As reported in The Lancet Oncology by Mrinal Gounder, MD, and colleagues, findings in a cohort of a phase II basket trial showed that the oral EZH2 inhibitor tazemetostat produced durable responses in some patients with advanced epithelioid sarcoma with loss of INI1 or SMARCB1 (the gene encoding INI1). 

As stated by the authors, “Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumors have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2.”  

Mrinal Gounder, MD

Study Details

The international study has enrolled patients into seven cohorts with different INI1-negative solid tumors or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort had locally advanced or metastatic disease with documented loss of INI1 expression by immunohistochemical analysis, biallelic SMARCB1 alterations, or both.

Patients received tazemetostat at 800 mg twice daily continuously in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate on Response Evaluation Criteria in Solid Tumors version 1.1.

Responses

A total of 62 patients who received at least one dose of tazemetostat were included in the modified intent-to-treat analysis. Previous anticancer therapy included surgery in 77%, radiotherapy in 56%, and systemic therapy in 61%.

Objective responses (all partial responses) were observed in nine patients (15%). The response rate was the same on independent radiology review committee assessment, with one patient considered to have had a complete response.

At median follow-up of 13.8 months, median duration of response was not reached (95% confidence interval [CI] = 9.2 months­–not estimable). The patient deemed to have a complete response on independent review had a response duration of 24.4 months and ongoing at data cutoff. The disease control rate at 32 weeks was 26%. Median time to response was 3.9 months. Median progression-free survival was 5.5 months (95% CI = 3.4–5.9 months) and median overall survival was 19.0 months (95% CI = 11.0 months–not estimable).

Adverse Events

The most common grade 3 or 4 adverse events were anemia (13%), weight loss (6%), pleural effusion (5%), decreased appetite (5%), and cancer pain (5%). Serious adverse events occurred in 40% of patients, with the most common being pleural effusion (6%), hemoptysis (6%), dyspnea (5%), cellulitis (3%), and cancer pain (3%). No treatment-related deaths were observed.  

The investigators concluded, “Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterized by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A … trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941).”

Dr. Gounder, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Epizyme. For full disclosures of the study authors, visit thelancet.com.