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Poster Discussion session - Sarcoma

4830 - A phase 2, multicenter study of the EZH2 inhibitor tazemetostat in adults (rhabdoid tumor cohort) (NCT02601950)


22 Oct 2018


Poster Discussion session - Sarcoma


Cytotoxic Therapy;  Clinical Research

Tumour Site



Robin Jones


Annals of Oncology (2018) 29 (suppl_8): viii576-viii595. 10.1093/annonc/mdy299


R.L. Jones1, J. Blay2, M. Agulnik3, R. Chugh4, O. Mir5, A. Italiano6, D. Thomas7, A. Gupta8, T. Jahan9, G. Cote10, V. Villalobos11, G.D.D. Demetri12, M. Roche13, I. Sapir14, S. Daigle14, A. Clawson14, M. Gounder15

Author affiliations

  • 1 Medical Oncology, The Royal Marsden Hospital and Institute for Cancer Research, SM2 5NG - London/GB
  • 2 Medicine, Centre Léon Bérard, Lyon/FR
  • 3 Hematology/ Oncology, Northwestern Memorial Hospital, Chicago/US
  • 4 Medical Oncology, Michigan Medicine Comprehensive Cancer Center, Ann Arbor/US
  • 5 Cancer Medicine, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 6 Early Phase Trials Unit, Institute Bergonié, 33076 - Bordeaux/FR
  • 7 Cancer Division, Chris O'Brien Lifehouse, Camperdown/AU
  • 8 Department Of Hematology And Oncology, Princess Margaret Hospital, Toronto/CA
  • 9 Medical Oncology, University of California, San Francisco/US
  • 10 Medical Oncology, Massachusetts General Hospital, Boston/US
  • 11 Medical Oncology, University of Colorado, Denver/US
  • 12 Ludwig Center At Harvard Medical School, Dana-Farber Cancer Institute, Boston/US
  • 13 Clinical, Epizyme, 02139 - Cambridge/US
  • 14 Clinical, Epizyme, Cambridge/US
  • 15 Oncology, Memorial Sloan-Kettering Cancer Center, New York/US


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Abstract 4830


Malignant rhabdoid tumors (MRTs), including small cell carcinoma of the ovary hypercalcemic type (SCCOHT) and thoracic sarcoma (TS; distinct, aggressive SMARCA4 negative tumors with rhabdoid features), are highly aggressive with limited response to conventional systemic therapy. Dysfunction of the SWI/SNF complex, due to loss of INI1 or SMARCA4, leads to oncogenic dependence on EZH2 through transcriptional repression caused by aberrant H3K27me3. Tazemetostat, a potent, selective, oral inhibitor of EZH2, demonstrated antitumor activity in both INI1 and SMARCA4-negative preclinical models.


Tazemetostat (800 mg BID) was studied in adults with MRT (confirmed by histology and INI1 loss) in this phase 2 multicenter, open-label, single arm, 2-stage Green-Dahlberg design study. Futility assessment was performed at stage 1 after the first 15 pts completed ≥24-weeks dosing, the final study visit, or terminated early. Success at stage 1 required ≥1 pt achieving a PR or CR. Stage 2 success required confirmed PR or CR in ≥ 5 treated pts. The primary endpoint was overall response rate. Key secondary endpoints included safety/tolerability.


With enrollment complete (N = 31; median age of 32 years; 58% female; n = 10 SCCOHT; n = 10 TS; n = 11 other INI1-neg tumors), futility was passed for stage 1, but not for stage 2. There were a total of 2/31 PRs; 1 pt with SCCOHT with a duration of response of 32 weeks and 1 pt with TS with an ongoing response at 8 weeks. Stable disease as best overall response was observed in 7 (23%) pts. Adverse events (AEs) were generally mild. Vomiting (42%), nausea (32%), cancer pain (26%), fatigue (23%), and abdominal pain (23%) were the most frequently reported AEs of any grade. Grade ≥3 AEs, regardless of relationship to study drug, included: death (19%; not treatment-related), anemia (16%), and abdominal pain (10%). No pts discontinued due to treatment-related AEs.


Tazemetostat demonstrated clinical activity in 2 difficult to treat tumors (SCCOHT and TS), with generally mild to moderate AEs. Although stage 2 futility was not passed, further understanding of the heterogeneity of these highly aggressive tumors may help to build upon the PR seen in 2 pts.

Clinical trial identification


Legal entity responsible for the study

Epizyme, Inc.


Epizyme, Inc.

Editorial Acknowledgement

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


R.L. Jones: Consultant: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, PharmaMar. M. Agulnik: Consulting/Advisory: Janssen, Eisai, Novartis, Lilly; Speakers' bureau: Eisai, Bristol-Myers Squibb. R. Chugh: Research funding: Epizyme; Scientific advisor/consultant: Epizyme. O. Mir: Consultancy: Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Eli Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor. Board membership: Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Eli Lilly, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor; Speakers’ bureau: Eli Lilly, Roche, Servie; Stock ownership: Amplitude Surgical, Transgene. Employee: Gustave Roussy. A. Italiano: Advisory board consulting: Epizyme. T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, Aztrazeneca/MedImmune, Lilly, Boehringer Ingelheim, Kadmon, BMS, Polaris, Epizyme. 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 with Epizyme. M. Gounder: Paid consultant and board member for Epizyme Medical Advisory Board Karyopharm – advisory board and honorarium Daiichi – advisory board and honorarium TRACON – honorarium Amgen – honorarium. All other authors have declared no conflicts of interest.

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