Dr Park on the Rationale for the SYMPHONY-1 Trial in Relapsed/Refractory FL

Steven Park, MD, hematologist, oncologist, vice chair, research, Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, discusses the mechanism of action of tazemetostat (Tazverik) and the rationale for the phase 3 SYMPHONY-1 trial (NCT04224493) in patients with relapsed follicular lymphoma (FL).

The SYMPHONY-1 trial is investigating the oral agent tazemetostat vs placebo in combination with rituximab (Rituxan) and lenalidomide (Revlimid) in patients with relapsed/refractory FL. This 3-stage trial included a phase 1b safety run-in portion, in which all patients received tazemetostat plus rituximab and lenalidomide. The ongoing phase 3, stage 2 portion will randomly assign patients to receive the investigative triplet or placebo plus lenalidomide and rituximab. In the optional stage 3 portion, patients will receive the investigative combination in 28-day cycles.

Tazemetostat is a first-in-class EZH2 inhibitor that received accelerated FDA approval in 2020 for patients with relapsed/refractory, EZH2-positive FL who have received at least 2 prior lines of therapy. EZH2 is part of the PI3K complex, and silences tumor suppressor genes, Park says. Overexpression of EZH2 has been associated with cancer progression and worse clinical outcomes, Park notes. EZH2 is an attractive target in FL since approximately 20% to 30% of patients with FL harborEZH2 mutations, Park explains.

In the phase 1/2 study E7438-G000-101 (NCT01897571), tazemetostat monotherapy generated an overall response rate of 69% (95% CI, 53%-82%) in patients with EZH2-positive FL who had received at least 2 prior systemic therapies. These data supported the 2020 accelerated approval of the agent. Additionally, tazemetostat is a good option for patients who cannot tolerate a more intense treatment regimen, Park emphasizes.

SYMPHONY-1 aims to determine whether clinical outcomes seen with tazemetostat can be improved by combining it with lenalidomide plus rituximab, a commonly used second-line regimen for patients with relapsed/refractory FL, Park says. This trial contributes toward a larger goal of bringing more effective regimens into earlier lines of therapy in FL, Park concludes.