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Micrograph showing DLBCL

The EZH2 inhibitor tazemetostat demonstrated a “favorable safety profile and antitumor activity” in a phase 1 study, according to researchers.

The drug produced responses in 8 of 21 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including 3 complete responses (CRs).

The maximum tolerated dose of tazemetostat was not reached, and there were no fatal adverse events (AEs) related to treatment.

Grade 3/4 treatment-related AEs included thrombocytopenia, neutropenia, hepatocellular injury, and hypertension.

Antoine Italiano, MD, PhD, of Institut Bergonié in Bordeaux, France, and his colleagues reported these results in The Lancet Oncology. The trial was sponsored by Epizyme and Eisai.

The study enrolled 64 patients—43 with solid tumors and 21 with B-cell NHL. The following characteristics and dosing information pertain only to the patients with NHL.

Thirteen patients had diffuse large B-cell lymphoma (DLBCL), 7 had follicular lymphoma (FL), and 1 had marginal zone lymphoma (MZL).

The patients’ median age was 62 (range, 53-70), and 71% were male. They had an ECOG performance status of 0 (62%) or 1 (38%).

Most patients had received at least 3 prior therapies—38% had 3, 14% had 4, and 33% had 5 or more prior therapies. Forty-eight percent had prior hematopoietic stem cell transplant.

The patients received escalating doses of tazemetostat twice daily—100 mg (n=1), 200 mg (n=2), 400 mg (n=1), 800 mg (n=8), and 1600 mg (n=4).

The remaining 5 patients were enrolled in a substudy to evaluate food effect. These patients received a single 200 mg dose on day -8 and day -1, with or without food, followed by 400 mg twice daily starting on day 1. Specific results on the food effects were not included in the paper.


In the entire study cohort, there was 1 dose-limiting toxicity—grade 4 thrombocytopenia—at the 1600 mg dose. The maximum tolerated dose of tazemetostat was not reached, but the researchers decided upon 800 mg twice daily as the recommended phase 2 dose.

Overall, 77% (n=49) of patients had treatment-related AEs. Grade 3/4 treatment-related AEs included thrombocytopenia (4%, n=2), neutropenia (4%, n=2), hepatocellular injury (2%, n=1), and hypertension (2%, n=1).

Serious treatment-related AEs were neutropenia in 1 patient (800 mg group) and anemia and thrombocytopenia in another patient (1600 mg group).

Seven patients (11%) had fatal AEs, but none were considered treatment-related. They included general physical health deterioration (1 at 200 mg, 1 at 1600 mg, and 2 at 400 mg), respiratory distress (2 at 400 mg), and septic shock (1 at 1600 mg).


Eight of the 21 NHL patients responded to treatment. Three patients had a CR—1 with DLBCL and 2 with FL. Of the 5 partial responders, 3 had DLBCL, 1 had FL, and 1 had MZL.

The median time to first response was 3.5 months, and the median duration of response was 12.4 months.

The 3 complete responders remained on tazemetostat beyond 27.6 months (FL patient), 28.8 months (FL patient), and 33.6 months (DLBCL patient).

Two of the 43 patients with solid tumors responded to tazemetostat—1 with a CR and 1 with a partial response.

The complete responder had an INI1-negative malignant rhabdoid tumor, and the partial responder had a SMARCA4-negative malignant rhabdoid tumor of the ovary.

“Today’s publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” Dr Italiano said. “I’m also encouraged by the preliminary antitumor activity observed in this study.”

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