Clinical trials of tazemetostat

Tazemetostat is approved for the first time for the treatment of epithelioid sarcoma with INI1/SMARB1 loss of function based on the results of a Phase II trial in 62 patients with histologically confirmed locally advanced or metastatic epithelioid sarcoma (ES). Based on clinical results from the Phase I trial, patients with this tumor will need documented loss of INI1 expression, biallelic SMARCB1 alterations, or both. Tazerestat was administered at a dose of 800 mg twice daily until disease progression or unacceptable toxicity. Baseline characteristics showed that the patient population was predominantly ECOG 0 or 1 good status (92%), but the majority had stage IV disease at diagnosis (60%).

Fifteen percent of patients achieved the primary endpoint of objective response, and investigators assessed all patients as having partial responses. Similar to the Phase I trial, the median time to response was 3.9 months; however, the median duration of response was not reached. At 12 months, 21% of patients had progression-free survival, and the median survival was 5.5 months. At the time of data cutoff, 50% of patients had died, and the median overall survival was 19.0 months. While most adverse events in the trial were grade 1 or 2, the most common grade 3 or higher adverse events were anemia (13%), weight loss (6%), pleural effusion (5%), decreased appetite (5%), and cancer pain (5%).

The second approval of tazerestat is for relapsed or refractory (R/R) follicular lymphoma (FL) and relapsed or refractory (R/R) follicular lymphoma (FL) EZH2 mutants based on results from another Phase II trial. There were 99 patients enrolled who received 800 mg twice daily, 45 of whom had EZH2 mutations and 54 who were EZH2 WT. Drugs were administered until disease progression, unacceptable toxicity, or up to 2 years of treatment. After more than 2 years, patients can continue treatment.

In this trial, patients primarily performed well(ECOG 0-1), 100% for EZH2 mutant and 91% for WT. Patients in the EZH2 mutation group had a median of two series of prior anticancer treatments, compared with a median of three series in the WT group, which included at least alkylating agents, anthracyclines, and anti-CD20 drugs. 39% of patients also received PI3K inhibitors or immunomodulators.

The ORR in patients with EZH2 mutations was 69%, while the response rate in the EZH2 WT cohort was 35%. Tumor volume was reduced in 98% of the mutant cohort and 65% of the WT cohort. The median duration of response was numerically shorter in the mutant cohort compared with the WT cohort (10.9 months vs. 13.0 months), although this was not statistically significant. Likewise, the median duration was similar to the Phase I trial: 3.7 months in both groups. 6.7% of EZH2 mutant and 14.8% of WT patients remained on treatment throughout 2 years and were included in the rolling study. The median progression-free survival of the EZH2 mutated and WT cohorts was 13.8 and 11.1 months, respectively. Serious adverse events occurred in 27% of patients, with the most common grade 3 or higher events being anemia (5%), thrombocytopenia (5%), neutropenia (4%), dyspnea (3%), and fatigue (3%).

The original drug of tazerestat is not yet available in the domestic market and is therefore not included in medical insurance. Tazerestat US version of the original drug, specification200mg*240 tablets, which is marketed overseas, may cost around 200,000 yuan per bottle (the price may fluctuate due to exchange rates), which is very expensive. At present, there are no generic drugs of tazerestat produced and launched. For more drug information and specific prices, please consult the medical consultant of the drug.