Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950).

Abstract

11057 Background: Synovial sarcoma (SS) accounts for 5-10% of all soft tissue sarcomas (STS). Metastatic and/or locally advanced disease occurs in up to 70% of patients (pts), with reported median overall survival (OS) as short as 22 months. SS18-SSX translocations, a defining molecular feature of SS, generate a fusion protein that competes with native SS18 during SWI/SNF complex assembly disrupting complex function. SWI/SNF complexes containing the fusion protein lack INI1 and cellular INI1 expression levels are reduced to varying degrees in SS. This mechanism of INI1 reduction is distinct to that observed in malignant rhabdoid tumors, epithelioid sarcoma or other INI1 negative tumors. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated activity in preclinical SS models with the proposed mechanism of sensitivity being via INI1 reduction inducing compromised SWI/SNF activity and tumor dependence on EZH2. Methods: This is a phase 2 multicenter open-label non-randomized study with 5 cohorts of different tumor types with INI1 loss/reduction or evidence of SS18 rearrangement. Adult pts in the SS cohort were treated with tazemetostat (800 mg po BID). Up to 30 pts were enrolled using a 2-stage Green-Dahlberg design. The primary endpoint is complete response, partial response or stable disease (SD) at 16 wks. Success at the end of stage 2 requires ≥9 of 30 treated pts meet this criterion. Key secondary endpoints include overall response rate, PFS, OS, safety/tolerability, PK and biomarkers of response. Results: In 33 treated SS pts with a median of 2 prior systemic treatments, best response of SD was observed in 11 pts (33%) with 5 pts (15%) having SD lasting ≥16 wks. No objective responses were observed. The protocol-defined success criterion at the end of study was not met. Tazemetostat was well-tolerated with grade 1/2 cough (36%), dyspnea (33%) and fatigue (33%) as the most frequently reported adverse events regardless of attribution. Conclusions: Tazemetostat was well tolerated with a favorable safety profile. Although there were no objective responses in heavily pretreated pts, the observation of SD in a subset of pts suggests further studies with tazemetostat in combination may be warranted in SS. Clinical trial information: NCT02601950.