting in durable confirmed responses, a DCR of 26%, and favorable safety. As these tumors are aggressive with limited response to current treatment, tazemetostat represents a potential therapeutic option warranting further investigation.