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 mutations 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 tumour DNA (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 prednisolone 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 phase 2 interim assessment shows preliminary clinical activity of tazemetostat with a favourable safety profile in pts with R/R DLBCL and FL, with preferential benefit in pts whose tumours bear activating EZH2 mutations. Pts continue to be followed for tazemetostat treatment outcomes in light of previously reported observations that the onset of clinical response may be delayed and evolve over time from SD to PR and from PR to CR. Keywords: diffuse large B-cell lymphoma (DLBCL); EZH2; follicular lymphoma (FL).