Safety profile of EZH2 inhibitors for cancer: a systematic review and meta-analysis.

Objective: To evaluate the safety profiles of EZH2-targeted inhibitors in cancer treatment, focusing on treatment-related adverse events (TRAEs) across various clinical trials.

Methods: We conducted a systematic review and meta-analysis using data from clinical trials involving EZH2 inhibitors reported up to May 31, 2024. Databases searched included PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov. Studies included were those involving patients treated with EZH2 inhibitors as monotherapy or in combination, specifically detailing the incidence of TRAEs. Data on all-grade TRAEs, grade 3 or higher TRAEs, and severe TRAEs were extracted and analyzed using random-effects models.

Results: Our systematic review and meta-analysis included 22 studies encompassing 1,002 patients who met the inclusion criteria. TRAEs were commonly observed during EZH2 inhibitor therapy, affecting 86% of patients (95% CI [79-94%]%; I = 89.5%). The incidence of grade 3 or higher TRAEs was 33% (95% CI [21-44%]; I = 93.5%), while severe TRAEs occurred in 15% of the cases (95% CI [9-22%]; I = 87.5%). The most frequently reported grade 3 or higher TRAEs in the pooled analysis were neutropenia (8%), thrombocytopenia (8%), and anemia (6%). Specifically, for tazemetostat, the most common grade 3 or higher TRAE was neutropenia (5%). For SHR2554, the most prevalent grade 3 or higher TRAEs were thrombocytopenia (17%), neutropenia (8%), and anemia (7%). Notably, treatment-related fatalities were rare, with only 0.9% of patients experiencing potentially fatal outcomes due to therapy.

Conclusion: EZH2 inhibitors demonstrate a manageable safety profile with a low incidence of severe TRAEs, emphasizing their potential as safe therapeutic options in cancer treatment. The low rate of severe TRAEs and the rare occurrences of treatment-related deaths support the continued clinical use and further investigation of EZH2 inhibitors.