5261 - A phase 2, multicenter study of the EZH2 inhibitor tazemetostat in adults: (epithelioid sarcoma cohort) (NCT02601950)

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.

Methods

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.

Results

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 an ORR of 13% and DCR 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, and 70 + (+ 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%). Treatment-related AEs ≥Grade 3 reported in ≥ 2 pts were anemia (5%) and decreased weight (3%).

Conclusions

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.

Clinical trial identification

NCT02601950.

Legal entity responsible for the study

Epizyme, Inc.

Funding

Epizyme, Inc.

Editorial Acknowledgement

Third-party writing assistance was provided by Rob Steger, PhD, and Andrea Eckhart, PhD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), and supported by Epizyme, Inc.

Disclosure

M. Gounder: Paid consultant and board member: Epizyme; Medical advisory board: Karyopharm; Advisory board and honorarium: Daiichi, Tracon; Honorarium: Amgen. P. Schöffski, B.A. van Tine: Institutional honorarium for advisory function: Epizyme. R. Chugh: Research funding, scientific advisor/consultant: Epizyme. T.W-W. Chen: Research fund, honorarium: Eisai; Honorarium: Novartis. T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, AstraZeneca/MedImmune, Lilly, Boehringer Ingelheim, Kadmon, BMS, Polaris, Epizyme. A. Italiano: Advisory board consulting: Epizyme. M. Agulnik: Consulting/advisory: Janssen, Eisai, Novartis, Lilly; Speakers' bureau: Eisai, Bristol-Myers Squibb. R.L. Jones: Consultant: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar. G.D.D. Demetri: Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta, Loxo Oncology, AbbVie, Epizyme, Adaptimmune - Research support to Dana-Farber for GD as PI in clinical trial agreements in DFCI sarcoma unit; Novartis, Pfizer, EMD Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals - consultant/fees; Novartis - patent licensed from Dana-Farber with royalty paid to Dana-Farber; Blueprint Medicines, Merrimack Pharmaceuticals - Member, board of directors, member, scientific advisory board; Blueprint Medicines, Merrimack Pharmaceuticals, G1, Caris Life Sciences, Champions Oncology - consultant advisory board, consulting fees and equity (minor stake, public or non-public); Bessor Pharmaceuticals - consultant, equity (minor stake, non-public). M. Roche, I. Sapir, S. Daigle, A. Clawson: Paid employee and stock: Epizyme. All other authors have declared no conflicts of interest.