302 A phase 1 study of EPZ-6438 (E7438), an Enhancer of Zeste-Homolog 2 (EZH2) inhibitor: Preliminary activity in INI1-negative tumors

Italiano, Antoîne; Keilhack, Heike; Toulmonde, Michel; Coindre, JM; Michot, Jean‐Marie; Massard, C.; Ottesen, Lone H.; Reyderman, Larisa; Blakemore, Stephen J.; Kraljevic, S.; Thomson, Bennett; McDonald, Alice; Ho, Peter; Ribrag, Vincent

doi:10.1016/s0959-8049(16)30168-x

Cited by 17 publications

(22 citation statements)

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“…Within this study of 51 patients (30 solid tumor and 21 non-Hodgkin's lymphoma) immunohistochemistry of tumor tissue identified five INI1-deficient MRT patients and two SMARCA4-deficient SCCOHT patients. As reported by Ribrag and colleagues (46) responses observed in patients with MRT after 8 weeks of treatment included one complete response (CR), one partial response (PR), two stable disease (SD), and one progressive disease (PD). Clinical responses observed in patients with SCCOHT after 8 weeks of treatment included one PR and one SD.…”

Section: Discussionmentioning

confidence: 72%

“…Indeed, we reported the first clinical activity of an EZH2 inhibitor in patients with INI-deficient MRT and SMARCA4-deficient SCCOHT in our Phase 1, first-in-human study (E7438-G000-001, NCT01897571), testing the effects of tazemetostat in INI1-deficient and SMARCA4-deficient relapse and/or refractory solid tumors (46). Within this study of 51 patients (30 solid tumor and 21 non-Hodgkin's lymphoma) immunohistochemistry of tumor tissue identified five INI1-deficient MRT patients and two SMARCA4-deficient SCCOHT patients.…”

Section: Discussionmentioning

confidence: 99%

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Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

Chan-Penebre

Armstrong

Drew

et al. 2017

Molecular Cancer Therapeutics

148

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The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850-60. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

Chan-Penebre

Armstrong

Drew

et al. 2017

Molecular Cancer Therapeutics

148

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Section: Discussionmentioning

confidence: 99%

“…Clinical results for tazemetostat support the importance of loss of SWI/SNF function as one predictor for sensitivity to the agent . In a phase 1 trial for adults with cancer, dose levels from 100 to 1600 mg twice daily were evaluated with expansion cohorts at 800 and 1,600 mg twice daily . Among 30 solid tumor patients, eight had SMARCB1 ‐negative tumors (five with MRTs and three with epithelioid sarcomas [ES]) and three had SMARCA4‐negative tumors (two with SCCOHT and one with thoracic sarcoma).…”

Section: Discussionmentioning

confidence: 99%

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Kurmasheva

Sammons

Favours

et al. 2016

Pediatric Blood & Cancer

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Background Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2, currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors. Procedures Tazemetostat was tested against the PPTP solid tumor xenografts using a dose of 400 mg/kg administered twice-daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors. Results Tazemetostat induced significant differences in event free survival (EFS) distribution compared to control in 9 of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in 5 of 7 (71%) rhabdoid tumor xenograft lines compared to 4 of 23 (17%) non-rhabdoid xenograft lines [chi square (χ2) test p=0.006]. Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated to control (T/C) activity in 2 of 25 (8%) and 1 of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (3 of 5 rhabdoid tumor versus 0 of 22 non-rhabdoid tumors (χ2 test p<0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared to controls. Conclusions Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models, but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.

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“…Lately, few studies have shown loss of SMARCB1/INI1 in certain EMCs, while another study has shown contrasting results [9,[13][14][15]. Considering there is emerging preclinical data to show role of EZH2 inhibitor in tumors lacking INI1, it is important to correctly identify such tumors [16,17].…”

Section: Introductionmentioning

confidence: 99%

Extraskeletal Myxoid Chondrosarcomas are not Characterized by Loss of INI1/SMARCB1: Immunohistochemical Analysis of 16 Cases

Rekhi¹,

Ramadwar²,

Bajpai³

2017

J Carcinog Mutagen

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Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, characterized by t (9; 22) translocation, including EWSR1 and NR4A3 gene rearrangements, observed in most cases. On histopathologic examination, an EMC has certain diagnostic mimics, such as myoepithelial tumors, epithelioid malignant peripheral nerve sheath tumor and epithelioid sarcomas. All these tumors are included in the category of INI1/SMARCB1-deficient tumors. Lately, few studies have shown loss of INI1 in certain EMCs. Considering there is preclinical data regarding role of EZH2 inhibitor in "INI1 deficient" tumors, it is crucial to recognize such tumors.

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302 A phase 1 study of EPZ-6438 (E7438), an Enhancer of Zeste-Homolog 2 (EZH2) inhibitor: Preliminary activity in INI1-negative tumors

Cited by 17 publications

References 0 publications

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

Initial testing (stage 1) of tazemetostat (EPZ‐6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program

Extraskeletal Myxoid Chondrosarcomas are not Characterized by Loss of INI1/SMARCB1: Immunohistochemical Analysis of 16 Cases

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