FDA Issues Warning Regarding Risk of Secondary Primary Malignancies With Tazemetostat in Follicular Lymphoma, Epithelioid Sarcoma

The FDA issued an alert to patients and health care providers underscoring the voluntary withdrawal of tazemetostat (Tazverik) from its approved indications in follicular lymphoma and epithelioid sarcoma due to an increased rate of hematologic secondary primary malignancies (SPMs).¹

In March 2026, Ipsen, the developer of tazemetostat, announced the voluntary withdrawal of tazemetostat indications in the United States, which included the treatment of:^2,3

• adult and pediatric patients 16 years of age and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection
• adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation, as detected by an FDA-approved test, and who have received at least 2 prior systemic therapies
• adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options

When the agent received its initial accelerated approvals in 2020, the incidence of SPMs was 1.7%, according to the FDA.¹ However, in the phase 3 SYMPHONY-1 trial (NCT04224493) evaluating tazemetostat in combination with lenalidomide (Revlimid) and rituximab (Rituxan; R²) for the treatment of adult patients with relapsed/refractory follicular lymphoma, SPMs occurred at a rate of 5.7% at a median treatment duration of 15.8 months (range, 6.9-33) in patients treated with the combination (n = 318). Notably, no instances of SPMs were reported in the control arm, where patients received R² plus placebo.

The majority of SPMs were myelodysplastic syndrome and acute myeloid leukemia, but they also comprised B-cell acute lymphoblastic leukemia and clonal cytopenia of undetermined significance. Among the 18 patients who experienced SPMs in the tazemetostat plus R² arm, 3 died and 14 remained without resolution of the hematologic SPM as of March 6, 2026.

According to the FDA, SPMs were reported as early as 7.5 months following the start of treatment, and they also occurred in patients following the conclusion of treatment.

As part of its voluntary withdrawal, Ipsen began steps to stop treatment with tazemetostat in SYMPHONY-1, with the plan for all patients to receive R² alone.²

How was the SYMPHONY-1 trial designed?

SYMPHONY-1 was a phase 1b/3, double-blind, randomized, active-controlled, 3-stage trial that enrolled patients at least 18 years of age with histologically confirmed grade 1 to 3A follicular lymphoma who had received prior treatment with at least 1 systemic chemotherapy, immunotherapy, or chemoimmunotherapy.⁴

Patients needed to have relapsed/refractory disease or disease progression following prior systemic therapy. Other key inclusion criteria comprised measurable disease per Lugano classification, an ECOG performance status of 0 to 2, and adequate organ function.

In the trial’s first stage during phase 1b, patients received tazemetostat at escalating doses of 400 mg twice per day, 600 mg twice per day, and 800 mg twice per day. This was given in combination with rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1, then on day 1 of cycles 2 to 5; and lenalidomide at 20 mg or 10 mg per day on days 1 to 21 for 12 cycles, with dosing based on creatinine clearance. Tazemetostat was continued as monotherapy for up to 2 years following the initial 12 months of combination therapy.

In stage 2 during phase 3, patients were randomly assigned to receive tazemetostat at 800 mg twice per day in combination with R² at the same dosing schedule as in stage 1; or placebo plus R².

After the recommended phase 3 dose of tazemetostat plus R2 served as the primary end point in stage 1, progression-free survival in the EZH2-mutant and wild-type populations represented the primary end points in phase 3.

Although treatment with tazemetostat was discontinued in SYMPHONY-1, the study remains open for long-term safety follow-up.¹

References

1. FDA alerts health care providers and patients about increased risk of new blood cancers with Tazverik (tazemetostat) use; sponsor to voluntarily withdraw product from market. FDA. May 11, 2026. Accessed May 12, 2026. https://www.fda.gov/drugs/drug-alerts-and-statements/fda-alerts-health-care-providers-and-patients-about-increased-risk-new-blood-cancers-tazverik
2. Ipsen voluntarily withdraws Tazverik (tazemetostat) in follicular lymphoma and epithelioid sarcoma. March 9, 2026. Accessed May 12, 2026. https://www.ipsen.com/press-release/ipsen-voluntarily-withdraws-tazverik-tazemetostat-in-follicular-lymphoma-and-epithelioid-sarcoma-3251503/
3. Tazverik. Prescribing information. FDA. Updated August 2024. Accessed May 12, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211723s005lbl.pdf
4. A study to assess the efficacy, safety, pharmacodynamics, and pharmacokinetics of tazemetostat in combination with lenalidomide plus rituximab versus placebo in combination with lenalidomide plus rituximab in adult patients at least 18 years of age with relapsed/​refractory follicular lymphoma. (SYMPHONY-1). ClinicalTrials.gov. Updated April 20, 2026. Accessed May 12, 2026. https://clinicaltrials.gov/study/NCT04224493