4814 - Molecular characterization of epithelioid sarcoma (ES) tumors derived from patients enrolled in a phase 2 study of tazemetostat (NCT02601950)

Background

Loss of INI1/SMARCB1 protein expression in tumor cells is characteristic of ES and impairs activity of the SWI/SNF chromatin remodeling complex inducing oncogenic dependence on EZH2. Tazemetostat, a potent, selective, orally available EZH2 inhibitor has shown clinical activity in INI1-negative tumors including durable objective responses and disease stabilization. While loss of protein expression is a key characteristic of ES, the molecular basis of loss is poorly understood; here we report genetic characterization results of the largest ES cohort to date.

Methods

DNA was isolated from matched tumor and normal samples from 62 ES cases with confirmed INI1 protein loss by IHC. Sufficient DNA was isolated for WES (N = 43), WGS (N = 37), and DNA methylation analysis (N = 35). WGS and WES were performed on tumor and matched normal samples at 30-200X and 10-50X, respectively.

Results

Interim WES analysis on 19 ES cases established that SMARCB1 was the most frequently altered gene (16/19 cases). Review of 325 cancer specific genes, including all SWI/SNF complex members demonstrated that CTNNA1, LRP1B, and NOTCH1 were the next most commonly mutated genes (3/19 cases each). Additionally, the median mutation burden for ES cases was 25.8 mutations/MB suggesting a greater genetic complexity than other predominantly INI1-negative tumors (e.g. AT/RT and MRT). SMARCB1 alterations were consistent with potential causes of INI1 protein expression loss and included both large and focal chromosomal deletions (n = 13), and SNVs (n = 5). Evidence of SMARCB1 bi-allelic loss occurred in 7/19 ES cases, whereas 9/19 cases only had evidence of monoallelic loss. Analysis of DNA methylation data from cases with either no or monoallelic SMARCB1 loss did not support DNA methylation as a mechanism for SMARCB1 silencing.

Conclusions

Alterations of SMARCB1 were the predominant genetic event observed in ES and is the underlying molecular mechanism leading to loss of INI1 protein expression. Notably, multiple genetic mechanisms leading to protein INI1 loss were detected. Updated genetic characterization data on N = 43 ES cases, including analyses to explore potential genetic associations with clinical outcome will be presented.

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

S. Daigle, A. Clawson, M. Roche, S. Blakemore: Employee, stock owner: Epizyme. P. Schöffski, B.A. van Tine: Honorarium: Epizyme. R. Chugh: Research funding, scientific advisor/consultant: Epizyme. T.W-W. Chen: Research fund, honorarium: Eisai, Novartis T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, Aztrazeneca/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: 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. Gounder: Paid consultant and board member: Epizyme Medical Advisory Board Karyopharm; Advisory board, honorarium: Daiichi, Tracon; Honorarium: Amgen. All other authors have declared no conflicts of interest.