Wild-type Enhancer Of Zeste Homolog 2 Research Articles

Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Updated Phase 1b Results of Symphony-1 with 22.5 Months Follow-up

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies, or patients with R/R FL who have no satisfactory alternative treatment options. We previously reported the efficacy and safety of TAZ in combination with lenalidomide and rituximab (R 2) in patients with R/R FL from the SYMPHONY-1 study (EZH-302; NCT04224493) after complete enrollment and following the phase 1b safety run-in period. Here, we report the updated efficacy and safety results after a median follow-up of 22.5 months. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2. After the initial 12 months of combination therapy, tazemetostat 800 mg BID was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoints of the phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). Secondary endpoints included pharmacokinetic (PK) parameters. Efficacy analysis was performed on the intent-to-treat (ITT) population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of July 10, 2023, 44 patients were enrolled and receiving TAZ + R 2 (400 [n=6], 600 [n=19], or 800 mg [n=19]). Median age was 67 years, 31.8% of patients had received >1 prior therapy, and patients had a median of 1 prior line of therapy (range, 1-4). Overall, 81.8% (n=36) of patients had wild-type (WT) EZH2 FL, 34.1% (n=15) of patients had rituximab-refractory disease, and 27.3% (n=12) of patients had POD24. Median durations of treatment exposure for TAZ, lenalidomide, and rituximab were 13.3, 10.8, and 4.6 months, respectively. In the 800-mg cohort, the median relative dose intensity was 94.1%, 92.9%, and 100% for TAZ, lenalidomide, and rituximab, respectively. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The most common grade 3-4 TEAE was neutropenia (40.9%; n=18). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (70.5%), followed by dose reduction (38.6%) and treatment discontinuation (20.5%); protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for neutropenia and thrombocytopenia. Of the 44 patients, 42 patients were evaluable for tumor assessment and 2 patients had no postdose tumor assessments. Of 42 patients evaluable for tumor assessment, 23 (54.8%) had a complete response, 17 (40.5%) had a partial response, and 2 (4.8%) had stable disease. The ORR in the ITT population was 90.9% (n=40/44). The ORRs in patients with WT EZH2 and MT EZH2 were 88.9% (n=32/36) and 100% (n=7/7), respectively. The ORR in patients with rituximab-refractory disease was 93.3% (n=14/15) and in patients with POD24 was 91.7% (n=11/12). With a median follow-up of 22.5 months, median PFS and median DOR were not reached. In the ITT population, 18-month PFS and DOR estimates were 79.5% and 81.0%, respectively; in the 800-mg cohort (n=19), 18-month PFS and DOR estimates were 94.4% and 100%, respectively. PFS appeared to be dose dependent, with durable response in the 800-mg cohort. Conclusions: The safety profile of TAZ + R 2 combination therapy was consistent with previous reports, with no new safety signals identified in the phase 1b data of this study. The 12 months of initial combination therapy resulted in long-lasting remission. Dose-dependent response was seen with durable response in patients receiving TAZ 800 mg, regardless of their mutation status. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

A Novel and Potent EZH1/2 Dual Inhibitor, HM97662 Demonstrated a Wide Spectrum of Therapeutic Potential for Hematological Malignancies

Chromatin remodeling is a crucial process for transcriptional regulation, of which dysregulation is often observed in various human cancers. The enhancer of zeste homolog 2 (EZH2) and its homolog EZH1 are catalytic components of polycomb repressive complex 2 (PRC2), which tri-methylate histone H3 at lysine 27 (H3K27me3) to repress transcription of their target genes. Hyperinduction of H3K27me3 mediated by EZH2 overexpression or EZH2 gain-of-function (GOF) mutation (e.g. Y641, A677, and A687) has been associated with the progression of hematological malignancies including B-cell lymphoma, T-cell lymphoma, and multiple myeloma. Hence, it has been suggested that suppressing PRC2 activity by EZH2 inhibition is a potential therapeutic target for hematological malignancies. Although the methyltransferase activity of PRC2 is mainly contributed by EZH2, EZH1 also conducts a compensatory role to maintain tri-methylation of H3K27. Moreover, EZH1 directly binds to chromatin and modulates its condensation. Therefore, dual inhibition of EZH1 and EZH2 can give better effect than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Herein, we presented a novel EZH1/2 dual inhibitor, HM97662, which simultaneously inhibited the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations. SPR analysis of HM97662 on trimeric complexes (EZH1/EZH2, SUZ12, and EED) demonstrated that HM97662 binds both EZH1- and EZH2-PRC2 complexes. HM97662 potently repressed tri-methylation of H3K27 in KARPAS 422 DLBCL, HH PTCL, and MM.1S MM cell lines. Furthermore, HM97662 showed broader and stronger activities than EZH2 selective inhibitors in long-term proliferation assay against a variety of hematological cancer cell lines. HM97662 induced the differentiation of DLBCL to plasma cells with the increment of cell lineage specific markers (e.g. PRDM1 and CD38), and caused cell cycle G0/G1 arrest and apoptosis in KARPAS 422 DLBCL cells harboring EZH2 Y641N GOF mutation. Additionally, HM97662 increased mRNA expression of several target genes inducing cell cycle arrest and apoptosis in gene panel assay performed in HH PTCL cell line. Two cell cycle repressors, CDKN2A (p16) and CDKN1C (p57), and a pro-apoptotic marker, BTG-2, were significantly increased by HM97662. We further conducted a chromatin accessibility assay and identified that the chromatin structures of that genes were loosened and highly transcribed after the treatment of HM97662. As a result, HM97662 showed potent antitumor activity in various hematological cell lines xenograft mouse models including B-cell lymphoma, T-cell lymphoma, and multiple myeloma (e.g. KARPAS 422, HuT-102, and MM.1S). Once daily oral dosing of HM97662 greatly inhibited tumor growth in a dose-dependent manner without significant clinical signs compared to the known EZH2 selective or EZH1/2 dual inhibitor. In conclusion, the present preclinical studies demonstrated that HM97662, an EZH1/2 dual inhibitor, had a promising and wide spectrum of therapeutic potential for hematological malignancies. It is urgent to assess the effectiveness of HM97662 in further clinical trials.

Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1

Background: The preferred second-line treatment for patients with relapsed/refractory (R/R) follicular lymphoma (FL) is either lenalidomide in combination with rituximab (R2) or an anti-CD20 antibody in combination with chemotherapy/immunotherapy. Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with R/R FL whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or who have no satisfactory alternative treatment options. EZH2 modulates the B-cell tumor microenvironment, supporting combination approaches to treatment. SYMPHONY-1 (EZH-302; NCT04224493) is a phase 1b/3 study designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + lenalidomide and rituximab (R2) in patients with R/R FL after ≥1 prior therapy. We report the results after complete enrollment of the phase 1b safety run-in to assess safety and clinical activity of TAZ when administered with R2, including data for subsets of patients by mutation status, rituximab-refractory disease, and progression of disease in 24 months (POD24). Methods: Patients aged ≥18 years with histologically confirmed FL grade 1-3A who were previously treated with ≥1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy were enrolled. The phase 1b portion enrolled patients regardless of EZH2 mutation status. Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R2. Protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for grade 3 neutropenia and thrombocytopenia. Primary endpoints of the phase 1b portion were safety and determination of the RP3D. Secondary endpoints included pharmacokinetic (PK) parameters. Preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of June 14, 2022, 44 patients were enrolled and receiving TAZ + R2 (400 [n=6], 600 [n=19], and 800 mg [n=19]). Median age was 67 years, and 31.8% of patients had received >1 prior therapy. Overall, 35/42 patients (83.3%) had wild-type (WT) EZH2 FL. Patients with high-risk disease include 15 patients (34.1%) with rituximab-refractory disease and 12 patients (27.3%) with POD24 disease. Median duration of treatment exposure of tazemetostat was 9.1 months. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The PK of TAZ at all dose levels was not altered by concomitant administration of daily oral lenalidomide 20 mg, and the PK of lenalidomide was not altered by concomitant administration of any of the TAZ doses. The RP3D of TAZ was determined to be 800 mg BID in combination with R2. The most common grade 3-4 TEAE was neutropenia (n=15; 34.1%). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (n=30; 68.2%). In the 800-mg cohort, the median dose intensity was 98%, 93%, and 100% for tazemetostat, lenalidomide, and rituximab, respectively. Of 41 patients evaluable for tumor assessment, 21 (51.2%) had a complete response, 19 (46.3%) had a partial response, and 1 (2.4%) had stable disease. The overall response rate (ORR) in the response-evaluable population was 97.6% (n=40). The ORRs in patients with WT EZH2 and MT EZH2 were 97% (n=32) and 100% (n=7), respectively. ORRs in patients with rituximab-refractory disease was 100% (n=14) and in patients with POD24 disease was 100% (n=11). With a median follow-up of 11.2 months, median PFS and median DOR were not reached and appeared to be similar, regardless of rituximab-refractory, POD24, or EZH2 mutation status. Conclusions: TAZ + R2 combination therapy demonstrates a consistent and manageable safety profile, with no new safety signals. The combination therapy maintained its efficacy, regardless of mutation status. Durable responses were seen in patients with high-risk disease, including those with rituximab-refractory and POD24 disease. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

A Matching-Adjusted Indirect Comparison of Single-Arm Trials in Patients with Relapsed or Refractory Follicular Lymphoma Who Received at Least Two Prior Systemic Treatments: Tazemetostat was Associated with a Lower Risk for Safety Outcomes Versus the PI3-Kinase Inhibitors Idelalisib, Duvelisib, Copanlisib, and Umbralisib.

IntroductionTazemetostat 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.MethodsA 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).ResultsMatched 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).ConclusionsIn this statistically adjusted comparison, tazemetostat was associated with lower RR for safety outcomes versus idelalisib, duvelisib, copanlisib, and umbralisib, while achieving similar efficacy outcomes.

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

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

IBCL-165: Tazemetostat in Relapsed/Refractory (R/R) Follicular Lymphoma (FL): Propensity Score-Matched Analysis of E7438-G000-101 Trial Outcomes

Context Tazemetostat, an oral enhancer of zeste homolog 2 (EZH2) inhibitor, received FDA approval based on a phase 2 study (NCT01897571); in this study, the wild-type (WT) EZH2 cohort included more patients with poor-risk features than the mutant (MT) EZH2 cohort. Objective Assess outcomes in patients with WT versus MT EZH2 R/R FL after minimizing baseline characteristic differences by creating a matched sample of comparable WT and MT patients. Design In a post hoc analysis of NCT01897571, we generated propensity scores for each WT (n=54) and MT (n=45) EZH2 patient based on the likelihood of being selected, given their baseline characteristics. Characteristics prognostic for clinical outcomes with appreciable baseline differences between cohorts included ECOG performance status, number of prior anticancer therapies, progression of disease within 24 months, double-refractory status, and prior hematopoietic stem cell transplant. Patients were matched using a 1:1 nearest-neighbor approach. Baseline covariates between the matched groups were sufficiently balanced. Setting Thirty-eight global clinics/hospitals. Patients Adults with R/R FL who received ≥2 prior systemic therapies. Interventions Tazemetostat 800 mg orally in continuous 28-day cycles. Main Outcome Measures Objective response rate (ORR) estimates were measured for the matched groups. Progression-free survival (PFS) was described using Kaplan–Meier analyses. Results The propensity-matched sample included 56 patients (28 WT, 28 MT). Before matching, ORR was 35% (95% CI [22%, 48%]) in WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in WT and 13.8 months (95% CI [11.1, 22.1]) in MT prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 months (95% CI [10.7, inf]) in WT and MT matched groups, respectively. Conclusion As expected, efficacy remained higher in the MT group; however, after adjustment, ORR and PFS improved in the WT group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with tazemetostat may have been more similar to those with MT EZH2 in the phase 2 trial if baseline disease characteristics were more equally matched.

Abstract 1142: A novel and potent EZH1/2 dual inhibitor, HM97662, demonstrates antitumor activity in malignant tumors

Abstract Either enhancer of zeste homolog 2 (EZH2) or its homolog EZH1, the enzymatic core subunit of polycomb repressive complex 2 (PRC2), acts an essential role for the maintenance of transcriptional repression by the methylation of histone H3 lysine 27 (H3K27). EZH2 gain-of-function (GOF) mutations (e.g. Y641, A677, and A687) or wild-type activation cause an increased activity leading to hyperinduce trimethylation of H3K27 (H3K27me3). Meanwhile, loss-of-function (LOF) mutation of major components (e.g. ARID1A, PBRM1, INI1) in chromatin remodeling complex, SWItch/Sucrose Non-Fermentable (SWI/SNF), results in a loss of its ability to oppose PRC2 and subsequently activation of EZH2. Accordingly, the dysfunctions of EZH2 or the alterations of regulatory SWI/SNF complex proteins have been reported to be associated with the development and progression of a variety of malignant tumors. Although PRC2 is suppressed by EZH2 inhibition, the activity of EZH1 is complementarily increased to replace the role of EZH2. Consequently, dual inhibition of EZH1 and EZH2 could be more effective than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Thus, we have developed a novel EZH1/2 dual inhibitor, HM97662, which simultaneously inhibited the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations. Herein, we presented that HM97662, having enhanced EZH1 inhibitory activity compared to EZH2 inhibitors currently approved or in clinical development, potently and dose-dependently decreased global H3K27me3 in cancer cells. HM97662 showed broader and stronger anti-proliferative activities against various hematological cancer cell lines with EZH2 activating mutations as well as solid tumor cell lines with negatively mutated components of regulatory protein complexes. At this time, it was confirmed in the MCL cell line that HM97662, unlike the EZH2 selective inhibitor, does not cause the elevation of EZH1. HM97662 was observed to effectively modulate cell cycle arrest and induce apoptotic markers in a dose-dependent manner, as well as decrease intracellular H3K27me3, a pharmacodynamic marker, even at low concentration. As a result, HM97662 inhibited tumor growth more effectively than known EZH2 selective inhibitor without abnormal clinical signs at once daily dose in an EZH2 GOF mutant lymphoma cell xenograft mice model as well as in a bladder cancer cell xenograft mice model harboring a genetically mutated regulatory SWI/SNF complex protein (e.g. ARID1A). Taken together, the present studies demonstrated that HM97662 is a novel and potent EZH1/2 dual inhibitor and has the promising potential for the treatment of patients with several types of cancers. Clinical trials to prove the effectiveness of HM97662 identified in preclinical studies need to be carried out immediately. Citation Format: Seung Hyun Jung, DongJin Hong, Jiyoung Hwang, Somin Park, Jooyun Byun, Miyoung Lee, Kyounghwa Koo, Gunwoo Lee, Yu-Yon Kim, Yesol Bak, Young Gil Ahn, YoungHoon Kim, Kwee Hyun Suh. A novel and potent EZH1/2 dual inhibitor, HM97662, demonstrates antitumor activity in malignant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1142.

Tazemetostat (TAZ) in relapsed/refractory (R/R) follicular lymphoma (FL): Propensity-score matched analysis of E7438-G000-101 trial outcomes.

e18627 Background: Oncology drug development often requires the use of non-randomized, open-label, phase 2 basket studies to better understand the early activity and safety of a potential new therapy. As such, baseline demographics and disease characteristics may differ between cohorts which can impact the perception of efficacy between cohorts. TAZ, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was approved by the US FDA after demonstrating single-agent, antitumor activity in a phase 2 study in adults with wild-type (WT) or mutant (MT) EZH2 R/R FL who had received ≥2 prior systemic therapies (NCT01897571). Differences between the cohorts in baseline characteristics known to be prognostic for clinical outcomes were noted, with the WT EZH2 cohort enrolling more patients with poor-risk features. This analysis assessed outcomes in the 2 groups after minimizing differences in baseline characteristics by creating a matched sample of directly comparable WT and MT patients. Methods: Propensity scores for each WT (n = 54) and MT (n = 45) EZH2 patient in the study were generated, based on the likelihood of being selected given their baseline characteristics. Characteristics identified for inclusion in the model were chosen if they were prognostic based on peer-reviewed literature and where larger differences were observed between cohorts at baseline: ECOG performance status, number of prior lines of anticancer therapy, progression of disease within 24 months, double refractory status, and prior history of hematopoietic stem cell transplant. Patients were matched 1:1 on propensity score, using a nearest-neighbor approach with caliper restrictions. Baseline covariates between the two matched groups were found to be sufficiently balanced. Objective response rate (ORR) point estimates were measured for the matched WT and MT EZH2 groups, and progression-free survival (PFS) was described using Kaplan-Meier analyses. Results: The propensity-matched sample included 56 patients (28 WT and 28 MT). Prior to matching, ORR was 35% (95% CI [22%, 48%]) in the WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, the ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in the WT and 13.8 months (95% CI [11.1, 22.1]) in the MT EZH2 groups prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 (95% CI [10.7, inf]) months in the WT and MT EZH2 matched groups, respectively. Conclusions: As expected, efficacy remained higher in the MT EZH2 group; however, after adjustment, the ORR and PFS improved in the WT EZH2 group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with TAZ may have been more similar to those in the MT EZH2 group in the phase 2 trial had the baseline disease characteristics been more equally matched.

Health care cost impact associated with adverse events (AEs) among treatments in third-line+ (3L+) relapsed/refractory follicular lymphoma (R/R FL).

e18836 Background: Tazemetostat, a first-in-class oral, selective methyltransferase inhibitor of enhancer of zeste homolog 2 (EZH2) activity, was approved by the US Food and Drug Administration for treatment of patients with R/R FL after demonstrating single-agent antitumor activity in patients with wild-type or mutant EZH2. Phosphoinositide 3-kinase inhibitors (PI3Kis; idelalisib, duvelisib, and copanlisib) are also indicated for 3L+ R/R FL, but these drugs are associated with serious toxicities, such as neutropenia, infection, and immune-mediated toxicities. A matching-adjusted indirect comparison (MAIC) of tazemetostat with these 3 PI3Kis was previously presented in 3L+ R/R FL, showing that tazemetostat is associated with more favorable safety, and similar efficacy compared to each of the PI3Kis. The objective of this study was to estimate the difference in AE-related health care costs for each treatment. Methods: AE-related costs were sourced from a study of costs in patients hospitalized with AEs, using oncology-specific data when available. Matching-adjusted AE incidence was multiplied by costs related to each AE. Grade ≥3 AEs with incidence ≥5% for any of the evaluated treatments were included. Cost differences were estimated per treatment episode, based on duration of exposure in the tazemetostat clinical trial (9.3 months for tazemetostat, &lt;7 months for the 3 comparators). Incidence rates were then converted to a monthly basis using an exponential curve. Results: The PI3Kis are estimated to incur $13,534 to $18,737 higher AE-related management costs per episode compared with tazemetostat. Adjusting for duration of exposure, each of the PI3Kis is project to cost $2,563 to $3,820 more per month than tazemetostat in AE-related costs. These estimates indicate that the AE-related cost impact of PI3Kis compared with tazemetostat is 3.4- to 6.1-fold higher on a per-episode basis, and 5.0- to 10.4-fold higher on a monthly basis. Conclusions: Quantifying the AE cost impact of tazemetostat based on AE incidence rates estimated by MAIC analysis adjusts for population differences and allows for more direct cost savings comparisons when accounting for duration of exposure to different treatments. Patients with 3L+ R/R FL who are treated with tazemetostat are estimated to incur substantially lower AE-related costs compared with PI3Kis (idelalisib, duvelisib, and copanlisib). [Table: see text]

Analyzing Efficacy Outcomes from the Phase 2 Study of Single-Agent Tazemetostat As Third-Line Therapy in Patients with Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response

Analyzing Efficacy Outcomes from the Phase 2 Study of Single-Agent Tazemetostat As Third-Line Therapy in Patients with Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response

A Phase 2, Open-Label, Multicenter Study of Tazemetostat in Combination with Rituximab for the Treatment of Relapsed or Refractory Follicular Lymphoma

Background: Patients with follicular lymphoma (FL) who do not achieve a response after 2 or more prior lines of systemic therapy have a poor prognosis when treated with salvage chemotherapy alone or PI3K inhibitors. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that supports germinal center (GC) formation and suspends differentiation during B-cell development by silencing genes that limit proliferation and promote exit from the GC. Throughout the pathogenesis of FL, EZH2 plays a consistent underlying role in maintaining the GC and B-cell proliferation, regardless of the oncogenic drivers. Dysregulation of EZH2 or gain-of-function mutations in EZH2 can lead to accumulation of malignant B cells and may contribute to the development of FL. Tazemetostat, a first-in-class oral EZH2 inhibitor, recently gained approval by the US Food and Drug Administration in patients with relapsed or refractory (R/R) FL after demonstrating single-agent, antitumor activity in patients with mutant (MT) or wild-type (WT) EZH2 R/R FL. Here we examine the efficacy and safety of tazemetostat in combination with rituximab for the treatment of R/R FL. Study Design and Methods: This trial is a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab in patients with R/R FL who have received at least 2 prior lines of systemic therapy, including an anti-CD20-based regimen. Patients eligible for inclusion are aged ≥18 years with grade 1 to 3A FL who have met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria to receive treatment, have an Eastern Cooperative Oncology Group (ECOG) score ≤2, have &amp;gt;5.0 x 109/L circulating malignant cells, and have not received any prior treatment with EZH2 inhibitors. Patients with transformed FL, a history of clinically significant gastrointestinal conditions, or any uncontrolled illness are excluded from this study. EZH2 mutation testing will be performed during patient screening. Patients will receive tazemetostat 800 mg by mouth twice daily beginning on cycle 1 day 1 for continuous 28-day cycles until the end of cycle 24, for a total of 24 months of therapy. Patients will also receive rituximab 375 mg/m2 intravenously (IV) on cycle 1 day 1, then 375 mg/m2 IV or 1400 mg subcutaneously on days 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 4, 5, and 6, for a total of 8 doses of rituximab. The primary endpoint is the objective response rate (ORR; the proportion of patients with complete or partial response) in patients with WT EZH2. Key secondary endpoints include median progression free survival (PFS) in patients with WT EZH2; median PFS in all patients, regardless of mutational status; ORR in patients with MT EZH2; efficacy outcomes in rituximab-refractory patients; and incidence of adverse events. Efficacy and safety analyses will be performed on all patients who receive ≥1 dose of study drug. The evaluation of ORR will be based on Lugano 2014 response criteria and will be presented with corresponding 2-sided Clopper-Pearson 95% confidence intervals. The Kaplan-Meier method will be used to estimate PFS. Survival follow-up will be done following the study treatment period every 6 months for 2 years or until disease progression or death for all patients who complete the 24 months of tazemetostat therapy. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy.

Tazemetostat Is Associated with Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib and Copanlisib, in Patients with Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials

Background: Tazemetostat, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. The PI3K inhibitors idelalisib, duvelisib, and copanlisib are indicated for third-line or later (3L+) treatment of R/R FL, but they are associated with safety concerns, and clinical studies with these agents did not include grade 3B or transformed FL. However, tazemetostat idelalisib, duvelisib, and copanlisib were all approved based on single-arm studies and have not been compared in head-to-head randomized trials for the treatment of 3L+ R/R FL. Here, we present an indirect treatment comparison (ITC) of tazemetostat with idelalisib, duvelisib, and copanlisib for the treatment of 3L+ R/R FL. Methods: A systematic literature review identified clinical trial publications for idelalisib (DELTA), duvelisib (DYNAMO), and copanlisib (CHRONOS-1 Part B) for use in an ITC with tazemetostat for 3L+ treatment of R/R FL. Matching-adjusted indirect comparison (MAIC) methodology was selected as all comparator trials were single-arm and individual patient data (IPD) were available for the tazemetostat E7438-G000-101 trial (n=99). Three MAIC analyses were conducted by weighting individual patients treated with tazemetostat to baseline characteristics reported from each comparator trial. FL subpopulation baseline characteristics and outcomes data were available for matching idelalisib (n=72); full trial mixed-NHL populations were reported for duvelisib (n=129, 64% FL) and copanlisib (n=142, 73% FL). Baseline characteristics for matching-adjustment were chosen using clinical advice, an evaluation of prognostic factors associated with outcomes, and published data availability. Characteristics included: age, ECOG performance status, disease stage, histology (tumor grade, transformed FL), number of prior lines of treatment, prior stem cell therapy, and refractory status (to last therapy). Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Safety and efficacy outcome definitions were similar across trials. Primary safety outcomes included risk of any grade ≥3 treatment-emergent adverse event (TEAE), any treatment-emergent serious adverse event (TESAE), and TEAEs leading to dose reduction, drug discontinuation, or interruption. The primary efficacy outcome was objective response rate (ORR), reported across all trials. Rates of individual grade ≥3 TEAEs also were compared. Limitations of such indirect methods include inability to account for any unmeasured covariates that may be effect modifiers, and reductions in the effective sample size. Results: After matching, all baseline characteristics were successfully balanced. Matched patients treated with tazemetostat had lower relative risk for all safety outcomes compared with all treatments, including any grade ≥3 TEAE (vs idelalisib: RR=0.45; vs duvelisib: RR=0.35; vs copanlisib: RR=0.37; all, P&amp;lt;0.001), any TESAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. These results were statistically significant (where comparator data were reported) for all but 2 safety outcomes (Figure). Several grade ≥3 TEAEs occurred at a significantly lower incidence with tazemetostat compared with matched patients treated with idelalisib, duvelisib, or copanlisib, including neutropenia (vs idelalisib: 3% vs 22%; vs duvelisib: 3% vs 25%; vs copanlisib: 4% vs 24%; all, P&amp;lt;0.05). The ORR was similar after matching for tazemetostat versus all treatments, with no statistically significant difference between therapies (vs idelalisib: 43% vs 56%, P=0.16; vs duvelisib: 48% vs 47%, P=0.91; vs copanlisib: 49% vs 61%, P=0.11). Conclusion: More tolerable treatment options are needed for 3L+ treatment of R/R FL because patients in this setting are often elderly and have exhausted multiple prior lines of treatment. Results from this ITC indicate that, after adjusting for baseline population differences, tazemetostat addresses this unmet need, as it is associated with lower relative risk for safety outcomes versus idelalisib, duvelisib, or copanlisib while achieving similar efficacy outcomes. Disclosures Proudman: Analysis Group, Inc.: Consultancy. Nellesen:Analysis Group, Inc.: Consultancy. Gupta:Analysis Group, Inc.: Consultancy. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Yang:Epizyme, Inc.: Current Employment. Keith:Epizyme: Current Employment, Current equity holder in publicly-traded company. Mamlouk:Epizyme: Current Employment, Current equity holder in publicly-traded company.

Abstract IA26: What do the results from the trials tell us?

Abstract The relatively high prevalence of somatic mutations in several epigenetic modifying genes in germinal center lymphomas suggests a role in pathogenesis, with a variety of potential mechanisms for this. The first of these somatic changes to be successfully targeted by small-molecule inhibitors was the activating mutation of the enhancer of Zeste Homolog-2 (EZH2), which is found in up to a quarter of follicular lymphomas and germinal center-type diffuse large B-cell lymphomas, where it drives the methylation of histone H3 on lysine 27, inhibiting exit from the germinal center and accelerating lymphoma development in preclinical models. Two inhibitors of EZH2 have entered clinical trials, GSK2816126 and tazemetostat. GSK2816126 is a highly selective and potent inhibitor of wild-type (WT) and mutant (Y641N, A677G, and A687V) EZH2, with IC50 of 28–861 nM for proliferation in EZH2-mutant lymphoma cell lines. It is not orally bioavailable, but pharmacokinetic/pharmacodynamic studies suggested that therapeutic levels could be achieved with intravenous doses of between 900mg and 2,700mg twice a week. Tazemetostat is a similarly selective and orally bioavailable small-molecule inhibitor of EZH2 with an IC50 of 0.49-5800 nM for proliferation in EZH2-mutant lymphoma cell lines. Both of these molecules have been tested in phase I dose escalation studies. GSK2816126 was given by twice-weekly intravenous infusion at doses of up to 3,000mg, with dose-limiting liver enzyme rises at the highest dose, achieving trough levels of 410 ng/mL. No changes in H3K27me3 could be seen in peripheral blood mononuclear cells, and only one short-lived partial response was seen among 20 patients with B-cell lymphoma. Tazemetostat was given at doses of up to 1,600mg twice daily without reaching dose-limiting toxicity, although significant thrombocytopenia was seen at this dose level. The mean pre-dose trough level at the recommended phase II dose of 800mg bd was 75 ng/mL, and skin biopsies showed a reduction of H3K27me3 by approximately 40% from baseline. Tazemetostat has shown moderate efficacy as a single agent in relapsed/refractory follicular lymphoma (FL), with overall response rate (ORR) 33/43 (77%) and median duration of response (mDOR) 8.3 months in EZH2-mutant cases and ORR 18/53 (34%), mDOR 13 months in those without mutations. In relapsed/refractory diffuse large B-cell lymphoma (DLBL) the response rate was lower, ORR 6/36 (17%), mDOR 11+ months in mutant cases and 20/121 (17%), mDOR 7+ months in wild-type. In both studies the treatment was well tolerated, with the most frequently reported adverse events being thrombocytopenia, anemia, asthenia, vomiting, and fatigue, all in less than 5% of patients with FL and less than 20% in DLBL. Combination therapy of tazemetostat with atezolizumab did not increase the response rate in DLBL, but giving it with R-CHOP chemotherapy was well tolerated in a phase Ib study, and a dose of 800mg BD could be given without apparently increased toxicity over R-CHOP in patients between 60 and 80 years old, and without adverse effects on the pharmacology of the chemotherapy or tazemetostat. In keeping with many agents targeting a single molecular abnormality, inhibitors of EZH2 have demonstrated clear but transient efficacy, with the most promising results in follicular lymphoma. The higher response rate among cases with an activating mutation is notable, but wild-type lymphomas also show responsiveness in a minority of cases, indicating other potential mechanisms of action. The combination of tazemetostat with chemoimmunotherapy appears promising, although the relatively good prognosis for DLBL bearing an EZH2 mutation may make it difficult to demonstrate clear clinical benefit with this approach. Citation Format: Peter W. M. Johnson. What do the results from the trials tell us? [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA26.

IBCL-178: A Phase 1b/3 Randomized, Double-Blind, 3-Stage Study of Tazemetostat or Placebo Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma

Background: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that is essential for BCL6-driven germinal center (GC) formation. Relapsed/refractory (R/R) follicular lymphoma (FL) is derived from GC B-cells and is generally dependent on EZH2 function. EZH2 mutations are observed in ∼20% of patients with FL; however, as FL is commonly reliant on other epigenetic modulator mutations, EZH2 is relevant in both mutant (MT) and wild-type (WT) EZH2 FL. Tazemetostat (TAZ), a selective, oral EZH2 inhibitor, has demonstrated durable single-agent antitumor activity in MT or WT EZH2 R/R FL. Aims: Study EZH-302 (NCT04224493) will determine the recommended phase 3 dose (RP3D) and assess efficacy and safety of rituximab, lenalidomide, and TAZ (R2+TAZ) versus rituximab, lenalidomide, and placebo (R2) in R/R FL. Methods: Patients aged ≥18 years with histologically confirmed FL (grades 1–3A; WT or MT EZH2 status) previously treated with ≥1 line of chemotherapy, immunotherapy, or chemoimmunotherapy will be enrolled. Phase 1b (safety run-in; stage 1) will evaluate safety and tolerability and establish the maximum tolerated and/or RP3D of TAZ+R2 in 3–18 patients. TAZ will be evaluated at 3 escalating dose levels (400 mg, 600 mg, and 800 mg orally twice daily) if no dose-limiting toxicities are observed. Rituximab (375 mg/m2) will be administered intravenously on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5. Lenalidomide (20 mg) will be administered orally once daily on days 1–21 every 28 days for up to 12 cycles. Phase 3 (stage 2) will be a 1:1 randomized study of ∼500 patients receiving TAZ (twice daily at the RP3D)+R2 (dosed per stage 1) or placebo+R2. Enrollment with MT EZH2 status will be capped at 150–210 patients (≤30%) to reflect real-world prevalence. Randomization will be stratified by EZH2 status (WT or MT), response to prior systemic therapy (sensitive or refractory), and number of prior treatment lines (1 or ≥2). Primary endpoint is investigator-assessed progression-free survival per 2014 Lugano Classification. An interim futility analysis will be initiated when 100 patients are evaluable for objective response rate.

Abstract 3844: EZH2 engages TGF-β signaling to promote breast cancer bone metastasis

Abstract Metastasis, the dissemination of cancer cells to second organs, is an important hallmark of cancer. About 90% of cancer patients die of metastasis and approximately 55% of breast cancer patients develop bone metastases. However, prevention or treatment of bone metastasis remain challenging. To improve the clinical outcome and the quality of life of breast cancer patients with bone metastasis, the mechanisms of bone metastasis needs to be better understood. Enhancer of zeste homolog 2 (EZH2) is the functional enzymatic component of the Polycomb Repressive Complex 2 (PRC2). EZH2 is a histone methyl transferase that generally suppresses downstream target genes through tri-methylation of H3K27, but it also can work as a transcription co-activator. It is frequently over expressed in breast cancer and in bone metastasis of prostate cancer. To explore the function of EZH2 in breast cancer bone metastasis, we knocked down EZH2 by shRNAs in a MDA-MB-231 bone-seeking subline (231.1566. shEZH#3) and intra-cardiaclly injected into nude mice with 231.1566.shEZH#3 and its control cells (231.1566.shCtrl). Mice injected with 231.1566.shEZH#3 have longer bone metastasis free survival than the control mice. Furthermore, we generated a MDA.MB.231 subline that had CRISPR/Cas9-mediated EZH2-knockout (231.KO) and stably re-expressed in the 231.KO cells the wild-type EZH2 (231.KO.EZH2), or the pLenti control vector (231.KO.pLenti). These two derived sublines were intracardiaclly injected into nude mice, and the mice injected with 231.KO.EZH2 had poorer bone metastasis free survival than the control mice (231.KO.pLenti). Both loss-of-function and gain-of-function experiments demonstrated that EZH2 promotes breast cancer bone metastasis. To gain initial insight on the underlying mechanism of EZH2-induced bone metastasis, we co-cultured MDA-MB-231 cells or 231.KO with pre-osteoclasts (RAW264.7) and osteoblasts (MC3T3) under TGF-β treatment (triple co-culture) to mimic bone metastasis tumor microenvironment. We examined osteoclast maturation and breast cancer cell proliferation because osteolysis induced by mature osteoclasts is critical for breast cancer cell growth in the bone metastasis. In triple co-culture of MDA.MB.231 cells, more RAW264.7 pre-osteoclasts were differentiated to mature osteoclasts, as measured by TRAP+ staining, a marker of mature osteoclasts, and MDA.MB.231 cells grew faster than the 231.KO cells in triple co-culture. In addition, we found that the mRNA level of PTHrP, a master regulator of the “vicious cycle” of bone destruction, was expressed at significantly higher level in MDA.MB.231 cells than that in 231.KO cells under TGF-β stimulation. We also detected higher p-Smad2, the downstream of TGF-β in MDA.MB.231 cells than that in 231.KO cells. The data indicated that EZH2 promotes breast cancer bone metastasis through TGF-β/p-Smad2/PTHrP pathway. Currently, we are exploring how EZH2 regulates p-Smad2 in breast cancer cells to promote bone metastasis. Our studies may reveal novel biomarkers and/or therapeutic targets for bone metastasis. Citation Format: Yu-Wen Huang, Lin Zhang, Jingkun Qu, Zhifen Zhou, Dihua Yu. EZH2 engages TGF-β signaling to promote breast cancer bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3844.

Deregulation of Polycomb Repressive Complex-2 in Mantle Cell Lymphoma Confers Growth Advantage by Epigenetic Suppression of cdkn2b.

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2Δ550−738 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity (p < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of cdkn2b gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the cdkn2b promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.

Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors

Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the “tail” region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.

Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), catalyzes the methylation of lysine 27 of histone H3 (H3K27) up to its trimethylated form (H3K27me), inducing by this way block of transcription and gene silencing. High levels of H3K27me3 have been found in both hematological malignancies and solid cancers, due to EZH2 overexpression and/or EZH2 mutation. From 2012, a number of highly potent and selective catalytic inhibitors of EZH2 have been reported, almost all bearing a 2-pyridone group in their structure. Typically, 2-pyridone inhibitors are selective for EZH2 over other methyltransferases, and some of them are specific for EZH2 over EZH1, others behave as dual EZH2/EZH1 inhibitors. The 2-pyridone moiety was crucial for the enzyme inhibition, as revealed later by crystallographic studies because it occupies partially the site for the co-substrate SAM (or the by-product, SAH) in the binding pocket of the enzyme, accounting for the SAM-competitive mechanism of action displayed by all the 2-pyridone inhibitors. The 2-pyridone warhead is linked to a support substructure, that can be either a bicyclic heteroaromatic ring (such as indazole, see for instance EPZ005687 and UNC1999, or indole, see for instance GSK126, EI1, and the more recent CPI-1205) or a simple monocyclic (hetero) aromatic ring (tazemetostat, MC3629, (R)-OR-S1/2), eventually annulated with the amide chain carrying the 2-pyridone group (3,4-dihydroisoquinoline-1(2H)-ones). Different substitutions at the support moiety influence the pharmacokinetics and pharmacodynamics of the compounds as well as their water solubility. In cancer diseases, the first reported 2-pyridone inhibitors displayed high antiproliferative effects in vitro and in vivo in lymphomas characterized by mutant EZH2 (such as Y641N), but the most recent compounds exert their anticancer activity against tumors with wild-type EZH2 as well. The dual EZH2/1 inhibitors have been recently reported to be more effective than EZH2 selective inhibitors in specific leukemias including leukemias cancer stem cells.

Structural insights into conformational stability of both wild-type and mutant EZH2 receptor.

Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes, of which enhancer of zeste homolog 2 (EZH2) acts as tumor suppressor. Overexpression of EZH2 results in hyper activation found in a variety of cancer. Point mutation on two important residues were induced and the results were compared between the wild type and mutant EZH2. The mutation of Y641 and A677 present in the active region of the protein alters the interaction of the top ranked compound with the newly modeled binding groove of the SET domain, giving a GLIDE score of −12.26 kcal/mol, better than that of the wild type at −11.664 kcal/mol. In depth analysis were carried out for understanding the underlying molecular mechanism using techniques viz. molecular dynamics, principal component analysis, residue interaction network and free energy landscape analysis, which showed that the mutated residues changed the overall conformation of the system along with the residue-residue interaction network. The insight from this study could be of great relevance while designing new compounds for EZH2 enzyme inhibition and the effect of mutation on the overall binding mechanism of the system.

A phase I, open-label study of GSK2816126, an enhancer of zeste homolog 2 (EZH2) inhibitor, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), other non-Hodgkin’s lymphomas (NHL), multiple myeloma (MM) and solid tumor.

TPS2595Background: EZH2 is the methyltransferase component of the polycomb repressive complex 2 that represses transcription of target genes via trimethylation of histone H3 at lysine 27 (H3K27me3). These targeted genes are involved in fundamental cellular processes, e.g., development and cell differentiation. EZH2 is deregulated (via mutation or overexpression) in many cancers; increased expression correlates with more aggressive tumor progression and poor prognosis. GSK2816126, a selective and potent inhibitor of wild-type (WT) and mutant EZH2, can decrease H3K27me3 levels in vitro and has demonstrated antiproliferative activity in several cell lines derived from EZH2 WT/mutant cancers. Methods: This is a Phase I, open-label, first-time-in-human, 2-part study. Part 1 is a dose-escalation phase to determine the safety, tolerability and recommended Phase 2 dose (RP2D) of GSK2816126 in patients ( ≥ 18 years) with relapsed/refractory DLBCL, tFL, other NHL, MM and solid tumors (all with ECOG PS of 0/1). An a...