INTERIM UPDATE FROM A PHASE 2 MULTICENTER STUDY OF TAZEMETOSTAT, AN EZH2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA

Introduction: Relapsed or refractory (R/R) follicular lymphoma (FL) remains an area of unmet medical need and treatments with novel mechanisms of action are desirable. The histone methyltransferase EZH2 is an important regulator of the germinal center (GC) reaction that is involved in preventing terminal differentiation of GC B-cells. EZH2 activating mutations are present in ~20% of FL patients (pts) and are postulated to be oncogenic drivers. Tazemetostat, a selective, oral EZH2 inhibitor has shown antitumor activity in a phase 1/2 study that included non-Hodgkin lymphoma pts with mutant (MT) or wild-type (WT) EZH2tumors, providing rationale for further investigation. Methods: This open-label, multicenter, phase 2 study of tazemetostat enrolled pts with either MT or WT EZH2 R/R diffuse large B-cell lymphoma or FL (Grade 1-3b). Key inclusion criteria included: age ≥18 years, ≥2 prior treatment regimens, and measurable disease. Tumor tissue was analyzed for EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, investigational use only). Tazemetostat 800 mg was administered orally, twice daily. Response was assessed every 8 weeks using 2007 IWG-NHL criteria. The primary endpoint was ORR (CR + PR). Secondary endpoints included PFS and safety/tolerability. Efficacy and safety were analyzed for the EZH2 MT and EZH2 WT groups. Results: As of February 1, 2019, interim data were summarized from 95 FL pts (41 EZH2 MT and 54 EZH2 WT). The overall median age was 61 years, and median prior lines of therapy was 2 (range: 0-11) in the EZH2 MT group and 3 (range: 1-8) in the EZH2 WT group. Median follow-up times, ORR, median duration of response for 92 response evaluable patients in both EZH2 MT and WT groups are highlighted in the table. Response duration was greater than 24 weeks in 83% of pts, and 50% of pts had a response duration greater than 1 year. Treatment-emergent adverse events (TEAEs) leading to dose reductions occurred in 8% of pts and study drug discontinuation due to TEAEs occurred in 9% of FL pts. The overall safety profile was similar to what has been previously reported. Grade ≥3 treatment-related TEAEs were reported in 18% of pts; no Grade 5 AEs were reported. Keywords: follicular lymphoma (FL); germinal center B cell-like (GCB). Disclosures: Morschhauser, F: Consultant Advisory Role: Gilead, Servier, Roche/Genentech; Honoraria: Celgene, BMS, Janssen. Tilly, H: Consultant Advisory Role: Celgene, Astra-Zeneca, Karyopharm, Roche; Honoraria: BMS, Janssen, Gilead; Research Funding: Celgene. Phillips, T: Consultant Advisory Role: Genentech, Gilead, Bayer, Seattle Genetics, Pharmacyclics; Research Funding: Pharmacyclics, Abbvie. Ribrag, V: Consultant Advisory Role: Epizyme, Servier, Nanostring, Gilead, Pharmamar, BMS, MSD, Incyte, Roche, Infinity; Honoraria: ESAI; Research Funding: Epizyme, ArgenX. Jurczak, W: Consultant Advisory Role: AstraZeneca/Acerta, European Medicines Agency, Sandoz-Nowartis, Janssen, Gilead; Research Funding: Afimed, BeiGene, Celgene, Epizyme, AstraZeneca/Acerta. McKay, P: Consultant Advisory Role: Epizyme; Honoraria: Epizyme. Opat, S: Consultant Advisory Role: Roche, Celgene, Mundipharma, Janssen; Honoraria: Roche, Celgene, Mundipharma, Janssen. Radford, J: Consultant Advisory Role: Takeda, Bristol-Myers Squibb, Seattle Genetics, Novartis; Stock Ownership: GSK, AstraZeneca; Honoraria: Takeda; Research Funding: Takeda, Pfizer, ADC Therapeutics, Celgene, AstraZeneca. Rajarethinam, A: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Yang, J: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Howell, H: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Newberry, K: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Adib, D: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Salles, G: Honoraria: Roche, Jannsen, Gilead, Celgene, Novartis, Amgen, BMS, Merck, Servier.