Franck Morschhauser MD, PhD
Tazemetostat, a small molecule that targets epigenetic activity of the EZH2
gene, is being investigated as a treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). The drug is being administered as monotherapy or in combination with prednisone in a 6-cohort, biomarker-driven phase II trial (NCT01897571).
The goal of the research, according to key trial investigators, is to develop another alternative for patients with the non-Hodgkin lymphoma subtypes. The study, which includes patients with FL, has more cohorts for adults 18 years and older with DLBCL, the paradigm for whom is frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
“In the last 10 years, there have been no new drugs approved for frontline treatment of patients living with DLBCL. Forty perfecnt of those patients will go on to relapse or become refractory to R-CHOP,” said Franck Morschhauser, MD, PhD, professor of hematology at the Centre Hospitalier Régional Universitaire de Lille, Hôpital Claude Huriez, Service des Maladies du Sang, France.
“Unfortunately, only a small percentage of patients with DLBCL are eligible for stem cell transplantation, and patients often aren’t ideal candidates for high-dose, complex chemotherapy due to their age or other comorbidities associated with their disease,” added Morschhauser, who is the lead investigator of the phase II portion of the study.
EZH2, a histone methyltransferase, is an important target as an epigenetic regulator of cellular differentiation programs. Mutations in EZH2
, the enhancer of zeste homolog 2 gene, lead to abnormal histone methylation profiles, which can result in oncogenic transformation. Tazemetostat inhibits EZH2, and therefore promotes a tumor-suppressive environment. Somatic mutations in EZH2
have been observed in 21.7% of germinal center B-cell like (GCB) DLBCLs, a subset of the malignancy, and in 7.2% of FL samples.1
will alter the expression of an array of different genes, but for some reason the resultant expression pattern favors tumor formation. By blocking it with an EZH2 inhibitor, we tend to favor the more tumorsuppressive environment,” said John F. Gerecitano, MD, PhD, the lead trial investigator at Memorial Sloan Kettering Cancer Center in New York City, where he is a medical oncologist and clinical director of lymphoma outpatient services. “It is still not known which of those genes is most important in tumorigenesis, but there are many cases where affecting a wide variety of gene expressions can lead to either a more or less oncogenic milieu.”
The tazemetostat trial is being conducted in 2 parts: a phase I portion for patients with B-cell lymphomas and advanced solid tumors to establish the appropriate dose and a phase II portion that is intended to demonstrate the efficacy of the drug as monotherapy or in combination with prednisone. The phase I portion is closed to new participants. The phase II portion is currently recruiting in several cohorts, with more than 60% of the projected total of 340 patients already enrolled.
The trial includes 3 cohorts for patients with DLBCL subtypes who will receive tazemetostat monotherapy: EZH2
wild-type GCB, EZH2
-mutant GCB, and non-GCB (Figure).2
“The reason for that is that these mutations occur in EZH2
almost exclusively in GCB. The study wanted to look at mutated versus nonmutated [EZH2
], and the non-GCB subtype almost never has this mutation, so that was its own category,” said Gerecitano.
Another cohort was added this year for patients with DLBCL who will receive the drug in combination with prednisone. Additionally, there are 2 cohorts for patients with FL who will receive tazemetostat monotherapy, stratified by whether the patients have EZH2
wild-type or mutant disease.2
Tazemetostat has demonstrated favorable antitumor activity in early clinical trial results, according to interim phase II findings. Among participants evaluable for efficacy on June 1, the objective response rate (ORR) was 29% among patients with EZH2
-mutated DLBCL (5 of 17 patients) and 15% among those with wild-type disease (18 of 119). For patients with FL, the ORR was 92% for those with the mutation (12 of 13) and 26% for those with wildtype disease (14 of 54).2
The overall safety profile of tazemetostat has been favorable, according to Morschhauser, with low rates of dose reductions and study discontinuations. The common adverse events (AEs) include fatigue, anemia, neutropenia, thrombocytopenia, anorexia, constipation, and diarrhea, and are typically grade 1 or 2. Ten percent of patients experienced serious treatment-related AEs.2 “This gives us a nontoxic targeted therapy for patients who would be best served by avoiding chemotherapy, and patients tend to tolerate it very well with a promising response rate,” Gerecitano said.
In April 2017, the FDA granted a fast track designation to tazemetostat for both relapsed/refractory FL with or without an EZH2
activating mutation, and DLBCL with EZH2
activating mutations, according to Epizyme, the company developing the drug.3
- Morin RD, Johnson NA, Severson TA, et al. Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin. Nat Genet. 2010;42(2):181-185. doi: 10.1038/ng.518
- Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Paper presented at: 14th International Conference on Malignant Lymphoma; Lugano, Switzerland; June 14-17, 2017. Abstract 4. doi: 10.1002/hon.2437_3.
- Epizyme announces tasemetostat fast track designation for follicular lymphoma and plenary session on phase 2 NHL data at ICML [press release]. Cambridge, MA: Epizyme, Inc; April 25, 2017. amda-1rbic2.client. shareholder.com/releasedetail.cfm?ReleaseID=1022650. Accessed September 29, 2017.