Tazemetostat, a first-in-class EZH2 inhibitor, has demonstrated single-agent antitumor activity in patients with relapsed or refractory follicular lymphoma, according to data presented at the 2019 American Society of Hematology (ASH) annual meeting. Results of a phase 2 clinical trial showed an overall response rate of 69% and 35% in mutant and wild-type cohorts, respectively. Clinical activity was durable across both cohorts, with patients on therapy up to 2 years and responses continuing to deepen over time, researchers in the study reported.
“Patients receiving tazemetostat had a median progression-free survival of 13.8 and 11.8 months in mutant and wild-type disease, respectively, and those clinically meaningful responses were observed across a spectrum of patients, including high-risk subgroups,” said Franck Morschhauser, MD, PhD, Department of Hematology, Centre Hospitalier Régional Universitaire de Lille, France. “Tazemetostat was also generally well tolerated, with a low incidence of treatment-related adverse events, which makes it a very nice agent for future combinations.”
According to Dr Morschhauser, relapsed or refractory follicular lymphoma remains a difficult-to-treat condition, with limited therapeutic options. New, tolerable treatments with unique mechanisms of action are needed, he said.
EZH2 is an epigenetic regulator of gene expression and cell fate decisions that is required for normal B-cell biology and germinal center formation. EZH2 gain-of-function mutations reshape the microenvironment and reprogram the epigenome to lock the B-cell in a germinal state thereby promoting lymphomagenesis. EZH2 biology is thus relevant in mutant and in wild-type lymphoma, especially follicular lymphoma where the incidence of this gain-of-function mutation is approximately 20%.
For this open-label, multicenter, phase 2 study, Dr Morschhauser and colleagues evaluated tazemetostat, an investigational, selective, oral EZH2 inhibitor, in patients with activating mutations and wild-type EZH2. The researchers enrolled adult patients with Eastern Cooperative Oncology Group performance status of 0-2, at least 2 previous treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary end point of the study was objective response rate (complete response plus partial response). Subgroup analysis focused on patients with refractory disease or those who experienced disease progression or relapse within 24 months of diagnosis or the start of front-line treatment with immunochemotherapy (POD24).
Clinically Significant, Durable Responses
As Dr Morschhauser reported, 31 (69%) patients in the mutant cohort had an objective response, including 6 (13%) complete responses and 25 (56%) partial responses. Importantly, in the mutant cohort, all but 1 patient had evidence of tumor shrinkage. In the wild-type cohort, by contrast, 71% of patients had tumor shrinkage, but not all met the response criteria. The objective response rate was 35% in the wild-type cohort, including 6% complete responses and 29% partial responses.
Regarding the durability of response, Dr Morschhauser called the results “pretty good.” Patients in the mutant cohort were recruited later, so that data are not completely mature, he said, but the duration of response “looks promising.” Approximately 30% of patients remain on study, with a median follow-up of 22 months.
“It’s also important to note that 8 patients (18%) continued on treatment past progression because the clinician felt that there was clinical benefit to the patient, which suggests some kind of immune response,” said Dr Morschhauser.
In the wild-type cohort, the median duration of response was 13 months, but with a median follow-up close to 3 years, there are no more patients on study.
The median progression-free survival was 13.8 months and 11.8 months in the mutant and wild-type cohorts, respectively. These data demonstrate a clear benefit in both subgroups, said Dr Morschhauser, although the benefit was slightly better in the mutant subgroup. The median overall survival was also impressive and has not been reached in either cohort, he reported.
Finally, the response rates in deemed higher-risk subgroups were also notable. Data were consistent with responses in all-comers, with 64% of refractory patients and 63% of the POD24 subgroup achieving an objective response in the mutant cohort. These responses were also durable.
“Tazemetostat presents a potential therapeutic option as a single agent in patients with relapsed or refractory lymphoma,” Dr Morschhauser concluded. “The next step will be a phase 3 randomized trial for patients that are relapsed or refractory after one line of therapy.”