ICML 2017: Phase II Trial of Tazemetostat in Relapsed or Refractory Follicular Lymphoma and DLBCL
Positive interim efficacy data from an ongoing phase II clinical trial of tazemetostat, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor, as a single-agent treatment for relapsed or refractory patients with follicular lymphoma or diffuse large B-cell lymphoma (DLBCL) grouped by EZH2 mutational status were presented by Morschhauser et al at the International Conference on Malignant Lymphoma (ICML), in Lugano, Switzerland.
Interim data as of June 1, 2017, showed that tazemetostat treatment resulted in a clinically meaningful benefit in patients with follicular lymphoma. The subset of patients with follicular lymphoma with EZH2-activating mutations had a 92% objective response rate (ORR). Patients with follicular lymphoma with EZH2 wild-type had an ORR of 26%, and 22% 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%. In addition, tazemetostat continues to demonstrate a favorable safety profile across all patient populations in this study.
“I believe that tazemetostat may play a significant role in disease management for my patients, and am particularly excited by the impact observed in patients with follicular lymphoma,” said Franck Morschhauser, MD, PhD, Centre Hospitalier Régional Universitaire de Lille, France, and lead investigator of the phase II study. “I am also encouraged by the level of activity in DLBCL patients with EZH2 mutations, especially in light of the bleak prognosis associated with advanced disease. Tazemetostat has demonstrated a uniquely tolerable safety profile, and I look forward to further exploring its full benefit in patients with relapsed or refractory follicular lymphoma and DLBCL as the data mature.”
“These interim data findings represent an important step forward for our tazemetostat program, with antitumor activity observed across all groups of the study,” said Rob Bazemore, Chief Executive Officer of Epizyme. “The activity we have observed in patients with an EZH2 mutation exceeds what we have seen so far with wild-type EZH2, consistent with our scientific hypothesis, and we are encouraged by both the objective responses and durability of responses in follicular lymphoma and DLBCL. Our focus is on continuing to increase enrollment of patients with an EZH2 mutation...”
Follicular Lymphoma Efficacy Data
Approximately 25,000 patients in the U.S. and major European countries are diagnosed with follicular lymphoma every year, of which an estimated 15% to 20% have an EZH2 mutation. There are no approved treatments indicated for patients with follicular lymphoma with an EZH2 mutation.
As of June 1, 2017, 19 follicular lymphoma patients with EZH2-activating mutations were enrolled in the phase II trial, of which 13 are evaluable for efficacy. Enrollment of follicular lymphoma 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% of evaluable follicular lymphoma patients had three or more prior treatments, and approximately 50% of patients in each group were refractory to their last prior therapy.
The objective response rate was 92% in follicular lymphoma patients with EZH2 mutations. In patients with EZH2 wild-type, objective response rate was 26%.
The activity of tazemetostat across follicular lymphoma patients is encouraging, and when combined with the well-tolerated safety profile, supports its potential utility as both as monotherapy and a combination agent.
Diffuse Large B-Cell Lymphoma Efficacy Data
Among patients with germinal center DLBCL, an estimated 15% to 20% have an EZH2 mutation. Forty percent to 50% of patients will relapse on their first-line treatment, which is most commonly the chemotherapy regimen R-CHOP, and there are few treatment options for patients who relapse or become refractory to chemotherapy.
As of June 1, 2017, 22 patients with DLBCL patients with EZH2 mutations were enrolled in the trial, 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.
The objective response rate for patients with DLBCL with EZH2 mutations was 29%. In patients with EZH2 wild-type, the objective response rate was 15%.
Tazemetostat Safety Profile
Safety data from patients in the phase II 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 3% and 2%, respectively.
The majority of treatment-emergent adverse events were grade 1 or 2, with only 18% of grade 3 or higher being considered treatment-related. Treatment-emergent adverse events, regardless of attribution and affecting more than 5% of patients, were 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).
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