Phase 2 study reports responses with tazemetostat in relapsed or refractory follicular lymphoma

Evidence before this study

We searched PubMed for articles on clinical trials published between database inception and April 3, 2020, with no language restrictions. First, we used the search terms “epigenetic OR epigenetics” AND “lymphoma”, which produced 25 results. Of these 25, only two clinical trials included patients with follicular lymphoma. Second, we used the search terms “EZH2” AND “lymphoma”. Of the four results generated, three focused on patients with follicular lymphoma. Given the paucity of results, we supplemented our literature search with a description of key studies relevant to the medical literature on this topic. Among studies of epigenetic therapies, investigators concluded that epigenetic mechanisms might cause the change in CD20 expression following rituximab treatment. Two phase 2 studies evaluated the safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in patients with non-Hodgkin lymphoma or chronic lymphocytic leukaemia, including patients with follicular lymphoma, and found clinical activity in heavily pretreated patients with follicular lymphoma and a manageable toxicity profile, although grade 3–4 thrombocytopenia and any grade diarrhoea were noted. The histone deacetylase inhibitor vorinostat was investigated in a small, phase 1 study of ten patients with malignant lymphoma. Results from a study of PRMD1 expression in follicular lymphoma might suggest a biological basis for which pan-histone deacetylase inhibitors might have activity in patients with non-functional CREB-binding protein. Investigators found that follicular lymphoma tumours with non-functional CREB-binding protein were unable to upregulate PRDM1 expression, despite a functional capacity to activate IL-21–phosphorylated STAT3 signalling, and pan-histone deacetylase inhibitors restored PRDM1 expression. The bromodomain inhibitor OTX015, another epigenetic modulator, was investigated in a phase 1 study of patients with lymphoma or multiple myeloma; however, the study included only two patients with follicular lymphoma. Among studies identified in our PubMed search that included “EZH2”, two evaluated the prognostic significance of EZH2 mutation status in patients with follicular lymphoma, and the third summarised data from a phase 1 study of tazemetostat in patients with relapsed or refractory B-cell non-Hodgkin lymphoma or advanced solid tumours.

Added value of this study

Treatment options are urgently needed for patients with relapsed or refractory follicular lymphoma. As an epigenetic therapy and a first-in-class EZH2 inhibitor, tazemetostat has a novel mechanism of action for the treatment of follicular lymphoma. Results from this phase 2 study show that tazemetostat can produce clinically meaningful and durable responses and has a favourable safety profile in heavily pretreated patients with follicular lymphoma. These results support the promising anti-tumour activity and favourable tolerability of tazemetostat observed in the phase 1 setting.

Implications of all the available evidence

Other than abexinostat, tazemetostat is the only epigenetic regulator tested in patients with follicular lymphoma with published data. Tazemetostat is unique in that it targets a specific protein (EZH2) rather than epigenetic modification in general (ie, acetylation). Although the observed anti-tumour activity of tazemetostat in patients with relapsed or refractory follicular lymphoma suggests that this drug can be used as a single agent in this patient population, tazemetostat's tolerability makes it an attractive candidate for combination use. Future studies should examine concomitant use of tazemetostat with agents commonly used in the treatment of patients with follicular lymphoma.

Source: The Lancet Oncology