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In: The Lancet Oncology, Elsevier BV, Vol. 21, No. 11 ( 2020-11), p. 1433-1442

Type of Medium: Online Resource

ISSN: 1470-2045

URL: Article

DOI: 10.1016/S1470-2045(20)30441-1

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2049730-1

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1183-1183

Abstract: 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 & gt;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 & lt;0.05) . EZH2 GoF mutations were exclusive to the MT EZH2 cohort (P & lt;0.001) and were most significantly associated with response to tazemetostat (P & lt;0.01). We found that MYD88, GNA13, and PAX5 were exclusively mutated in the WT EZH2 cohort (all P & lt;0.05). Across the full cohort, we identified several additional genomic drivers of FL associated with PFS (ARID1B, P & lt;0.005; TP53, P & lt;0.01; and HIST1H1C, P & lt;0.05) as well as OS (FOXP1, P & lt;0.05) following treatment with tazemetostat. Gene-set enrichment analysis indicated a significant association of the signature of genes regulated by nuclear factor kappa B in response to tumor necrosis factor in patients with MT EZH2 vs WT EZH2 (P & lt;0.01). The interferon-α response signature, as well as the stromal-1 signature described by Lenz et al (N Engl J Med 2008), were associated with tazemetostat responders across the full cohort (both P & lt;0.001). Furthermore, we examined the influence of the tumor microenvironment on survival and found that a monocyte expression signature was associated with shorter PFS (P & lt;0.001). 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151452

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2519-2519

Abstract: 2519 Background: Despite recent therapeutic developments for patients with advanced, metastatic, unresectable HER2+ solid cancers, significant unmet medical needs still exist, especially in tumors other than breast and gastric. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. The TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in mouse models of human cancer, without any TAC-related toxicities. Methods: In the ongoing clinical trial (NCT04727151), TAC01-HER2 treatment of HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses. Subjects undergo leukapheresis, bridging therapy (if needed) while their TAC01-HER2 are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. In phase I dose escalation, the primary objective is to evaluate the safety of TAC01-HER2 at increasing doses of 0.3, 0.8, 3, and 8 x 10 6 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ as identified by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from cell infusion. In Phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ breast and other solid tumor types. Results: As of 10 Feb 2023, 18 patients have been treated in Cohorts 1-4 with breast, colorectal, gall bladder, gastroesophageal junction, gastric, esophageal, lung, and ovarian cancers. One DLT event of grade 3 pneumonitis has been reported in one subject in Cohort 4 (8 x 10 6 cells/kg). No neurotoxicity has been reported. Most subjects treated at Cohorts 3 and 4 experienced Grade ≤2 CRS which resolved with standard therapy. Twelve subjects have reported a total of 21 serious adverse events, 17 unrelated to TAC01-HER2 except for one Grade 3 pneumonitis, one Grade 1 and two Grade 2 CRS. Most adverse events were related to LDC or the underlying malignancy. At Cohort 2 (0.8 x 10 6 cells/kg), a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) at 1 st scan, with a 35% reduction in measurable disease and clinical benefit was maintained for 4 months. A 55% disease control rate was observed at Cohorts 2-4 at 1 st scan. Conclusions: Dose escalation of TAC01-HER2 is ongoing, with seven subjects treated and three more scheduled in Cohort 4. These results in a heavily pre-treated cancer population show manageable safety and promising clinical activity with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Clinical trial information: NCT04727151 .

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2023.41.16_suppl.2519

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2023

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2207-2207

Abstract: Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 inhibitor, showed antitumor activity as monotherapy in patients with wild-type and mutant EZH2 relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R 2) demonstrated an objective response rate (ORR) of 73%-78% and median progression-free survival of 36-39 months. Preclinical data demonstrated synergistic activity of TAZ + lenalidomide, and clinical experience with TAZ + rituximab in diffuse large B-cell lymphoma supports the combination of TAZ + R 2 in patients with R/R FL. This global, multicenter phase 1b/3 study (NCT04224493) is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R 2 in patients with R/R FL after ≥1 prior therapy. We report an interim analysis of the phase 1b safety run-in. Methods: The methods of this randomized, double-blind, 3-stage study were previously described (Leonard JP, et al. ASH 2020). 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 using a 3+3 design. The RP3D of TAZ will be selected at the dose level with a target dose-limiting toxicity (DLT; NCI CTCAE v5) rate of & lt;33%. Preliminary efficacy analysis was performed on the intent-to-treat population and reported as best overall response per investigator assessment according to Lugano 2014 response criteria. Results: As of February 26, 2021, 15 patients were enrolled and receiving treatment with TAZ + R 2 (400 mg [n=4], 600 mg [n=4] , and 800 mg [n=6]). Data for the 15th patient enrolled at 800 mg BID were not available as of the cutoff date; thus, this patient is not included in the current safety analysis. The 14 patients included had a median age of 65.5 years (range, 51-83) and received a median of 2 prior therapies (range, 1-5). Median duration of treatment exposure was 16.9 weeks (range, 8-28); dose modifications for treatment-emergent adverse events (TEAEs) are shown in the Table. No DLTs were observed in phase 1b, and no new safety signals were identified as of the February 2021 data cutoff. A summary of TEAEs is provided in the Table. Serious TEAEs were observed in 3 (21.4%) patients. Grade 3/4 TEAEs were observed in 7 (50.0%) patients; the most common grade 3/4 TEAE (≥20%) was decreased neutrophil count (21.4%). Febrile neutropenia and severe cytopenias have not been reported to date. Treatment-related TEAEs (TR-TEAEs) of any grade were observed in 12 (85.7%) patients; grade 3/4 TR-TEAEs were observed in 5 (35.7%) patients. The TR-TEAEs were attributable to either study agent. Of the 12 patients evaluable for tumor assessment, 5 (41.7%) had a complete response, 6 (50.0%) had a partial response, and 1 (8.3%) had stable disease. The ORR was 91.7% (n=11). Conclusions: The TAZ + R 2 combination demonstrates a favorable safety profile that is consistent with the respective safety information for TAZ and for R 2. The high response rates reported from the preliminary efficacy analysis support a benefit with the combination of TAZ + R 2. The randomized phase 3 portion will further explore the efficacy and safety of TAZ + R 2 in ~500 patients with R/R FL. Figure 1 Figure 1. Disclosures Batlevi: Dava Oncology: Honoraria; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Medscape: Honoraria; TouchIME: Honoraria; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Park: Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding; Gilead: Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; Genentech: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Amengual: Daiichi Sankyo, Inc: Consultancy; Epizyme, Inc.: Speakers Bureau; Seagen: Consultancy; Appia Pharmaceuticals: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Campbell: Novartis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding. McKay: Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel: Epizyme: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. O'Connor: Epizyme, Inc.: Current Employment, Other: May own stock/options . Hamlett: Epizyme: Current Employment. Adib: Epizyme, Inc.: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Chugai: Honoraria; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy. OffLabel Disclosure: Tazemetostat is not approved in combination with other therapies.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-148199

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 16-16

Abstract: 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 & 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 & 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-137772

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT247-CT247

Abstract: Background: Despite recent therapeutic advances for patients (pts) with breast, colorectal and gastroesophageal cancers with HER2 overexpression, there is still a significant unmet medical need for better treatment options for HER2-positive solid tumors, especially those with low or intermediate HER2 expression (1+ and 2+ by immunohistochemistry (IHC)). T Cell Antigen-Coupler (TAC) technology is a novel way to genetically modify T cells and to redirect these T cells to target cancer antigens and to activate T cells naturally by co-opting the natural T cell Receptor (TCR). TAC01-HER2 is an autologous T-cell product comprising T cells expressing the HER2 TAC, a chimeric receptor that is genetically engineered into T cells via lentiviral transduction to furnish T cells with two main functions: redirection to and specific recognition of HER2-positive cells, and T cell activation via the endogenous TCR. In vivo models, TAC T-cells can infiltrate tumors and persist for extended period of time, leading to robust and persistent anti-tumor efficacy, with a favorable safety profile. The safety and efficacy of TAC01-HER2 is investigated in the ongoing (TACTIC-2) first-in-human phase I-II study (NCT04727151). Methods: Eligible pts are ≥ 18 years with HER2-positive solid tumors (1+, 2+ or 3+ by IHC, regardless of amplification status) who progressed after at least two lines of systemic therapy. Upon enrollment, pts undergo leukapheresis to obtain T cells for TAC01-HER2 manufacturing. Bridging therapy can be administered prior to lymphodepleting chemotherapy (LDC). TAC01-HER2 is a single infusion after LDC with a starting dose of 1-3 x 105 cells/kg and escalating based on the keyboard statistical dose escalation method. Data safety monitoring committee meetings will be held after each dose level. Once the recommended phase 2 dose (RP2D) is identified, an additional 3-6 pts will be treated at that dose level. Current planned phase II expansion cohorts include HER2 3+ breast cancer (N=20), HER2 3+ other solid tumors (N=20), and HER2 2+ breast and other solid tumors (N=10). The primary objective for the trial is to determine the safety and tolerability of TAC01-HER2 with primary endpoints of incidence of dose limiting toxicities (DLTs) and type, frequency, and severity of adverse events (AEs). Secondary endpoints include the RP2D, overall response rate, duration of response, overall survival and pharmacokinetics. Exploratory endpoints include assessment of potential biomarkers of response or resistance and characterization of soluble immune factors and relationship to cytokine release syndrome (CRS), neurotoxicity and TAC T cell engraftment. Tumor response assessments are performed at 4 weeks, then at months 3, 6, 9, 12, 18 and 24. After study completion, subjects are followed for survival and long-term safety for up to 15 years. The trial opened in January 2021 and it is actively enrolling pts. Citation Format: Ecaterina E. Dumbrava, Daniel Olson, Benjamin L. Schlechter, Sam Saibil, Donna Rill, Andreas Bader, Deyaa Adib, Michael Bishop. A phase I/II trial investigating safety and efficacy of autologous TAC T cells targeting HER2 in relapsed or refractory solid tumors (TACTIC-2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT247.

Type of Medium: Online Resource

ISSN: 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2022-CT247

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2022

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 20 ( 2020-09), p. S279-

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/S2152-2650(20)30900-9

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 6_suppl ( 2020-02-20), p. TPS255-TPS255

Abstract: TPS255 Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2020.38.6_suppl.TPS255

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2020

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 123-123

Abstract: Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center (GC) formation. Conversely, a reduction in EZH2 catalytic activity is required for centroblast differentiation and initiation of the GC exit program. Activating mutations (MT) in EZH2, present in ~20% of FL patients, and enhanced H3K27me3 prevent GC exit, resulting in GC hyperplasia and lymphomagenesis. Tazemetostat, an investigational, selective, oral EZH2 inhibitor, has demonstrated durable, single-agent, antitumor activity in R/R FL patients with MT or wild-type (WT) EZH2. Herein, we report newly emerging interim efficacy and safety data from the MT and WT cohorts and the POD24 subgroup. Methods: This open-label, multicenter, phase 2 study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1-3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary endpoint was objective response rate (complete response + partial response). Secondary endpoints included progression-free survival and safety. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy. Results: As of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%] ). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9 (50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Updated data from the fully enrolled MT cohort, and sub-group analyses from both WT and MT cohort, will be presented. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in Table 1. These results demonstrate the potent, antitumor activity of tazemetostat regardless of the prognostic category of patients. Treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported. Conclusion: Tazemetostat was generally well tolerated, with a low incidence of treatment-related AEs. Tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations. Disclosures Morschhauser: BMS: Honoraria; Roche/Genentech: Consultancy; Servier: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead: Consultancy. Tilly:servier: Honoraria; merck: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. Phillips:Bayer: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding. Ribrag:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses . Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Jurczak:Servier: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Takeda: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Roche: Research Funding; Morphosys: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. McKay:Epizyme: Consultancy, Honoraria. Opat:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Radford:GSK: Equity Ownership; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Whalen:Epizyme: Employment, Equity Ownership. Rajarethinam:Epizyme: Employment, Equity Ownership. Navia:Epizyme: Employment, Equity Ownership. Adib:Epizyme: Employment, Equity Ownership. Salles:Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Epizyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128096

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Oncology, Elsevier BV, Vol. 27 ( 2016-06), p. ii84-

Type of Medium: Online Resource

ISSN: 0923-7534

URL: Article

DOI: 10.1093/annonc/mdw199.277

Language: English

Publisher: Elsevier BV

Publication Date: 2016

detail.hit.zdb_id: 2003498-2