Tazemetostat for the treatment of R/R FL

The Lymphoma Hub was pleased to speak to Gilles Salles, Memorial Sloan Kettering Cancer Center, New York, US. We asked, What are the key clinical considerations in prescribing tazemetostat for the treatment of relapsed/refractory follicular lymphoma (R/R FL) progressing after ≥2 systemic therapies?

In this interview, Salles discusses the use of tazemetostat, an EZH2 inhibitor, in treating R/R FL following multiple systemic therapies. He highlights the rationale for the development of EZH2 inhibitors, their mechanism of action, and the clinical trial findings that led to tazemetostat's approval. The discussion includes key trial data, including response rates and safety profiles, clinical considerations, and ongoing research into combination therapies.

Key points

During the interview, Salles discusses the following key points^1,2:

• EZH2 is crucial in regulating gene expression in B cells and EZH2 mutations play a key role in FL pathogenesis; 20–25% of patients with FL have EZH2 mutations.
• Inhibition of EZH2 may also be of value in patients with wild-type EZH2 FL, in part due to off-target effects on immune cells within the tumor microenvironment. 
• Tazemetostat is a first-in-class oral EZH2 inhibitor that is approved by the FDA for adult patients with R/R FL whose tumors are positive for an EZH2 mutation and who have received ≥2 prior systemic therapies or who have no satisfactory alternative treatment options.
• Approval of tazemetostat was based on the phase II E7438-G000-101 trial (NCT01897571) in patients with both mutated and wild-type EZH2. 
• At data cutoff, with a median follow-up of 22.0 months for the mutated EZH cohort and 35.9 months for the wild-type EZH2 cohort, key efficacy data from this trial include:
  • In patients with mutated EZH2 (n = 45), overall response rate (ORR) was 69% and complete response rate (CRR) was 13%.
  • In patients with wild-type EZH2 (n = 54), ORR was 35% and CRR was 4%.
  • Progression-free survival was similar between both groups (13.8 months for mutated EZH2 and 11.1 months for wild-type EZH2).
  • The duration of response was 10.9 months in patients with a mutated EZH2 and 13 months in patients with wild-type EZH2.
  • Tazemetostat benefited both patients with mutated and wild-type EZH2, even though patients with mutated EZH2 have notably better prognostic factors.
• Key safety data from the trial include:
  • The majority of patients experienced mild treatment-emergent adverse events (AEs), although only 9% required a dose reduction.
  • Common AEs included Grade 1 or 2 nausea, diarrhea, asthenia, alopecia, and fatigue.
  • Severe hematologic toxicities were rare.
  • 8% of patients discontinued treatment due to AEs.
• Overall, tazemetostat represents a well-tolerated oral treatment for R/R FL, which can provide disease control for a substantial period of time.

• Ongoing trials, for example the SYMPHONY-1 study (NCT04224493), exploring tazemetostat in combination with other agents are showing high response rates, and may further establish its role in combination treatments for FL.

This educational resource is independently supported by Ipsen Biopharmaceuticals. All content is developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.