In a phase II trial reported in The Lancet Oncology, Franck Morschhauser, MD, and colleagues found that the oral EZH2 inhibitor tazemetostat produced durable responses in patients with relapsed or refractory follicular lymphoma with or without an EZH2 mutation.

As noted by the investigators, “Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma.”

Franck Morschhauser, MD

Study Details

In the international trial, 99 patients were enrolled between July 2015 and May 2019 into cohorts categorized by EZH2 mutation (EZH2mut cohort, n = 45) and wild-type EZH2 (EZH2WT cohort, n = 54). Patients had grade 1, 2, 3a, or 3b disease that had relapsed or was refractory to two or more systemic therapies.

Patients received tazemetostat at 800 mg twice daily continuously in 28-day cycles. The primary endpoint was objective response rate, based on the 2007 International Working Group criteria for non-Hodgkin lymphoma as assessed by an independent radiology committee.

Responses

At data cutoff in August 2019, the median follow-up was 22.0 months in the EZH2mut cohort and 35.9 months in the EZH2WT cohort. An objective response was observed in 31 (69%) of 45 patients in the EZH2mut cohort, including a complete response in 6 patients (13%), and 19 (35%) of 54 patients in the EZH2WT cohort, including a complete response in 2 (4%).

The median duration of response was 10.9 months (95% confidence interval [CI] = 7.2 months–not estimable) in the EZH2mut cohort and 13.0 months (95% CI = 5.6 months–not estimable) in the EZH2WT cohort. Among responders in the EZH2mut cohort, 19 (61%) had response lasting ≥ 6 months, 7 (23%) for ≥ 12 months, and 6 (19%) for ≥ 18 months. Of responders in the EZH2WT cohort, 10 (53%) had response lasting ≥ 6 months, 7 (37%) for ≥ 12 months, and 4 (21%) for ≥ 18 months.

Median progression-free survival in the two cohorts was 13.8 months (95% CI = 10.7–22.0 months) and 11.1 months (95% CI = 3.7–14.6 months). Median overall survival was not reached in either cohort.

Adverse Events

Treatment-related adverse events occurred in 81% of patients, with those of grade ≥ 3 including thrombocytopenia (3%), neutropenia (3%), and anemia (2%). Serious adverse events occurred in 27%, with the most common being sepsis, general physical health deterioration, and anemia (2 patients each [2%]). Serious adverse events were considered treatment-related in four patients (4%) and consisted of neutropenia, pancytopenia, and transient global amnesia in one patient each, and arrhythmia and myelodysplastic syndrome in one patient. No treatment-related deaths were observed.

The investigators concluded, “Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma.”

Dr. Morschhauser, of CHU de Lille, Université de Lille, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Epizyme. For full disclosures of the study authors, visit thelancet.com.