Date: 2015-07-09
Type of
information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the International Conference on Malignant Lymphoma (ICML)
Company: Epizyme (USA - MA)
Product: tazemetostat - EPZ-6438 (E7438)
Action
mechanism:
- enzyme inhibitor/histone methyltransferase inhibitor. EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include germinal center (GC) non-Hodgkin lymphomas, INI1-deficient cancers such as synovial sarcoma and malignant rhabdoid tumors, and a range of other solid tumors. EPZ-6438 is a small molecule inhibitor of EZH2 created with Epizyme’s proprietary product platform, for the treatment of non-Hodgkin lymphoma patients. In many human cancers, misregulated EZH2 enzyme activity results in misregulation of genes that control cell proliferation — without these control mechanisms, cancer cells are free to grow rapidly.
- Epizyme granted Eisai a worldwide license to EPZ-6438 (Eisai refers to this therapeutic candidate as E7438), subject to Epizyme's right to opt in for co-development, co-commercialization and profit share arrangement with Eisai in the United States. Epizyme is working with Roche and Eisai to develop a companion diagnostic to identify patients with non-wild type EZH2, where EZH2 contains point mutations.
Disease: diffuse large B-cell lymphoma, follicular lymphoma
Therapeutic
area: Cancer - Oncology
Country: Australia, France, Italy, UK, USA
Trial
details:
- This multicenter, open-label, Phase 1/2 study is being conducted in two parts. The Phase 1 portion comprises dose escalation and establishment of the recommended Phase 2 dose (RP2D) when EPZ-6438 (E7438) is given BID (twice daily) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of EPZ-6438 as well as the drug-drug interaction (DDI) potential of EPZ-6438 are being evaluated. When maximum tolerated dose (MTD) has been identified and the RP2D confirmed, the Phase 2 portion will enroll subjects that have relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphomas (FL) that have either mutant or wild-type EZH2. (NCT01897571)
Latest
news:
- • On June 14, 2017, Epizyme announced interim efficacy data from the company's ongoing Phase 2 clinical trial of tazemetostat, as a single-agent treatment for relapsed or refractory patients with follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) grouped by EZH2 mutational status. The data were presented during a plenary session at the International Conference on Malignant Lymphoma (ICML), which is being held June 14-17, 2017 in Lugano, Switzerland . Interim data as of June 1, 2017 show that tazemetostat treatment resulted in a clinically meaningful benefit in patients with FL. The subset of FL patients with EZH2 activating mutations have a 92 percent objective response rate (ORR). Patients with FL with EZH2 wild-type have an ORR of 26 percent and 22 percent of patients with stable disease are still on study. Promising activity was also observed in DLBCL patients with EZH2 mutations, which includes recently enrolled patients, with an ORR of 29 percent. As the size of the mutation study groups increase and patients remain on study, Epizyme expects the data will continue to evolve. In addition, tazemetostat continues to demonstrate a favorable safety profile across all patient populations in this study.
- Follicular Lymphoma Efficacy Data
As of June 1, 2017 , Epizyme enrolled 19 FL patients with EZH2 activating mutations in the Phase 2 trial, of which 13 are evaluable for efficacy. Enrollment of FL patients with EZH2 wild-type was completed in late 2016 with a total of 54 patients, all of which are evaluable for efficacy. More than 75 percent of evaluable FL patients had three or more prior treatments, and approximately 50 percent of patients in each group were refractory to their last prior therapy. Key interim efficacy findings are as follows:
|
FL with EZH2 MT |
FL with EZH2 WT |
| Evaluable for efficacy on June 1, 2017 |
n =13 |
n =54 |
| Objective Response Rate (CR + PR) |
12 (92%) |
14 (26%) |
| Complete Response (CR) |
1 (8%) |
3 (6%) |
| Partial Response (PR) |
11 (85%) |
11 (20%) |
| Stable Disease (SD) |
1 (8%) |
23 (43%) |
| SD study drug ongoing |
1 (8%) |
12 (22%) |
| Progressive Disease |
0 |
13 (24%) |
| No Data, Unknown (UNK) |
0 |
4 (7%) |
| Time to first Response (weeks)
median (range) |
11.9
(6.9 - 35.9) |
15.2
(8.1 - 32.1) |
The activity of tazemetostat across FL patients is encouraging, and when combined with the well-tolerated safety profile, supports its potential utility as both as monotherapy and a combination agent. Combination treatment has become the evolving standard-of-care for FL, and Epizyme plans to begin investigating tazemetostat as a combination agent in FL this year.
- Diffuse Large B-Cell Lymphoma Efficacy Data
As of June 1, 2017 , Epizyme had enrolled 22 DLBCL patients with EZH2 mutations, and efficacy was assessed on 17 patients. Enrollment of DLBCL patients with EZH2 wild-type (germinal center and non-germinal center) was completed in early 2017 with 120 patients, of which 119 were evaluable for efficacy. Patients with DLBCL with EZH2 activating mutations represent the most advanced and severely ill patients in the study, with 82 percent having been previously treated with at least three therapeutic regimens and refractory to their last treatment. Key interim efficacy findings are as follows:
|
DLBCL EZH2 MT |
DLBCL EZH2 WT |
| Evaluable for efficacy on June 1, 2017 |
n = 17 |
n = 119 |
| Objective Response Rate (CR + PR) |
5 (29%) |
18 (15%) |
| Complete Response (CR) |
0 |
10 (8%) |
| Partial Response (PR) |
5 (29%) |
8 (7%) |
| Stable Disease (SD) |
6 (35%) |
22 (18%) |
| SD study drug ongoing |
1 (6%) |
4 (3%) |
| Progressive Disease |
6 (35%) |
60 (50%) |
| No Data, Unknown (UNK) |
0 |
19 (16%) |
| Time to first Response (weeks)
median (range) |
8.3
(4.6 - 48.1) |
8.5
(5.3 - 24.7) |
Epizyme believes that activity is likely to be enhanced for wild-type disease through combination treatment. The company has a robust combination program underway in DLBCL evaluating tazemetostat in an immuno-oncology combination with atezolizumab and a steroid combination with prednisolone. In addition, tazemetostat is being evaluated in the front-line setting in combination with R-CHOP in newly diagnosed, high-risk DLBCL patients.
- Tazemetostat Safety Profile
Safety data from patients in this Phase 2 trial (n=210), as of the data cutoff, demonstrate a favorable tolerability profile, consistent with the experience observed in a nearly 400-patient safety database from tazemetostat clinical trials to date. Across all cohorts of this trial, dose reductions and discontinuations due to treatment-related adverse events are low, at only three and two percent, respectively.
- The majority of treatment-emergent adverse events are grade 1 or 2, with only 18 percent of grade 3 or higher being considered treatment-related. Treatment-emergent adverse events, regardless of attribution and affecting more than five percent of patients, are nausea (20%); thrombocytopenia (19%); anemia (16%); cough (14%); fatigue (12%); diarrhea (11%); asthenia, neutropenia, pyrexia and vomiting (10% each); bronchitis (7%); and constipation, decreased appetite, upper respiratory infection, abdominal pain, headache and urinary tract infection (6% each).
- The data in the poster detail both potential positive and negative predictors of response to tazemetostat. In the case of positive predictors, both EZH2 and MYD88 are mutations that appear to enhance patients' sensitivity to tazemetostat. The company has also detected EZH2 mutations by circulating tumor DNA in patient serum, indicating the potential future use of a tube of blood for patient identification of EZH2 mutations rather than testing patient's archival tumor samples.
- • On December 28, 2015, Epizyme announced the FDA's Division of Hematology Products has accepted the company's investigational new drug (IND) application for tazemetostat for the treatment of adults with diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin Lymphoma (NHL). An ongoing five-arm registration-supporting, international phase 2 clinical trial assessing the safety and activity of tazemetostat in patients with relapsed or refractory B-cell NHL was initiated in July 2015 . The IND acceptance will allow the company to enroll DLBCL patients in the United States into this ongoing trial.
Is
general: Yes
