Efficacy and safety of tazemetostat, an EZH2 inhibitor, in Chinese patients with relapsed/refractory follicular lymphoma: a multicentre, single-arm, phase 2 study.

Abstract

Background: Tazemetostat, the first enhancer of zeste homolog 2 (EZH2) inhibitor approved by the U.S. Food and Drug Administration, has shown efficacy in a global population with relapsed or refractory (R/R) follicular lymphoma (FL). This phase 2 study was primarily designed as a registration-intent bridging trial of tazemetostat in Chinese patients with EZH2-mutant (EZH2 ^mut) R/R FL; the study also included evaluation in the EZH2 wild-type (EZH2 ^wt) population.

Methods: This multicentre, single-arm, phase 2 study was conducted at 19 sites in China. Eligible patients (aged ≥18 years) with histologically confirmed grade 1-3a FL were categorised by EZH2 status: mutant (EZH2 ^mut, bridging cohort) and wild-type (EZH2 ^wt), and received oral tazemetostat 800 mg twice daily in continuous 28-day cycles until investigator-assessed disease progression, intolerable toxicity, withdrawal of consent, or other protocol-specified criteria. The EZH2 ^mut cohort primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Efficacy in the EZH2 ^mut cohort was assessed in patients who received at least one dose of tazemetostat and had centrally confirmed FL. Efficacy in the EZH2 ^wt cohort and safety in both cohorts were assessed in all patients who received at least one dose of tazemetostat. This study is registered with ClinicalTrials.gov, NCT05467943.

Findings: Between July 29, 2022, and Aug 31, 2023, 22 patients with EZH2 ^mut R/R FL were enrolled (three lines [3L] of prior therapy, 31.8%; four lines [4L] of prior therapy or more, 27.3%). As of Aug 31, 2024 (median follow-up 14.4 months), IRC-assessed ORR was 63.6% (95% confidence interval [CI], 40.7%-82.8%), clinical benefit rate (CBR) was 90.9% (70.8%-98.9%), median duration of response (DoR) was not reached (18-month DoR rate, 51.6% [18.2%-77.3%]), and median progression-free survival was 15.4 (8.2-not estimable) months. All patients experienced treatment-related adverse events (TRAEs), and 13.6% had grade ≥3 TRAEs; most common TRAEs were haematological toxicities. For the EZH2 ^wt cohort, 20 patients were enrolled (3L, 35.0%; ≥4L, 45.0%). Tazemetostat also demonstrated efficacy benefit and a manageable safety profile in the EZH2 ^wt cohort, with an investigator-assessed ORR of 35.0% (95% CI, 15.4%-59.2%), CBR of 85.0% (62.1%-96.8%), and median DoR of 8.4 (1.9-15.7) months.

Interpretation: These results suggest that tazemetostat has a clinically meaningful efficacy and was well tolerated in Chinese patients with R/R FL. Larger trials are warranted. A multicentre, randomised, phase 3 trial of tazemetostat combined with lenalidomide plus rituximab vs. lenalidomide plus rituximab in patients with R/R FL is ongoing (NCT04224493).

Funding: HUTCHMED.