Franck Morschhauser1, Hervé Tilly2, Aristeidis Chaidos3, Pamela McKay4, Tycel Phillips5, Sarit Assouline6, Connie Lee Batlevi7, Phillip Campbell8, Vincent Ribrag9, Gandhi Laurent Damaj10, Michael Dickinson11, Wojciech Jurczak12, Maciej Kazmierczak13, Stephen Opat14, John Radford15, Anna Schmitt16, Jay Yang17, Jennifer Whalen17, Shefali Agarwal17, Deyaa Adib17, Gilles Salles18. 1. Groupe de Recherche sur les formes Injectables et les Technologies Associées, CHU de Lille, Université de Lille, Lille, France. Electronic address: franck.morschhauser@chru-lille.fr. 2. Department of Hematology and INSERM U1245, Centre Henri Becquerel and Rouen University, Rouen, France. 3. Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital & Imperial College Healthcare NHS Trust, London, UK. 4. Department of Hematology, Beatson West of Scotland Cancer Centre, Glasgow, UK. 5. Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA. 6. Division of Hematology, Jewish General Hospital, Montreal, QC, Canada; Department of Oncology, McGill University, Montreal, QC, Canada. 7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8. Department of Clinical Haematology, Barwon Health, University Hospital Geelong, Geelong, VIC, Australia. 9. Hematology Department, Gustave Roussy, Villejuif, France. 10. Hematology Institute, Hematologie Clinique, University Hospital School of Medicine, Caen, France. 11. Department of Clinical Haematology, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. 12. Department of Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, Poland. 13. Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, Poznań, Poland. 14. Haematology Department, Monash University, Melbourne, VIC, Australia. 15. Department of Medical Oncology, University of Manchester, Manchester, UK; NIHR Manchester Clinical Research Facility, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK. 16. Department of Hematology, Institut Bergonié, Bordeaux, France. 17. Clinical Development, Epizyme, Cambridge, MA, USA. 18. Department of Hematology, Lyon-Sud Hospital, University of Lyon, Pierre-Bénite, France.
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.
RCT Entities:
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.
Authors: Diana Martinez-Baquero; Ali Sakhdari; Huan Mo; Do Hwan Kim; Rashmi Kanagal-Shamanna; Shaoying Li; Ken H Young; Dennis P O'Malley; Ahmet Dogan; Preetesh Jain; Michael L Wang; Timothy J McDonnell; Roberto N Miranda; Francisco Vega; L Jeffrey Medeiros; Chi Young Ok Journal: Mod Pathol Date: 2021-08-10 Impact factor: 7.842