Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Background: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator implicated as a genetic driver in multiple lymphoma types. Approximately 20% of patients with follicular lymphoma (FL) present with activating, gain-of-function (GoF) EZH2 mutations. The results of a phase 2 clinical trial of the first-in-class oral EZH2 inhibitor tazemetostat demonstrated clinically meaningful response in patients with relapsed/refractory (R/R) FL in wild-type (WT) and mutant (MT) EZH2 who were treated with single-agent tazemetostat. Tazemetostat is approved by the US Food and Drug Administration for treatment of patients with R/R FL. Beyond EZH2, the biologic drivers of response to tazemetostat remain unknown. To better understand the drivers of tazemetostat response, we performed DNA and RNA sequencing of archival tumor biopsy and cell-free DNA samples to determine the landscape of genetic mutations, copy number variations, and gene-expression profiles in trial patients.