Tazemetostat (EPZ-6438), an EZH2 methyltransferase inhibitor, is FDA-approved (January 20...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-SMARCB1-EPITHELIOID-SARCOMA |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-EPITHELIOID-SARCOMA |
| Sources | SRC-ESMO-SARCOMA-2024 SRC-EZH202-GOUNDER-2020 SRC-NCCN-SARCOMA |
Actionability Facts
| Biomarker | BIO-SMARCB1 |
|---|---|
| Variant | SMARCB1/INI1 biallelic loss-of-function — confirmed by loss of INI1 nuclear expression on IHC (BAF47/INI1 antibody); NGS/FISH for deletion confirmation optional |
| Disease | DIS-EPITHELIOID-SARCOMA |
| ESCAT tier | IA |
| Recommended combinations | tazemetostat 800 mg PO BID continuously (no food restriction; 28-day cycles; continue until disease progression or unacceptable toxicity) |
| Contraindicated monotherapy | tazemetostat in patients with germline SMARCB1 or SMARCA4 mutations without documented histologic confirmation — EZH2 inhibition can theoretically worsen SWI/SNF-deficient non-target tumors; clinical confirmation required |
| Evidence summary | Tazemetostat (EPZ-6438), an EZH2 methyltransferase inhibitor, is FDA-approved (January 2020) for adults and pediatric patients (≥16 years) with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. This was the first FDA approval in this disease and the first EZH2-targeted approval in solid tumors. EZH-202 phase II (Gounder et al., Lancet Oncology 2020): N=62 evaluable; primary endpoint ORR by RECIST 1.1. ORR: 15% (9/62; 1 CR, 8 PR); clinical benefit rate (CR+PR+SD ≥32 weeks): 26%. mDOR in responders: not reached at time of analysis. Disease control rate: ~26% with durable SD. Safety profile: generally well-tolerated; rare secondary T-cell lymphoma risk (class-wide EZH2 inhibitor concern); myeloid malignancy risk with long-term use (monitoring recommended). INI1 loss (IHC) is the companion diagnostic — required for diagnosis and eligibility. Standard chemotherapy (doxorubicin-based) remains an option for fit patients with rapidly progressive disease; tazemetostat preferred for slow-growing/indolent course. |
Notes
ESCAT IA (FDA accelerated approval based on ORR; confirmatory phase III for conversion to regular approval pending). INI1 IHC (BAF47 antibody) is simpler and faster than molecular testing — loss of nuclear staining in tumor cells confirms SMARCB1 deficiency. Important caveat: ~10% of epithelioid sarcomas retain INI1 by IHC despite molecular loss (heterogeneous or focal) — in equivocal cases, SMARCB1 NGS/FISH is recommended. Note: tazemetostat has a second FDA approval (EZH2-mutant follicular lymphoma; SRC-MORSCHHAUSER- 2020-TAZEMETOSTAT-FL) — that is a distinct indication driven by EZH2 gain-of-function mutation, not SMARCB1 loss. Secondary T-cell lymphoma risk: EZH2 inhibitors in EZH2 wild-type/SMARCB1-deficient context have a class-wide concern; monitor CBC, consider periodic bone marrow monitoring in long-term responders.
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