Tazemetostat for advanced epithelioid sarcoma: current status and future perspectives

Epithelioid sarcoma (ES) is an aggressive ultra-rare soft-tissue sarcoma marked by SMARCB1/INI1 deficiency. SMARCB1/INI1 deficiency leads to elevated expression of EZH2, a component of polycomb repressive complex 2, which mediates gene silencing by catalyzing H3K27me3. Tazemetostat is an oral, SAM-competitive inhibitor of EZH2, whose blockade prevents the methylation of histone H3K27, thus decreasing the growth of EZH2 mutated or over-expressing cancer cells. Tazemetostat has been approved for treatment of patients aged 16 years and older with metastatic or advanced ES not eligible for complete resection, based on the positive results of a single-arm Phase II basket study. Tazemetostat though represents a new treatment option for ES patients, although clinical/molecular predictors of response are still to be identified. The combination of tazemetostat with other drugs like doxorubicin and immunotherapeutic agents is currently under investigation in ES patients. Lay abstract 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 with metastatic 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.

Automated summary

Epithelioid sarcoma is a rare and aggressive soft tissue sarcoma marked by SMARCB1/INI1 deficiency. Tazemetostat, an oral inhibitor of EZH2, has shown clinical activity in ES patients with INI1-negative tumors, but there is still a need for further research to identify predictors of response and potential combination therapies.