Abstract
Introduction: The histone methyl transferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and responsible for methylation of lysine 27 of histone H3 (H3K27), a modification of DNA associated with repressed transcription when trimethylated (H3K27me3). Aberrant EZH2 activity has been implicated as an oncogenic driver in non-Hodgkin's lymphoma (NHL). Here we report the phase 1 first-in-human experience to date with tazemetostat in patients (pts) with NHL.
Methods: Tazemetostat was administered orally twice daily (BID) to subjects in five dose cohorts (100 mg [n=6], 200 mg [n= 3], 400 mg [n=3], 800 mg [n=14], 1600 mg [n=12], and one food effect cohort (400 mg [n=7]). Tumor response assessments were performed every 8 weeks. Archival tumor tissue from NHL pts was analysed for EZH2 hot spot mutations Y646X, A682G and A692V (by either amplicon-based next generation sequencing [NGS] or cobas ® EZH2 Mutation Test [in development]), and for additional somatic mutations by NGS focusing on a panel of 39 genes commonly mutated in NHL. In addition, cell-of-origin in Diffuse Large B-cell Lymphoma (DLBCL) patients was determined by immunohistochemistry on archival tumor tissue using the Hans algorithm (Blood, 2004).
Results: As of 9-July 2015, 45 pts were enrolled to this trial (CT.gov: NCT01897571). To date 19 NHL pts: 13 DLBCL, 5 follicular lymphoma (FL) and 1 marginal zone lymphoma (MZL) were enrolled. Results to date on the 26 solid tumor pts have been reported separately (ECC, 2015). Adverse events (AE) occurring in >10% of the 45 pts regardless of attribution were: asthenia, anorexia, constipation, nausea, dysgeusia, vomiting and muscle spasms with 5 grade 3 or greater related AE's: thrombocytopenia, neutropenia, hypertension, anorexia and transaminase elevation. The median age of the NHL patients enrolled was 62 yrs (range 23-82) and 74% of pts were male. Of the fifteen evaluable NHL pts, objective responses were seen in: 5/9 DLBCL, 3/5 FL and 1/1 MZL. The majority of objective responses occurred at the Recommended Phase 2 Dose of 800 mg BID. EZH2 status in patient tumors was determined for 14/19 NHL patients (n=3 data pending, n=2 tissue unavailable) with 13/14 found to be wild-type (WT) and one patient, who experienced an ongoing PR at week 16, expressing an Y646H mutation. Updated data including duration of response will be presented. In addition, 10/13 patients had evidence of somatic mutations in >1 non-EZH2 genes among the 39 genes tested (allelic frequency >10% with coverage >1000X) known to be commonly mutated in NHL, e.g. MYD88 & CARD11, or involved in epigenetic signalling, e.g. EP300 & CREBBP. Table.Relapsed or refractory NHLTotal(n=19)Evaluable(n=15)Best Response CR+PRaBest Response SDaDLBCLGCB4220Non-GCB6520undetermined3210FL5531MZL1110aper IWG (Cheson, 2007), complete response (CR), partial response (PR), stable disease (SD)
Conclusions: Tazemetostat demonstrates a safety profile favorable for chronic dosing and objective responses in pts with either EZH2 WT or mutant B-cell lymphoma, including both GCB and non-GCB sub-types of DLBCL. EZH2 pathway genes and genes commonly somatically mutated in lymphoma are under investigation to elucidate the mechanisms and biomarkers of clinical response to tazemetostat. Based upon the observed safety and efficacy profile of tazemetostat, a phase 2 trial in relapsed or refractory DLBCL and FL pts, stratified by cell-of-origin and EZH2 mutation status, is enrolling.
Disclosures
Ribrag: Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thomson:Epizyme, Inc: Employment. Keilhack:Epizyme: Employment, Equity Ownership. Blakemore:Epizyme: Employment. Reyderman:Eisai: Employment. Kumar:Eisai: Employment. Fine:Epizyme: Employment. McDonald:Epizyme: Employment. Ho:Epizyme, Inc: Employment.
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