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Poster Discussion session - Sarcoma

4790 - A phase 2, multicenter study of the EZH2 inhibitor tazemetostat in adults (INI1-negative tumors cohort) (NCT02601950)

Date

22 Oct 2018

Session

Poster Discussion session - Sarcoma

Presenters

Silvia Stacchiotti

Citation

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

Authors

S. Stacchiotti1, J. Blay2, R.L. Jones3, G.D.D. Demetri4, O. Mir5, A. Italiano6, D. Thomas7, T.W. Chen8, P. Schöffski9, T. Gil10, T. Jahan11, G. Cote12, R. Ratan13, S. Attia14, M. Roche15, S. Daigle15, I. Sapir15, A. Clawson15, M. Gounder16

Author affiliations

  • 1 Department Of Medical Oncology, Fondazione IRCCS Istituto Nazioale Tumori, 20133 - Milan/IT
  • 2 Medicine, Centre Léon Bérard, 69008 - Lyon/FR
  • 3 Medical Oncology, The Royal Marsden Hospital and Institute for Cancer Research, London/GB
  • 4 Ludwig Center At Harvard Medical School, Dana-Farber Cancer Institute, Boston/US
  • 5 Cancer Medicine, Institut Gustave Roussy, Villejuif/FR
  • 6 Early Phase Trials Unit, Institute Bergonié, Bordeaux/FR
  • 7 Cancer Division, Chris O'Brien Lifehouse, Camperdown/AU
  • 8 Medical Oncology, National Taiwan University Hospital, Taipei City/TW
  • 9 Department Of General Medical Oncology, University Hospitals Leuven, 3000 - Leuven/BE
  • 10 Medical Oncology, Institute Jules Bordet, Brussels/BE
  • 11 Medical Oncology, University of California, San Francisco/US
  • 12 Medical Oncology, Massachusetts General Hospital, Boston/US
  • 13 Medical Oncology, MD Anderson Cancer Center, Houston/US
  • 14 Oncology, Mayo Clinic, Jacksonville/US
  • 15 Clinical, Epizyme, Cambridge/US
  • 16 Oncology, Memorial Sloan-Kettering Cancer Center, New York/US
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Resources

Abstract 4790

Background

INI1 loss may occur in tumors exhibiting rhabdoid morphology, including sinonasal carcinoma (SNC) and spindle cell sarcoma (SCS). Loss of INI1, a critical subunit of the SWI/SNF complex, leads to oncogenic dependence on EZH2 through transcriptional repression caused by aberrant H3K27me3. Tazemetostat, a potent, selective, oral inhibitor of EZH2, has demonstrated tumor regression in INI1-negative preclinical models and clinical activity in phase 1 trials with INI1-negative tumors.

Methods

This was a phase 2 multicenter, open-label, single arm, 2-stage Green-Dahlberg design study of tazemetostat (800 mg BID) in adult patients (pts) with INI1-negative tumors or any solid tumor with an EZH2 gain-of-function mutation (GoFM). Stage 1 futility was performed after the first 15 pts enrolled completed at least the 24-week assessment, the final study visit, or terminated early and required ≥1 pt achieving an objective response. Stage 2 success required confirmed CR or PR in ≥ 5/30 treated pts. The primary/secondary endpoints were overall response rate and safety.

Results

Enrollment completed between 04 Feb 2016 and 16 Mar 2018 (N = 32; 13 sarcomas, 16 non-mesenchymal solid tumors, and 3 EZH2 GOFM; median 2 prior lines of systemic therapy; median age 46.5 years; 53% female). This cohort passed futility for stage 1, but not stage 2. There were a total of 3/32 PRs (2 SCS and 1 SNC). One pt with SNC had a PR lasting 24 weeks with progressive disease (PD) at week 56, but remains on treatment with clinical benefit (per investigator) at one year. Of the 2 SCS pts with PRs, 1 remains on treatment at 2 years with an ongoing PR of 48 weeks; the other pt continues tazemetostat dosing at 1 year with an ongoing PR of 16 weeks. Stable disease as best response was observed in 13 (41%) pts. Most frequent AEs (any grade) included fatigue (31%), nausea (28%), vomiting (25%), and cancer pain (25%). For grade ≥3 AEs, most frequent included death (16%; not treatment-related) and dyspnea (9%).

Conclusions

Although stage 2 futility was not passed, tazemetostat treatment resulted in long-term clinical activity in 2/13 pts with INI1-negative sarcomas and 1/16 with an INI1-negative solid tumor with generally mild to moderate AEs.

Clinical trial identification

NCT02601950.

Legal entity responsible for the study

Epizyme, Inc.

Funding

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.

Disclosure

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 - Consultant, fees; Novartis - patent licensed to Novartis from Dana-Farber with royalty paid; Blueprint, Merrimack, G1, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals - Consultant or member, scientific Advisory Board, fees, equity; Blueprint, Merrimack - Member, board of directors; Bessor Pharmaceuticals - Consultant, equity (minor-stake, non public). O. Mir: Consultancy: Amgen, Astra-Zeneca, Bayer, Blueprint, Bristol Myers-Squibb, Eli-Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor. Board membership: Amgen, Astra-Zeneca, Bayer, Blueprint, Bristol Myers-Squibb, Eli-Lilly, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor. Speakers bureau: Eli-Lilly, Roche, Servier. Stock ownership: Amplitude surgical, Transgene. Employee: Gustave Roussy. A. Italiano: Advisory board consulting: Epizyme. T.W-W. Chen: Research fund, honorarium: Eisai; Honorarium: Novartis. P. Schöffski: Institutional honorarium for advisory function: Epizyme. T. Jahan: Research funding: Aduro Biotech, Acerta Pharma, AstraZeneca/MedImmune, Lilly, Boehringer Ingelheim, Kadmon, BMS, Polaris, Epizyme. M. Roche, S. Daigle, I. Sapir, A. Clawson: Paid employee and stock: Epizyme. M. Gounder: Paid consultant and board member: Epizyme; Medical advisory board: Karyopharm; Advisory board and honorarium: Daiichi, TRACON; Honorarium: Amgen. All other authors have declared no conflicts of interest.

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