Background
Phase II single-arm trial with 2 cohorts: Cohort 1 — EZH2-activating mutation-positive R/R FL (n=45); Cohort 2 — EZH2 wild-type R/R FL (n=54). Patients had received ≥2 prior lines. Evaluated tazemetostat, a selective oral EZH2 inhibitor. EZH2 gain-of-function mutations occur in ~20–25% of FL and are associated with epigenetic dysregulation. Trial supported FDA approval of tazemetostat for R/R FL in June 2020.
Interventions and follow up
Regimen: Tazemetostat 800 mg orally twice daily continuously until progression or unacceptable toxicity, in two parallel cohorts (EZH2-mutant and EZH2-wild-type)
Primary endpoint: Overall response rate (ORR) per IRC
Median follow-up: 22 months (EZH2-mut); 36 months (EZH2-WT)
Primary endpoint: Overall response rate (ORR) per IRC
Median follow-up: 22 months (EZH2-mut); 36 months (EZH2-WT)
Results
ORR (Cohort 1, EZH2-mut): 69% (31/45); CR 13%, PR 56%
Median DOR (EZH2-mut): 10.9 months
ORR (Cohort 2, EZH2-WT): 35% (19/54); CR 4%, PR 31%
Median DOR (EZH2-WT): 13.0 months
Median DOR (EZH2-mut): 10.9 months
ORR (Cohort 2, EZH2-WT): 35% (19/54); CR 4%, PR 31%
Median DOR (EZH2-WT): 13.0 months
Adverse events
Grade ≥3 burden: 10% (EZH2-mut) and 15% (EZH2-WT); most common grade ≥3 thrombocytopenia 4%, asthenia 4%, neutropenia 2%, anemia 2%
Tolerability: no CRS (oral mechanism); discontinuation due to AEs 3%; exceptionally favorable profile with no significant immunosuppression
Tolerability: no CRS (oral mechanism); discontinuation due to AEs 3%; exceptionally favorable profile with no significant immunosuppression
Conclusions
Tazemetostat produced clinically meaningful responses in R/R FL, particularly in EZH2-mutant tumors (ORR 69%), with durable responses and an excellent tolerability profile. Activity was also observed in EZH2-WT tumors (ORR 35%), suggesting EZH2 inhibition has broader relevance beyond mutation-driven cases.
Key Limitations
Single-arm design without a comparator precludes direct comparison with other R/R FL options. Activity in EZH2-WT disease was modest (ORR 35%, CR 4%) and median DOR in the mutant cohort was relatively short (10.9 months), raising durability questions. EZH2 testing is required to identify the highest-benefit population. Sample sizes per cohort were small, limiting precision of subgroup estimates.
Clinical Context
FDA granted accelerated approval to tazemetostat in June 2020 for R/R FL with an EZH2 mutation after ≥2 prior lines, and for EZH2-WT R/R FL with no satisfactory alternative options; an FDA-approved companion diagnostic identifies EZH2 mutations. Its oral administration and favorable tolerability make it attractive for older or frailer patients. It represents the first EZH2 inhibitor approved in lymphoma and a paradigm for epigenetic targeting in FL.