epz-6438 and Lymphoma--Follicular

Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor recommended for patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type or mutant EZH2. The phosphoinositide 3-kinase (PI3K) inhibitors idelalisib, copanlisib, umbralisib and (formerly) duvelisib are indicated for third-line, fourth-line, and later (3L/4L+) treatment of R/R FL. The objective of this analysis was to provide an indirect treatment comparison of tazemetostat with each PI3K inhibitor for 3L/4L+ R/R FL treatment.. A systematic literature review was conducted to identify trials for idelalisib (DELTA), duvelisib (DYNAMO), copanlisib (CHRONOS-1 Part B), and umbralisib (UNITY-NHL) in 3L+ R/R FL. Matching-adjusted indirect comparisons were conducted by weighting tazemetostat individual patient data with available baseline characteristics from each comparator trial: age, Eastern Cooperative Oncology Group performance status, disease stage, histology, prior treatment lines, prior stem cell therapy, progression within 24 months, and refractory status to last therapy. Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Primary safety outcomes included risk of grade ≥ 3 treatment-emergent adverse events (TEAEs); primary efficacy outcomes included objective response rate (ORR).. Matched patients treated with tazemetostat had lower relative risk (RR) for all grouped safety outcomes, including any grade ≥ 3 TEAEs, compared with idelalisib (RR = 0.45), duvelisib (RR = 0.35), copanlisib (RR = 0.37), and umbralisib (RR = 0.65; all, p < 0.01), any serious TEAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. The ORR was not significantly different for tazemetostat versus other treatments (idelalisib 43% vs 56%, p = 0.16; duvelisib 48% vs 47%, p = 0.91; copanlisib 49% vs 61%, p = 0.11; and umbralisib 57% vs 47%, p = 0.10).. In this statistically adjusted comparison, tazemetostat was associated with lower RR for safety outcomes versus idelalisib, duvelisib, copanlisib, and umbralisib, while achieving similar efficacy outcomes.

Topics: Benzamides; Biphenyl Compounds; Child, Preschool; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Lymphoma, Follicular; Morpholines; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Purines; Pyridones; Pyrimidines; Quinazolines; Quinazolinones; Risk

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Genetic Testing; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy, Adoptive; Lenalidomide; Lymphoma, Follicular; Maintenance Chemotherapy; Morpholines; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Prednisone; Pyridones; Rituximab; Sulfonamides; Vincristine

Follicular lymphoma is a common indolent non-Hodgkin lymphoma with survival improving in the modern era. Despite favorable responses and improving remission duration, FL remains largely incurable with patterns of relapsing and remitting disease with many patients requiring multiple lines of therapy. As our understanding of the malignant B-cell biology evolves, more targeted therapies have emerged for the treatment of follicular lymphoma.. Targeted therapies entering the treatment landscape of follicular lymphoma include lenalidomide in combination with rituximab based on the randomized AUGMENT. Tazemetostat, an EZH2 inhibitor, joins the list of targeted therapies approved based on single-arm phase 2 studies in the relapsed setting. There are three PI3K inhibitors currently approved and more under development. Herein, I will review the available evidence that supports the use of targeted therapy across the disease course of follicular lymphoma.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biphenyl Compounds; Enhancer of Zeste Homolog 2 Protein; Humans; Lenalidomide; Lymphoma, Follicular; Molecular Targeted Therapy; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Pyridones; Rituximab

Enhancer of Zeste Homolog 2 (EZH2) is histone methyltransferase and catalyzes the methylation of histone 3 lysine 27, a mark of transcriptional repression. Various studies have elucidated the complex role of EZH2 in both normal biology and tumorigenesis. Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.. Activating mutations and overexpression of EZH2 are found in non-Hodgkin lymphoma (NHL). As a result, several EZH2 inhibitors have been developed and entered clinical investigation. Tazemetostat, first-in-class EZH2 inhibitor, demonstrated enhanced clinical activity in mutant follicular lymphoma and diffuse large B cell lymphoma. With the early activity noted by tazemetostat in B cell lymphomas, the role of EZH2 inhibition in NHL is becoming more evident. This can be leveraged in future rationale combinations to enhance the activity of EZH2 inhibitors.

Topics: Animals; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Morpholines; Neoplasm Proteins; Pyridones

In the tazemetostat E7438-G000-101 trial of relapsed/refractory (R/R) follicular lymphoma (FL), apparent superior efficacy was suggested for mutant-type (MT). Propensity scores for each participant with WT (. The propensity-matched sample included 56 participants (28 WT, 28 MT). Objective response rates (95% confidence interval [CI]) were 35% (22-48) in WT and 69% (55-83) in MT prior to matching and 50% (31-69) in WT and 71% (54-88) in MT after matching. Median progression-free survival values (95% CI) were 11.1 (5.4-16.7) in WT and 13.8 months (11.1-22.1) in MT prior to matching and 14.3 (11.1-∞]) and 14.8 months (10.7-∞]) in WT and MT matched groups, respectively.

Topics: Benzamides; Biphenyl Compounds; Humans; Lymphoma, Follicular; Morpholines; Propensity Score; Pyridones

Tazemetostat is a selective, reversible, small-molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open-label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28-day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B-cell lymphoma). At data cut-off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression-free survival (PFS) was not reached at the median follow-up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment-emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment-emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation-positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation-positive FL.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Cohort Studies; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Japan; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Morpholines; Mutation; Progression-Free Survival; Pyridones; Recurrence

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.. 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 (EZH2. Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2. 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.. Epizyme.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biphenyl Compounds; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Lymphoma, Follicular; Male; Middle Aged; Morpholines; Mutation; Neoplasm Recurrence, Local; Progression-Free Survival; Pyridones; Treatment Outcome

Follicular lymphoma (FL) is the second most common form of B cell lymphoma and generally presents as an indolent and relatively slow-growing tumor. However, most FLs are incurable with a shortening of subsequent responses. Therefore, novel and more effective treatments are desperately needed. Tazemetostat is a first-in-class, selective, oral inhibitor of EZH2, a lysine methyltransferase that is mutated in about 25% of FL. Tazemetostat has been recently approved for relapsed/refractory FL after two or more lines of therapy in the presence of an EZH2 mutation or independent of an EZH2 mutation in the absence of other options.. Here, the authors provide a review focusing on the molecular mechanisms of EZH2, clinical development of tazemetostat and other EZH2 inhibitors (EZH2i), as single-agent therapy and in combinatorial regimens. Finally, they provide a futuristic look at therapeutic approaches for this disease.. Tazemetostat monotherapy showed clinically meaningful and durable responses with a favorable toxicity profile, especially in EZH2 mutant lymphoma. Future studies should explore mechanism-based combinatorial regimens to maximize and prolong the anti-lymphoma effect.

Topics: Benzamides; Biphenyl Compounds; Enhancer of Zeste Homolog 2 Protein; Humans; Lymphoma, Follicular; Morpholines; Pyridones

Epigenetic alterations are major drivers of follicular lymphomagenesis, and these alterations are frequently caused by mutations in or upregulation of. Lay abstract Follicular lymphoma (FL) is a subtype of B-cell cancer. Initial prognosis of this disease is favorable as first-line treatments provide responses lasting 10 years on average. However, most patients will experience relapse and subsequent treatments are not as efficient nor as well tolerated as the first ones. An important driver of FL is a gene called

Topics: Benzamides; Biphenyl Compounds; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Humans; Lymphoma, Follicular; Maximum Tolerated Dose; Morpholines; Mutation; Neoplasm Recurrence, Local; Prognosis; Pyridones; Salvage Therapy; Survival Rate

Topics: Benzamides; Biphenyl Compounds; Enhancer of Zeste Homolog 2 Protein; Humans; Lymphoma, Follicular; Morpholines; Pyridones; Sarcoma

Topics: Adult; Benzamides; Biphenyl Compounds; Humans; Lymphoma, Follicular; Morpholines; Pyridones

In patients with follicular lymphoma, the prolonged clinical course consisting of multiple relapses is a fundamental challenge that requires clinicians to consider how to best balance treatment efficacy while minimizing toxicity and preserving quality of life. The treatment approaches and decisions regarding therapy are largely driven by the unique clinical features evident in each patient. The traditional treatment approaches for relapsed follicular lymphoma include chemoimmunotherapy regimens, targeted agents, radioimmunotherapy, and, occasionally, immunotherapy alone. The primary targeted agents used in the relapsed or refractory follicular lymphoma setting are the phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib, copanlisib, and duvelisib. PI3K inhibitors can have a significant toxicity profile. Radioimmunotherapy remains an underutilized option. The newest agent that has gained regulatory approval in the treatment of follicular lymphoma is tazemetostat, a methyltransferase inhibitor that inhibits and reduces the activity of EZH2. In June 2020, tazemetostat was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma who have tumors that are positive for an

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biphenyl Compounds; Disease Management; Drug Discovery; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Humans; Lymphoma, Follicular; Morpholines; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyridones