Tazemetostat for advanced epithelioid sarcoma. Current status and future perspectives

Epithelioid sarcoma (ES) is an ultra-rare and aggressive type of soft-tissue sarcoma. From the molecular point of view, >90% of ES patients show a complete absence of INI1/SMARCB1,which is a tumor suppressor belonging to the SWI/SNF complexes. SWI/SNF mediates chromatin remodeling processes that are critical for differentiation and proliferation of the tumor. INI1 loss leads to the activation of EZH2, an enzyme component of PRC2 that drives histone methylation and gene silencing. SWI/SNF and PCR2 work against each other and the loss of INI1 may interfere with this balance. Tazemetostat is a new oral compound able to inhibit EZH2, therefore neutralizing this effect. Tazemetostat has been investigated in a Phase II study and has shown clinical activity in INI1-negative ES in approximately 15% of the patients, with durable responses and an overall tolerable safety profile. Based on these results, the US FDA has approved tazemetostat for adults and pediatric patients aged 16 years and older withmetastatic or locally advanced ES not eligible for complete resection. Several questions still remains open on how to optimize the use of tazemetostat among which the identification of predictors of response, and whether it is possible to increase its activity by combining this with other drugs like doxorubicin and immunotherapeutic agents.