Abstract
Tazemetostat has antitumor activity in B-cell non-Hodgkin lymphoma and advanced solid tumors.
Major finding: Tazemetostat has antitumor activity in B-cell non-Hodgkin lymphoma and advanced solid tumors.
Approach: A first-in-human, open-label, phase I trial determined the recommended phase II dose of tazemetostat.
Impact: Tazemetostat may be beneficial in patients with non-Hodgkin lymphoma and INI1− or SMARCA4− tumors.
EZH2, the catalytic subunit of the chromatin remodeling polycomb repressive complex 2 (PRC2), catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to repress transcription. Gain-of-function mutations in EZH2 occur frequently in lymphoma. The SWI/SNF complex opposes EZH2 function, and loss of the SWI/SNF components INI1 or SMARCA4 has also been linked to tumorigenesis. In preclinical studies, the potent selective EZH2 inhibitor tazemetostat has demonstrated antitumor activity in EZH2-mutant B-cell non-Hodgkin lymphoma, INI1-negative malignant rhabdoid tumors, and SMARCA4-negative malignant rhabdoid tumor of the ovary. Based on these preclinical findings, Italiano and colleagues evaluated the safety and efficacy of tazemetostat in a first-in-human, open-label phase I dose-escalation study of 64 patients, 21 with relapsed or refractory B-cell non-Hodgkin lymphoma and 43 with advanced solid tumors. The primary endpoint was to determine the maximum tolerated or recommended phase II dose of tazemetostat. Secondary endpoints included tazemetostat safety and tolerability, and preliminary antitumor activity. Tazemetostat was well tolerated, with 36% of patients experiencing grade 3–4 adverse events. The maximum tolerated dose was not reached, and the recommended phase II dose was determined to be 800 mg twice daily. Overall, 8 of 21 patients (38%) with B-cell non-Hodgkin lymphoma achieved objective responses, including 3 complete responses. Objective tumor responses were observed only in solid tumor patients with INI1- or SMARCA4-negative tumors. Overall, 5 of 13 patients with IN1- or SMARCA4-negative tumors experienced clinical benefit, consisting of objective responses in 2 patients and prolonged stable disease in 3 patients. Taken together, these findings suggest that EZH2 inhibition with tazemetostat is well tolerated and produces antitumor activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumors. Further clinical investigation is under way in phase II studies, and a phase I study for pediatric patients.
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