Tazemetostat Yields Promising Results in Patients With Follicular Lymphoma

Tazemetostat, a first-in-class oral EZH2 inhibitor, yielded clinically meaningful, durable responses and was well tolerated in patients with relapsed or refractory follicular lymphoma, according to the results of a phase 2 trial published in The Lancet Oncology.

EZH2 is an epigenetic regulator that is activated in approximately 20% of patients with follicular lymphoma. Franck Morschhauser, MD, PhD, of Université de Lille in France, and an international team of colleagues investigated the activity and safety of the EZH2 inhibitor tazemetostat in patients with follicular lymphoma in an open-label, single-arm, phase 2 trial at 38 institutions in 9 countries (ClinicalTrials.gov Identifier: NCT01897571).

Eligible adults (99 patients) with relapsed/refractory follicular lymphoma (grade 1-3b; Eastern Cooperative Oncology Group performance status, 0-2) that had been treated with at least 2 systemic therapies were enrolled between July 9, 2015, and May 24, 2019. After tumor tissue was tested for EZH2 mutation status, patients were categorized in mutant (EZH2mut, 45 patients) or wild-type (EZH2WT, 54 patients) groups.

Patients received oral tazemetostat (800 mg) twice daily in continuous 28-day cycles. The primary endpoint was objective response rate as assessed by an independent radiology committee (2007 International Working Group criteria for non-Hodgkin lymphoma). All patients received at least 1 dose of tazemetostat and, thus, were included in the activity and safety analyses.

Patients in the EZH2mut cohort had a median age, 62 years (58% women), and patients in the EZH2WT cohort had a median age of 61 years (37% women). Follow-up is still ongoing; however, at data cutoff (August 9, 2019), the median follow-up duration was 22.0 months for the EZH2mut cohort and 35.9 months for the EZH2WT cohort.

The objective response rate and median duration of response were 69% (95% CI, 53-82) and 10.9 months (7.2-not estimable [NE]) in the EZH2mut cohort and 35% (95% CI, 23-49) and 13.0 months (95% CI, 5.6-NE) EZH2WT cohort, respectively. The best overall responses were 13% complete response (CR), 56% partial response (PR), 29% stable disease (SD) and 2% progressive disease (PD) in the EZH2mut cohort and 4% CR, 31% PR, 33% SD, 22% PD, and 9% unknown/NE in the EZH2WT cohort. The median progression-free survival was 13.8 months (95% CI, 10.7-22.0) in the EZH2mut cohort and 11.1 months (95% CI, 3.7-14.6) in the EZH2WT cohort.

Most patients (81%) experienced treatment-related adverse events (AE; any grade). The most common grade 1-2 treatment-related AEs were nausea (19%), alopecia (14%), asthenia (13%), diarrhea (12%), and fatigue (11%). Grade 3 or worse treatment-related AEs included thrombocytopenia (3%), neutropenia (3%), and anemia (2%). Serious treatment-related AEs occurred in 4 patients (neutropenia, pancytopenia, and transient global amnesia, each in 1 patient; arrhythmia and myelodysplastic syndrome, in 1 patient). No treatment-related deaths occurred.

The study was limited by the nonrandomized, single-arm design and small sample size. The authors also noted that the EZH2WT group had a higher proportion of patients with poor risk features.

“Combination treatment with tazemetostat plus lenalidomide and rituximab will be evaluated in a confirmatory phase 3 study of patients with relapsed or refractory follicular lymphoma ([ClinicalTrials.gov Identifier:] NCT04224493),” wrote the authors. “With its ability to produce clinically meaningful and durable responses, favorable safety profile, and unique mechanism of action, tazemetostat represents a new therapeutic option for patients with follicular lymphoma.”

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.