Tazemetostat produced responses and was generally well tolerated in a phase II trial.
Major Finding: Tazemetostat produced responses and was generally well tolerated in a phase II trial.
Concept: The response rate was higher in patients with EZH2-activating mutations but durable in all patients.
Impact: Tazemetostat warrants further study in first-line and relapsed or refractory follicular lymphoma.
Activating mutations affecting EZH2, the PRC2 subunit that trimethylates histone 3 lysine residue 27 to cause target-gene repression, are found in approximately 20% of patients with follicular lymphoma. Moreover, even wild-type (WT) EZH2 is implicated in the development of this disease because EZH2-mediated histone modification can lead to silencing of genes that would otherwise slow B-cell proliferation, enabling accumulation of mutant B-cell clones. Morschhauser and colleagues conducted a phase II, open-label, single-arm study of the first-in-class oral EZH2 inhibitor tazemetostat in 99 patients with relapsed or refractory grade 1, 2, 3a, or 3b follicular lymphoma, 45 of whom were classified into the EZH2-mutant (EZH2mut) cohort and 54 of whom were classified into the EZH2WT cohort. Among patients in the EZH2mut cohort, the objective response rate was 69% (13% complete responses and 56% partial responses) according to assessment by an independent radiology committee. The same committee determined that the objective response rate was 35% (4% complete responses and 31% partial responses) among patients in the EZH2WT cohort. An additional 29% of patients in the EZH2mut cohort and 33% of patients in the EZH2WT cohort experienced stable disease after a median follow-up period of 22.0 months in the EZH2mut cohort and 35.9 months in the EZH2WT cohort. The median duration of response was 10.9 months in the EZH2mut cohort (n=31) and 13.0 months in the EZH2WT cohort (n=19). Median progression-free survival was longer in patients in the EZH2mut cohort than in patients in the EZH2WT cohort at 13.8 months and 11.0 months, respectively. Ninety-nine percent of patients experienced at least one treatment-emergent adverse event (TEAE) of any grade, usually mild (grade 1 or 2), most commonly nausea (23%), diarrhea (18%), alopecia (17%), or cough (16%), and 8% of patients discontinued study treatment due to TEAEs; however, there were no treatment-related deaths. In summary, this trial demonstrates the potential utility of tazemetostat in relapsed or refractory follicular lymphoma, with durable responses seen in both the EZH2WT cohort and the EZH2mut cohort, with a higher overall objective response rate in patients with EZH2 mutations, and suggests that further trials with tazemetostat in combination are warranted both in first-line and relapsed or refractory follicular lymphoma.
Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 2020;21:1433–42.
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