Tazemetostat in Relapsed/Refractory follicular lymphoma and DLBCL: A systematic review of clinical trials

Abstract

Abstract Introduction Tazemetostat, an EZH2 inhibitor, received FDA approval (2020) for third-line treatment of relapsed/refractory follicular lymphoma (RRFL) in patients with EZH2 mutations after ≥2 prior therapies, and for EZH2 wild-type (WT) patients with no alternative options. Approximately 20% of FL cases have EZH2 mutation. Methods A literature search of PubMed, Embase, and Scopus identified 278 studies. 6 phase I/II trials with use of tazemetostat alone or in combination for treating RRFL and DLBCL, were included. Results 206 patients were identified: tazemetostat monotherapy(162) and tazemetostat in combination with lenalidomide and rituximab(44). 62 patients receiving tazemetostat monotherapy had mutated EZH2 while 54 had wild type (WT) EZH2. Similarly, 36 patients receiving tazemetostat combination therapy had WT EZH2, while 8 patients had EZH2 mutation. In EZH2-mutated FL, the objective response rate (ORR) ranged from 69.5–76.5% with a complete response (CR) of 13–35.3%. The median time to response was 3.6 months; one study reported PFS of 13.8 months and duration of response (DOR) of 10.9 months. In WT FL, the ORR was 35%, CR 4%, PFS 11.1 months, and DOR was 13 months. Patients with unknown mutation status had ORRs of 60–75%. A separate study reported a CR rate of 38% across NHL subtypes regardless of EZH2 status. Common adverse events (AEs) included thrombocytopenia, dysgeusia, lymphopenia, neutropenia, and anemia. Drug discontinuation due to AEs occurred in 5% and 23.5% of patients in two studies. However, in SYMPHONY-1 trial, the combination tazemetostat therapy group showed ORR of 90.9% (100% in MT, 88.9% in WT) and CR of 54.8%. ORR was 93.3% in rituximab-refractory and 91.7% in POD. The most common Grade 3–4 AE was neutropenia (40.9%), leading to dose reductions (38.6%), interruptions (70.5%), and discontinuations (20.5%). Conclusion Tazemetostat demonstrates promising efficacy as monotherapy in EZH2-mutant FL. Tazemetostat in combination with rituximab and lenalidomide regimen showed higher response even in high-risk subgroups, including WT, rituximab-refractory, and patients with disease progression. Ongoing phase 3 trials are evaluating tazemetostat-based regimens in both relapsed and untreated high-risk FL.