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.
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.
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%).
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
Legal entity responsible for the study
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. 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.