INTERIM REPORT FROM A PHASE 2 MULTICENTER STUDY OF TAZEMETOSTAT, AN EZH2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B‐CELL NON‐HODGKIN LYMPHOMAS

Abstract

Background: New treatments with novel mechanisms of action are needed for patients with relapsed/refractory (R/R) DLBCL and FL. Because tumor cells may depend on the histone methyltransferase EZH2 to perpetuate a less‐differentiated state, and activating muta- tions may be oncogenic drivers, tazemetostat, a potent, selective EZH2 inhibitor was developed. Tazemetostat shows antitumor activity in preclinical models and in a phase 1 study in patients (pts) with mutated or wild‐type (wt) EZH2 tumours. This open‐label, multicentre phase 2 study enrolled pts with either mutated or wt EZH2 R/R DLBCL or FL to determine efficacy and safety in 6 separate cohorts. Methods: Tazemetostat 800 mg is administered po BID. Tumour tissue is analysed prospectively to guide cohort assignment based on EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, in development). A 62‐gene panel is used to assess tissue DNA and circulating tumourDNA (ctDNA) for biomarkers of tazemetostat sensitivity. Key inclusion criteria include: ≥18 yrs old; ≥2 prior treatment regimens; measurable disease; and adequate organ function. The primary endpoint is overall response rate (ORR). Secondary endpoints include progression‐free survival and safety/tolerability. Enrolment for monotherapy has been completed in 3 cohorts with wt EZH2 and is ongoing in 2 cohorts of mutant EZH2. Enrolment for a tazemetostat combination with prednis- olone in wt EZH2 DLBCL was recently initiated. Results: As of Feb. 28, 2017, interim safety data are summarized from 165 DLBCL or FL pts with documented tazemetostat dosing. Grade- 3 treatment‐emergent adverse events related to tazemetostat were reported in 18% of pts. The most common (>10%) adverse events across all grades were: nausea; thrombocytopenia; cough; diarrhoea; fatigue; and asthenia. Interim efficacy results are summarized from 149 pts (median: 3 prior therapies) and exclude ongoing pts who lack an on‐study tumor assessment. The ORR (CR + PR) was 40% in pts with DLBCL with EZH2 mutations (N = 10), 18% in pts with DLBCL with wt EZH2 (N = 85), 63% in FL pts with EZH2 mutations (N = 8), and 28% in FL pts with wt EZH2 (N = 46). In the cohorts of EZH2 mutant FL and EZH2 wt FL, 38% and 30% of pts, respectively, remained on study with stable disease. Safety and efficacy data will be further updated at the conference. The genetic analysis of tumor biomarkers will be reported separately. Conclusion: This p…