Background
Phase II single-arm open-label study of tazemetostat — first-in-class oral EZH2 inhibitor — in INI1-negative (SMARCB1-deficient) metastatic or locally advanced epithelioid sarcoma. N=62 evaluable, global sites. SMARCB1 loss drives aberrant EZH2 activity and epigenetic dysregulation. NCT02601950; data cutoff October 2019.
Interventions and follow up
Treatment: Tazemetostat 800 mg PO twice daily continuously until progression or intolerance (INI1-negative epithelioid sarcoma)
Primary endpoint: ORR (confirmed PR+CR by modified RECIST 1.1, investigator-assessed)
mFollow up: 14.3 mo
Primary endpoint: ORR (confirmed PR+CR by modified RECIST 1.1, investigator-assessed)
mFollow up: 14.3 mo
Results
ORR (n=62 evaluable): 15% (9 confirmed: 1 CR, 8 PRs)
SD rate: 52%
DCR (SD + PR + CR): 67%
SD ≥32 weeks: 26%
mPFS: 5.5 mo (95% CI 3.4–5.9)
mOS: not reached at cutoff; 12-mo OS ~74%
mDOR: not reached (range 4.2–23.3+ mo)
SD rate: 52%
DCR (SD + PR + CR): 67%
SD ≥32 weeks: 26%
mPFS: 5.5 mo (95% CI 3.4–5.9)
mOS: not reached at cutoff; 12-mo OS ~74%
mDOR: not reached (range 4.2–23.3+ mo)
Adverse events
Grade ≥3 AEs: 39%
Most common any-grade: fatigue 47%, nausea 29%, decreased appetite 27%, vomiting 27%
Grade ≥3 specific: fatigue 10%, weight decrease 6%
Secondary malignancy: no secondary T-cell lymphoma at cutoff (theoretical EZH2-inhibition concern; reported later in other studies)
Discontinuation due to AEs: 8%
Most common any-grade: fatigue 47%, nausea 29%, decreased appetite 27%, vomiting 27%
Grade ≥3 specific: fatigue 10%, weight decrease 6%
Secondary malignancy: no secondary T-cell lymphoma at cutoff (theoretical EZH2-inhibition concern; reported later in other studies)
Discontinuation due to AEs: 8%
Conclusions
Tazemetostat achieved 15% ORR with 67% DCR in heavily pretreated INI1-negative epithelioid sarcoma, with durable responses and median OS over 12 months. The oral twice-daily regimen was well tolerated, establishing EZH2 inhibition as a rational targeted approach in a SMARCB1-loss disease.
Key Limitations
Single-arm, no comparator; modest 15% ORR; ORR surrogate with immature OS; theoretical secondary T-cell lymphoma risk with EZH2 inhibition requires long-term surveillance.
Clinical Context
FDA accelerated approval Jan 2020 for metastatic/locally advanced epithelioid sarcoma not eligible for complete resection — first approved targeted therapy for this disease. ESMO recognizes tazemetostat as a preferred option in INI1-deficient epithelioid sarcoma.