EZH2 inhibition by tazemetostat: mechanisms of action, safety and efficacy in relapsed/refractory follicular lymphoma

Epigenetic alterations are major drivers of follicular lymphomagenesis, and these alterations are frequently caused by mutations in or upregulation of EZH2, a histone methyltransferase responsible for PRC2-mediated gene repression. EZH2 hyperactivation increases proliferation of B cells and prevents them from exiting the germinal center, favoring lymphomagenesis. The first FDA-approved EZH2 inhibitor is tazemetostat, which is orally available and targets both mutant and wild-type forms of the protein to induce cell cycle arrest and apoptosis of lymphoma cells in preclinical models. Phase II trials have shown objective response rates of 69% for patients with lymphoma-carrying EZH2 mutations and 35% for those with wild-type EZH2 without major toxicity, leading to tazemetostat approval for this cancer by the US FDA in June 2020.Lay abstract Follicular lymphoma (FL) is a subtype of B-cell cancer. Initial prognosis of this disease is favorable as first-line treatments provide responses lasting 10 years on average. However, most patients will experience relapse and subsequent treatments are not as efficient nor as well tolerated as the first ones. An important driver of FL is a gene called EZH2 that makes B cells proliferate, either because of mutations that increase its activity or because of a net increase in its concentration in lymphoma cells. Tazemetostat is a drug that was designed to inhibit EZH2 protein and thus lymphoma cell growth. Phase I and II studies have been completed for this drug showing a good safety profile. In Phase II, reponses were seen in 69% of patients who have the EZH2 mutations and 35% of the other patients. The US FDA has approved tazemetostat for patients with FL who have had at least two previous treatments and harbor the EZH2 mutations, or for patients with FL who have no other therapeutic options. However, the drug has not yet been approved in Europe. Randomized trials and long-term follow-up will be of interest to make sure this drug is efficient and safe enough to be given to patients in earlier lines of treatment or in combination with other active agents used to treat patients with FL.