Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Autor: Gilles Salles, Lanie Happ, Neil R Michaud, Christopher Yasso, Sandeep S. Dave, Connie Lee Batlevi, Tycel Phillips, Franck Morschhauser, Jay Yang, Deyaa Adib
Rok vydání: 2021
Předmět:
Zdroj: Blood. 138:1183-1183
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2021-151452
Popis: Background: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator implicated as a genetic driver in multiple lymphoma types. Approximately 20% of patients with follicular lymphoma (FL) present with activating, gain-of-function (GoF) EZH2 mutations. The results of a phase 2 clinical trial of the first-in-class oral EZH2 inhibitor tazemetostat demonstrated clinically meaningful response in patients with relapsed/refractory (R/R) FL in wild-type (WT) and mutant (MT) EZH2 who were treated with single-agent tazemetostat. Tazemetostat is approved by the US Food and Drug Administration for treatment of patients with R/R FL. Beyond EZH2, the biologic drivers of response to tazemetostat remain unknown. To better understand the drivers of tazemetostat response, we performed DNA and RNA sequencing of archival tumor biopsy and cell-free DNA samples to determine the landscape of genetic mutations, copy number variations, and gene-expression profiles in trial patients. Methods: The clinical activity of tazemetostat was evaluated in an open-label, multicenter study (NCT01897571). Patients with MT or WT EZH2 R/R FL received oral tazemetostat 800 mg twice daily, and measures of clinical response, including objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS), were determined. Molecular characterization of archival formalin-fixed, paraffin-embedded tumor biopsies was performed by generating whole-exome sequencing and transcriptome sequencing from 88 patients enrolled in the original study (MT EZH2, n=34; WT EZH2, n=54). In addition, higher-depth targeted DNA sequencing (tumor biopsies, 1500×; circulating tumor DNA [ctDNA], 20,000×) of tumor biopsy samples and ctDNA isolated from serum at baseline (cycle 1 day 1, predose) was conducted for a panel of 62 genes known to be mutated in >5% of FL or diffuse large B-cell lymphoma cases. These molecular data were compared to clinical outcomes, including ORR, PFS, and OS, to investigate drivers of response to tazemetostat. Results: We identified 29 driver genes mutated in the patient cohort at a frequency of ≥8% of patients and found differences in the overall profile of driver gene mutations between MT and WT EZH2 cohorts, including MYD88, GNA13, and chromatin regulators EP300 and KMT2D (all P Conclusions: This molecular analysis of tumor biopsy and ctDNA samples from patients with R/R FL treated with the EZH2 inhibitor tazemetostat indicates that patients with MT or WT EZH2 activate several distinct genetic drivers. These results have implications for understanding the underlying disease biology and development of new treatments such as tazemetostat. In addition, mutations in several genes influence PFS and/or OS associated with tazemetostat, as do specific immune cell populations in the tumor microenvironment. Taken together, these data generate novel hypotheses for the biologic factors driving response to tazemetostat in patients with FL. Disclosures Dave: Data Driven Bioscience: Current equity holder in publicly-traded company. Happ: Duke University: Ended employment in the past 24 months; Data Driven Bioscience: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Yasso: Epizyme, Inc.: Current Employment, Current holder of stock options in a privately-held company. Salles: Incyte: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria; Regeneron: Consultancy, Honoraria; Takeda: Consultancy; Velosbio: Consultancy; Allogene: Consultancy; Rapt: Consultancy; Beigene: Consultancy; Morphosys: Consultancy, Honoraria; Miltneiy: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Janssen: Consultancy; Ipsen: Consultancy; Genentech/Roche: Consultancy. Batlevi: Roche/Genentech: Research Funding; Medscape: Honoraria; Janssen: Research Funding; Viatris: Current holder of individual stocks in a privately-held company; Xynomic: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; GLG Pharma: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Bayer: Research Funding; TouchIME: Honoraria; Dava Oncology: Honoraria; ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; Epizyme: Research Funding; Autolus: Research Funding. Phillips: Bayer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. Adib: Epizyme, Inc.: Consultancy. Michaud: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; AstraZeneca LLC: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Patents & Royalties: US 7,498,420 , US 8,821,869, US 8,207,306 , US 8,569,459 ; Pfizer: Patents & Royalties: US 7,498,420 , US 8,821,869, US 8,207,306 , US 8,569,459 . Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.
Databáze: OpenAIRE
Externí odkaz: