Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial

Abstract

Background: Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma.

Methods: This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0-2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov, NCT01897571, and follow-up is ongoing.

Findings: Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0-26·7) for the EZH2mut cohort and 35·9 months (24·9-40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53-82; 31 of 45 patients) in the EZH2mut cohort and 35% (23-49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2-not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6-NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7-22·0) and 11·1 months (3·7-14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths.

Interpretation: 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.

Funding: Epizyme.

Conflict of interest statement

Declaration of interests

FM has received honoraria from Bristol Myers Squibb and Janssen, and has served as a consultant or adviser to Celgene, Bayer, Abbvie, Verasteem, Gilead, Servier, Roche-Genentech, and Epizyme. HT has received honoraria from Merck and Servier and has served as a consultant or adviser to Roche-Genentech, Janssen, and Karyopharm. AC has received honoraria from Celgene, Takeda, Gilead, and Janssen. PM has received honoraria and educational support from, and has served on advisory boards for, Takeda, Janssen, Roche, Gilead, Celgene, and Epizyme. TP has received research funding from Pharmacyclics and Abbvie, and has served as a consultant or adviser to Genentech, Gilead, Bayer, Seattle Genetics, and Pharmacyclics. SAs has received honoraria from Roche-Genentech, Janssen, Abbvie, and Gilead. CLB has received research funding from Janssen, Novartis, Epizyme, Xynomics, and Bayer, and has served as a consultant or adviser to Juno-Celgene, Seattle Genetics, and Kite. VR has received research funding from ArgenX, and has served as a consultant or adviser to Gilead, Infinity, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Roche, AstraZeneca, and Servier. GLD has received honoraria and educational support from, and has served on advisory boards for, Takeda, Astellas, Genzyme, Roche, and Abbvie. MD has served as a consultant or adviser to Novartis, Roche, Amgen, Takeda, Merck Sharp & Dohme, Celgene, and Janssen, and has received research funding from Novartis, Roche, Amgen, Takeda, Merck Sharp & Dohme, and Celgene. WJ has served as a consultant or adviser to AstraZeneca, Janssen, Loxo, and Sandoz, and has received research funding from AstraZeneca, Bayer, Celgene, Celtrion, Epizyme, Gilead, Incyte, Janssen, Loxo, Morphosys, Novo Nordisk, Roche, Sandoz, Servier, Takeda, and TG Therapeutics. SO’s institution receives research funding from Abbvie, Amgen, Bristol Myers Squibb, AstraZeneca, Beigene, Celgene, Epizyme, Merck Sharp & Dohme, Pharmacyclics, Janssen-Cilag, and Roche. SO has served as a consultant or adviser to Abbvie, AstraZeneca, CSL, Merck Sharp & Dohme, Roche-Genentech, Janssen-Cilag, Gilead, Mundipharma, Novartis, and Takeda. JR has served as a consultant or adviser to Takeda, Bristol Myers Squibb, Seattle Genetics, and Novartis, owns stock in GlaxoSmithKline and AstraZeneca, has received honoraria from Takeda, and has received research funding from Takeda, Pfizer, ADC Therapeutics, Celgene, and AstraZeneca. JY, JW, DA, and SAg are salaried employees of, and own stock in, Epizyme. GS has served as a consultant or adviser to Abbvie, Amgen, Autolus, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, and Takeda. All other authors declare no competing interests.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. IRC-assessed change in tumour volume from baseline

(A) Patients with EZH2mut follicular lymphoma. (B) Patients with EZH2WT follicular lymphoma. Tumour responses were not estimable, missing, or unknown in five patients in the EZH2WT cohort. Tumour volume was calculated as the sum of the product of perpendicular diameters according to the 2007 International Working Group criteria for non-Hodgkin lymphoma. Dashed red lines represent thresholds for progressive disease (≥50% increase in tumour volume) and partial response (≥50% reduction in tumour volume). The shaded area represents tumour volume changes that correspond to stable disease (<50% increase or decrease in tumour volume). IRC=independent radiology committee.

Figure 2:. IRC-assessed outcomes in the modified intention-to-treat population by EZH2 mutation status

(A) Duration of response. (B) Progression-free survival. (C) Overall survival. The shaded areas represent 95% simultaneous confidence bands. IRC=independent radiology committee. NE=not estimable.