epz-6438 and Lymphoma--Large-B-Cell--Diffuse

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B-cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a "one-size-fits-all" approach in DLBCL.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biphenyl Compounds; Cyclophosphamide; Doxorubicin; Enhancer of Zeste Homolog 2 Protein; Etoposide; Gene Expression Profiling; Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Mediastinal Neoplasms; Molecular Diagnostic Techniques; Morpholines; Mutation; Prednisone; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; Pyridones; Receptors, Chimeric Antigen; Risk; Rituximab; Translocation, Genetic; Vincristine

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

The combination of atezolizumab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, and tazemetostat, an EZH2 inhibitor, may lead to selective epigenetic reprogramming, alter the tumor microenvironment, and provide additive or synergistic response to patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).. This was an open-label, phase Ib study assessing the safety, tolerability, and preliminary efficacy of atezolizumab plustazemetostat in patients with R/R DLBCL. Atezolizumab (1200 mg) was administered via intravenous (IV) infusion on day 1 of each cycle and tazemetostat (800 mg) was given orally twice daily (BID) on days 1 to 21. Primary endpoints were safety and tolerability, and to identify a recommended phase II dose (RP2D) for atezolizumab. Secondary efficacy endpoints included response rate and duration of response.. A total of 43 patients were enrolled, receiving a median of 3 prior lines of treatment (range: 1-9). The RP2D for atezolizumab was 1200 mg IV infusion every 3 weeks in combination with tazemetostat 800 mg BID. At the RP2D, adverse events reported in ≥20% patients were anemia(11 patients [26%]), fatigue (10 patients [23%]), and nausea (10 patients [23%]). Overall response rate was 16% (complete response rate: 7%). Median progression-free survival was 2 months (range: 0-24) and median overall survival was 13 months (range: 1-29).. The combination of atezolizumab and tazemetostat was determined to be safe and tolerable. However, anti-tumor activity of the combination was modest.

Topics: Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Benzamides; Biphenyl Compounds; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Morpholines; Pyridones; Tumor Microenvironment

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

The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma.. The primary objective of this dose-escalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat.. A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and C. The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Biphenyl Compounds; Cyclophosphamide; Doxorubicin; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Morpholines; Neoplasm Grading; Neoplasm Staging; Prednisone; Prognosis; Pyridones; Retreatment; Rituximab; Treatment Outcome; Vincristine

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

Topics: Benzamides; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Homeostasis; Humans; Iron; Lymphoma, Large B-Cell, Diffuse; Receptors, Transferrin

An inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2), tazemetostat, has been developed for the treatment of B-cell lymphoma, but its mechanisms of action are not fully elucidated. We screened for genes targeted by tazemetostat in eleven B-cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C-C motif) ligand 17 (CCL17)/thymus- and activation-regulated chemokine (TARC) in all, which codes for a chemokine that is a hallmark of Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin lymphoma. Notably, gene set enrichment analysis demonstrated a positive correlation between the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and those reported to be overexpressed in H/RS cells. The CCL17 promoter region was enriched in repressive histone modification H3K27me3, and tazemetostat induced H3K27 demethylation and activated gene transcription. CCL17 protein secretion was also induced by EZH2 inhibition, which was further enhanced by concurrent CpG stimulation. In vitro transwell migration assay demonstrated that CCL17 produced by tazemetostat-treated B cells enhanced the recruitment of T cells, which had the potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with the EZH2 activation signature and significantly paralleled the CD4

Topics: Benzamides; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Chemokine CCL17; Databases, Factual; Enhancer of Zeste Homolog 2 Protein; Humans; Jumonji Domain-Containing Histone Demethylases; Lymphocytes, Tumor-Infiltrating; Lymphoma, Large B-Cell, Diffuse; Morpholines; Promoter Regions, Genetic; Pyridones; Reed-Sternberg Cells; Tumor Microenvironment; Up-Regulation

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Crystallography, X-Ray; Dogs; Female; Haplorhini; Histones; Humans; Lymphoma, Large B-Cell, Diffuse; Lysine; Male; Methylation; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Polycomb Repressive Complex 2; Rats; Sulfones; Triazoles