Follicular lymphoma, an indolent form of non-Hodgkin lymphoma, is considered to be incurable with existing treatments and is characterized by cycles of relapse that become increasingly difficult to treat with each disease progression.
Approximately 25,000 patients in the U.S. and major European countries are diagnosed with follicular lymphoma every year, of which an estimated 15-20 percent have an EZH2 mutation.
Interim efficacy data from an ongoing phase II clinical trial show that single-agent treatment with tazemetostat, a first-in-class, oral EZH2 inhibitor, resulted in a clinically meaningful benefit in patients with relapsed or refractory patients with follicular lymphoma.
The phase II results were recently presented during a plenary session at the International Conference on Malignant Lymphoma (ICML), held June 14-17 in Lugano, Switzerland (Hematol Oncol 2017; doi:10.1002/hon.2437_3).
Tazemetostat has shown antitumor activity in preclinical models as well as in a phase II study in patients with mutated or wild-type EZH2 tumors.
In this open-label, multicenter phase II study, researchers enrolled patients with either mutated or wild-type EZH2 relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL) to determine efficacy and safety in six separate cohorts.
Investigators enrolled 218 patients (81% of total (n=270)) into monotherapy cohorts. The wild-type groups for both follicular lymphoma and DLBCL are closed to accrual. The mutated cohorts for both diseases remain open to accrual.
Enrolled patients were prospectively stratified by EZH2 mutational status and cell of origin. Key inclusion criteria included patients 18 years or older who have received at least two or more prior therapies, as well as measurable disease and adequate organ function.
The primary endpoint of the study was overall response rate (ORR). Secondary efficacy endpoints included progression-free survival and duration of response.
By June 1, 2017, 19 follicular lymphoma patients with EZH2-activating mutations were enrolled; of these patients, 13 are evaluable for efficacy. Enrollment of EZH2 activating mutation patients with EZH2 wild-type was completed in late 2016 with a total of 54 patients, all of which are evaluable for efficacy.
According to researchers, more than 75 percent of evaluable follicular lymphoma patients had three or more prior treatments, and approximately 50 percent of patients in each group were refractory to their last prior therapy
As of the cutoff date, researchers had enrolled 22 DLBCL patients with EZH2 mutations, and efficacy was assessed on 17 patients. Enrollment of DLBCL patients with EZH2 wild-type was completed in early 2017 with 120 patients; 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,” according to researchers.
Based on interim efficacy results, follicular lymphoma patients with EZH2 mutations have benefited significantly from tazemetostat therapy.
Researchers reported that the subset of follicular lymphoma patients with EZH2-activating mutations have a 92 percent ORR. Additionally, patients with EZH2 wild-type have an ORR of 26 percent and 22 percent of patients with stable disease are still on the study.
Promising activity was also observed in DLBCL patients with EZH2 mutations, which includes recently enrolled patients, with an ORR of 29 percent.
“This phase II interim assessment shows preliminary clinical activity of tazemetostat with a favorable safety profile in patients with R/R DLBCL and follicular lymphoma, with preferential benefit in patients whose tumors bear activating EZH2 mutations,” researchers concluded. “Patients 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 stable disease to partial response and from partial response to complete response.”
As the size of the mutation study groups increase and patients remain on study, researchers expect the data will continue to evolve. In addition, tazemetostat continues to demonstrate a favorable safety profile across all patient populations in this study.
Safety data from patients enrolled in the 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 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 5 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).
Additional data from a 62-gene panel biomarker study of tazemetostat in patients with various subtypes of non-Hodgkin lymphoma was also presented during a poster session at the ICML conference (Poster 154).
Blakemore et al. reported on “the molecular analysis of tumor material obtained in the phase II study and its associations with preliminary response data, including the discovery of a novel candidate molecular predictor of tazemetostat response.”
Next-generation sequencing analysis was performed on archive tumor and circulating tumor DNA (ctDNA) for a subset (n=92) of patients to identify somatic mutations, amplifications, and translocations. Researchers identified positive and negative predictors for tazemetostat response (PR/CR). Positive predictors included EZH2- and MYD88-activating mutations. MYC, TP53, and HIST1H1E were identified as negative predictors.
“Molecular genetic profiling of non-Hodgkin lymphoma patents identified potential predictors of response to tazemetostat beyond EZH2-activating mutations and offered new insights into mechanisms of response in EZH2 wild-type patients,” researchers concluded. “Plasma-based ctDNA screening may be a viable method to identify non-Hodgkin lymphoma patients with EZH2-activating mutations in the absence of archive tumor samples.”
The activity of tazemetostat across follicular lymphoma patients is encouraging, according to researchers, and when combined with the well-tolerated safety profile, supports its potential utility as both a monotherapy and a combination agent. Combination treatment has become the evolving standard of care for follicular lymphoma, and future research will include investigation of tazemetostat as a combination therapy.
Activity is likely to be enhanced for wild-type disease through combination treatment. A combination program is 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.
“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,” concluded 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.”