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
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.