The EZH2 Inhibitor Tazemetostat Shows Efficacy in 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 (EZH2^mut) cohort and 54 of whom were classified into the EZH2^WT cohort. Among patients in the EZH2^mut 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 EZH2^WT cohort. An additional 29% of patients in the EZH2^mut cohort and 33% of patients in the EZH2^WT cohort experienced stable disease after a median follow-up period of 22.0 months in the EZH2^mut cohort and 35.9 months in the EZH2^WT cohort. The median duration of response was 10.9 months in the EZH2^mut cohort (n=31) and 13.0 months in the EZH2^WT cohort (n=19). Median progression-free survival was longer in patients in the EZH2^mut cohort than in patients in the EZH2^WT 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 EZH2^WT cohort and the EZH2^mut 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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