Contributions
Abstract: S100
Type: Oral Presentation
Presentation during EHA23: On Friday, June 15, 2018 from 11:30 - 11:45
Location: Room A1
Background
R/R FL remains an area of unmet medical need and treatments with novel mechanisms of action are urgently needed. The histone methyltransferase EZH2 is an important regulator of the germinal center (GC) reaction that is involved in prevention of terminal differentiation of GC B-cells. EZH2 activating mutations are not uncommon in FL and are postulated to be oncogenic drivers. Tazemetostat, a potent, selective, oral EZH2 inhibitor has shown antitumor activity in a phase 1 study that included NHL patients with mutated (mt) or wild-type (wt) EZH2 tumors, providing rationale for further investigation.
Aims
This open-label, multicenter phase 2 study is enrolling patients with either mt or wt EZH2 R/R diffuse large B-cell lymphoma or FL (Grade 1-3b); Results of an interim analysis of FL patients are presented here.
Methods
Key inclusion criteria include: age ≥18 years old, ≥2 prior treatment regimens, measurable disease, and adequate organ function. Tazmetostat 800 mg is administered orally, twice daily (BID). Response is assessed every 8 weeks using 2007 IWG-NHL assessment criteria. Tumor tissue is analyzed for EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, investigational use only). The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and safety/tolerability.
Results
As of January 16, 2018, interim phase 2 safety and efficacy data were summarized from 76 FL patients (median 3 prior therapies; one patient who had not yet been evaluated at week 8 was excluded from the efficacy analysis). In patients with an activating EZH2 mutation (n=22), the ORR (complete response [CR] + partial response [PR]) was 82%, with best overall response of CR 5% (n=1), PR 77% (n=17), stable disease (SD) 18% (n=4), and no patients with progressive disease (PD). Median PFS was >48 weeks and median duration of response (DOR) was >32 weeks. Fifty-six percent of patients (10/18) have maintained their response and remain on study. In the EZH2 wt group (n=54), ORR was 35% (n=19), with best overall response of CR 6% (n=3), PR 30% (n=16), SD 30% (n=16), PD 30% (n=16); data not available for 3 patients. Median PFS was >30 weeks and median DOR >56 weeks. Fifty-eight percent of patients (11/19) have maintained their response and remain on study. Safety analysis showed that treatment-emergent adverse events (TEAE) leading to study drug discontinuation occurred in 12% of patients. Grade ≥3 treatment-related AEs were reported in 12% of patients. The most common (≥10%) treatment-related TEAEs (all grades) were: nausea (18%), anemia (13%), fatigue (13%), diarrhea (12%), and asthenia (10%).
Conclusion
Tazemetostat appears to be generally well tolerated at a dose of 800 mg BID with observed meaningful clinical activity and durability of response in FL patients who have had multiple prior therapies, as seen in this interim update. Clinical activity is pronounced in patients with EZH2 activating mutations; 100% had CR, PR, or SD as best response. For wt, 65% had CR, PR, or SD as best response. Late onset responses have been previously reported on tazemetostat, therefore clinical outcome in patients on continuing treatment may evolve from SD to PR and from PR to CR. These encouraging phase 2 data demonstrate that EZH2 inhibition may be an important and effective therapeutic target.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Phase II, Epigenetic, EZH2, Follicular lymphoma
Abstract: S100
Type: Oral Presentation
Presentation during EHA23: On Friday, June 15, 2018 from 11:30 - 11:45
Location: Room A1
Background
R/R FL remains an area of unmet medical need and treatments with novel mechanisms of action are urgently needed. The histone methyltransferase EZH2 is an important regulator of the germinal center (GC) reaction that is involved in prevention of terminal differentiation of GC B-cells. EZH2 activating mutations are not uncommon in FL and are postulated to be oncogenic drivers. Tazemetostat, a potent, selective, oral EZH2 inhibitor has shown antitumor activity in a phase 1 study that included NHL patients with mutated (mt) or wild-type (wt) EZH2 tumors, providing rationale for further investigation.
Aims
This open-label, multicenter phase 2 study is enrolling patients with either mt or wt EZH2 R/R diffuse large B-cell lymphoma or FL (Grade 1-3b); Results of an interim analysis of FL patients are presented here.
Methods
Key inclusion criteria include: age ≥18 years old, ≥2 prior treatment regimens, measurable disease, and adequate organ function. Tazmetostat 800 mg is administered orally, twice daily (BID). Response is assessed every 8 weeks using 2007 IWG-NHL assessment criteria. Tumor tissue is analyzed for EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, investigational use only). The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and safety/tolerability.
Results
As of January 16, 2018, interim phase 2 safety and efficacy data were summarized from 76 FL patients (median 3 prior therapies; one patient who had not yet been evaluated at week 8 was excluded from the efficacy analysis). In patients with an activating EZH2 mutation (n=22), the ORR (complete response [CR] + partial response [PR]) was 82%, with best overall response of CR 5% (n=1), PR 77% (n=17), stable disease (SD) 18% (n=4), and no patients with progressive disease (PD). Median PFS was >48 weeks and median duration of response (DOR) was >32 weeks. Fifty-six percent of patients (10/18) have maintained their response and remain on study. In the EZH2 wt group (n=54), ORR was 35% (n=19), with best overall response of CR 6% (n=3), PR 30% (n=16), SD 30% (n=16), PD 30% (n=16); data not available for 3 patients. Median PFS was >30 weeks and median DOR >56 weeks. Fifty-eight percent of patients (11/19) have maintained their response and remain on study. Safety analysis showed that treatment-emergent adverse events (TEAE) leading to study drug discontinuation occurred in 12% of patients. Grade ≥3 treatment-related AEs were reported in 12% of patients. The most common (≥10%) treatment-related TEAEs (all grades) were: nausea (18%), anemia (13%), fatigue (13%), diarrhea (12%), and asthenia (10%).
Conclusion
Tazemetostat appears to be generally well tolerated at a dose of 800 mg BID with observed meaningful clinical activity and durability of response in FL patients who have had multiple prior therapies, as seen in this interim update. Clinical activity is pronounced in patients with EZH2 activating mutations; 100% had CR, PR, or SD as best response. For wt, 65% had CR, PR, or SD as best response. Late onset responses have been previously reported on tazemetostat, therefore clinical outcome in patients on continuing treatment may evolve from SD to PR and from PR to CR. These encouraging phase 2 data demonstrate that EZH2 inhibition may be an important and effective therapeutic target.
Session topic: 21. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Phase II, Epigenetic, EZH2, Follicular lymphoma