Role of EZH2 in Tumorigenesis
EZH2 is a protein present in many human cells that helps regulate B‑cell development.Mutations in EZH2 cause hyperactivity, preventing normal B‑cell maturation and leading to uncontrolled proliferation and tumor growth. Such mutations are found in some cases of follicular lymphoma.
More than 90% of patients with epithelioid sarcoma have loss‑of‑function INI‑1 gene mutations, which render tumors dependent on EZH2 activity, driving invasiveness and growth.
Overview of TAZVERIK (tazemetostat)
TAZVERIK, developed by Epizyme, is an EZH2 methyltransferase inhibitor.It is not chemotherapy and does not directly kill cancer cells; it represents the first‑in‑class therapy designed to selectively target and block EZH2.
Under accelerated FDA approvals granted in January and June 2020, TAZVERIK is indicated for certain patients with epithelioid sarcoma and follicular lymphoma.
FDA‑Approved Indications in the United States
Adult and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma who are not candidates for complete resection.
Adult patients with relapsed or refractory follicular lymphoma whose tumors are EZH2 mutation‑positive by an FDA‑approved test and who have received at least two prior systemic therapies.
Adult patients with relapsed or refractory follicular lymphoma for whom no satisfactory alternative treatment options exist.
These indications are approved under accelerated approval based on overall response rate and duration of response.Continued approval is contingent upon verification and description of clinical benefit in confirmatory trials.
Efficacy and Safety in Advanced Epithelioid Sarcoma
Approval for epithelioid sarcoma was based on the Phase II, open‑label, single‑arm, multicenter study EZH‑202 (NCT02601950).
Total enrollment: 250 patients
Cohort 5: 62 patients treated with TAZVERIK 800 mg twice daily until disease progression or unacceptable toxicity.
Primary endpoint: Objective Response Rate (ORR).
Key Results
ORR: 15%
Complete response (CR): 1.6%
Partial response (PR): 13%
67% of responders had duration of response ≥ 6 months
Treatment was well‑tolerated and provided clinically meaningful, durable responses.
Common Adverse Reactions
Pain, nausea, fatigue, vomiting, decreased appetite, and constipation.
Efficacy and Safety in Follicular Lymphoma
Approval for follicular lymphoma was based on an open‑label, multicenter, Phase II study (NCT01897571).Patients received tazemetostat 800 mg twice daily as monotherapy.
EZH2‑mutant cohort: 45 patients
Wild‑type EZH2 cohort: 54 patientsAll had received at least two prior lines of systemic therapy.
Efficacy Results (Independent Review Committee)
EZH2‑Mutant Disease
ORR: 69%
CR: 12%
PR: 57%
Median duration of response (DoR): 10.9 months
Median progression‑free survival (PFS): 14 months
Wild‑Type EZH2 Disease
ORR: 34%
CR: 4%
PR: 30%
Median DoR: 13 months
Median PFS: 11 months
Safety Profile
Most common treatment‑emergent adverse events:Fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain.Serious adverse reactions occurred in 30% of patients, most commonly infection.
Ongoing Clinical Development
TAZVERIK is in Phase III confirmatory registration study SYMPHONY‑1, evaluating the combination of tazemetostat plus rituximab and lenalidomide in relapsed/refractory follicular lymphoma patients with at least one prior therapy.Preliminary results from the randomized portion are planned for 2026.
Clinical Significance
Follicular lymphoma is a subtype of non‑Hodgkin lymphoma.Epithelioid sarcoma is a rare, slow‑growing soft‑tissue tumor with limited treatment options worldwide.The EZH2 methyltransferase inhibitor tazemetostat provides an important new therapeutic option for selected patients.
