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Authors Franck Morschhauser, MD PhD, Herve Tilly, MD PhD, Aristeidis Chaidos, Tycel J. Phillips, MD, Vincent Ribrag, MD, Philip Campbell, MBBS, FRACP, FRCPA, Damaj Gandhi Laurent, MD PhD, Wojciech Jurczak, MD PhD, Pamela McKay, MD, Stephen Opat, John Radford, Jennifer Whalen, Anand Rajarethinam, Susan Benedict Navia, Deyaa Adib, Gilles Salles, MD PhD
Title Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma
Journal Blood
Vol 134
Issue Supplement_1
Date
URL https://ashpublications.org/blood/article/134/Supplement_1/123/426294/Phase-2-Multicenter-Study-of-Tazemetostat-an-EZH2
Abstract Text Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center (GC) formation. Conversely, a reduction in EZH2 catalytic activity is required for centroblast differentiation and initiation of the GC exit program. Activating mutations (MT) in EZH2, present in ~20% of FL patients, and enhanced H3K27me3 prevent GC exit, resulting in GC hyperplasia and lymphomagenesis. Tazemetostat, an investigational, selective, oral EZH2 inhibitor, has demonstrated durable, single-agent, antitumor activity in R/R FL patients with MT or wild-type (WT) EZH2. Herein, we report newly emerging interim efficacy and safety data from the MT and WT cohorts and the POD24 subgroup. Methods: This open-label, multicenter, phase 2 study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1-3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary endpoint was objective response rate (complete response + partial response). Secondary endpoints included progression-free survival and safety. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy. Results: As of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%]). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9 (50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Updated data from the fully enrolled MT cohort, and sub-group analyses from both WT and MT cohort, will be presented. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in Table 1. These results demonstrate the potent, antitumor activity of tazemetostat regardless of the prognostic category of patients. Treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported. Conclusion: Tazemetostat was generally well tolerated, with a low incidence of treatment-related AEs. Tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EZH2 Y646N follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646N (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
Unknown unknown follicular lymphoma not applicable Tazemetostat FDA approved Actionable In a Phase II trial that supported FDA approval, Tazemetostat (EPZ-6438) treatment was well-tolerated and demonstrated clinical activity in patients with relapsed/refractory follicular lymphoma, resulting in an objective response rate of 77% (33/43) and 34% (18/53), stable disease in 23% (10/43) and 30% (16/53), and median progression-free survival of 11.1 and 5.7 months in EZH2 mutant and wild-type cohorts, respectively (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail...
EZH2 A682G follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 A682G (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y641S follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646S (corresponds to Y641S in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 A692V follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 A692V (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y646H follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646H (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y646S follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646S (Blood (2019) 134 (Supplement_1): 123; NCT01897571). detail... detail... detail...
EZH2 Y641H follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646H (corresponds to Y641H in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y641N follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646N (corresponds to Y641N in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y641F follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646F (corresponds to Y641F in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y641C follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646C (corresponds to Y641C in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y646C follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646C (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 A677G follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 A682G (corresponds to A677G in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 A687V follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed/refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 A692V (corresponds to A687V in the canonical isoform) (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...
EZH2 Y646F follicular lymphoma sensitive Tazemetostat FDA approved - On Companion Diagnostic Actionable In a Phase II trial that supported FDA approval, Tazverik (tazemetostat) treatment was well-tolerated, resulted in a median progression-free survival of 11.1 months, objective response in 77% (33/43), and stable disease in 23% (10/43) of patients with relapsed or refractory follicular lymphoma, who had two or more prior therapies and harbored EZH2 mutations as detected by an approved test, including EZH2 Y646F (Blood (2019) 134 (Supplement_1):123; NCT01897571). detail... detail... detail...