Tazemetostat, First-in-Class EZH2 Inhibitor, Shows Impressive Activity in Relapsed or Refractory Follicular Lymphoma

JHOP - February 2020 Vol 10, No 1 - ASH Highlights, Lymphoma, Novel Pharmaceuticals

Tazemetostat (Tazverik), a first-in-class, oral, selective EZH2 inhibitor, has demonstrated single-agent antitumor activity in patients with relapsed or refractory follicular lymphoma, according to results of a phase 2 clinical trial presented at ASH 2019.

The overall response rate was 69% in patients with EZH2 mutation and 35% in patients with wild-type disease. The clinical activity was durable across both cohorts, with patients receiving therapy up to 2 years and responses continuing to deepen over time, the study investigators 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,” he added. Relapsed or refractory follicular lymphoma remains a difficult-to-treat cancer, with limited treatment options. New tolerable treatments with unique mechanisms of action are needed, said Dr Morschhauser.

Of note, on January 23, 2020, the FDA approved tazemetostat for the treatment of patients with locally advanced or metastatic epithelioid sarcoma who are not eligible for complete resection, making it the first EZH2 inhibitor to receive FDA approval.

Gain-of-Function EZH2 Mutation

The EZH2 gene is an epigenetic regulator of gene expression and cell fate decisions necessary 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 gene biology is therefore relevant in lymphoma that is associated with the EZH2 mutation and in wild-type lymphoma, according to Dr Morschhauser, especially in follicular lymphoma, where the incidence of this gain-of-function mutation is approximately 20%.

Study Details

In this open-label, multicenter, phase 2 clinical trial, Dr Morschhauser and colleagues investigated the activity of tazemetostat, a novel oral EZH2 inhibitor, in patients with follicular lymphoma and the activating EZH2 mutation or those with wild-type disease. Enrolled patients were adults with Eastern Cooperative Oncology Group performance status of 0 to 2, had received ≥2 previous treatment regimens, and had measurable disease per the 2007 International Working Group (IWG) response criteria for non-Hodgkin lymphoma.

The study primary end point was objective response rate (complete response plus partial response). A subgroup analysis focused on patients with refractory disease or those who had disease progression or relapsed disease within 24 months of diagnosis (ie, POD24) or the beginning of front-line treatment with immunochemotherapy.

In all, 31 (69%) patients in the EZH2 mutation cohort had an overall response, including 6 (13%) complete responses and 25 (56%) partial responses. In that cohort, all but 1 patient had evidence of tumor shrinkage with tazemetostat therapy.

By contrast, in the mutation wild-type cohort, 71% of the patients had tumor shrinkage with tazemetostat therapy, but not all patients met the IWG response criteria. The objective response rate was 35% in the wild-type cohort, including 6% complete responses and 29% partial responses.

Durable Responses

Addressing the question of the durability of response, Dr Morschhauser called the results “pretty good.” Patients with EZH2 mutation were recruited to the study later than those without the mutation, so their data are not completely mature, he said, but the duration of response “looks promising.” Approximately 30% of patients remain in the study, with a median follow-up of 22 months.

“It’s also important to note that 8 (18%) patients continued on treatment past progression, because the clinician felt that there was clinical benefit to the patient, which suggests some kind of immune response,” Dr Morschhauser said.

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 being followed up.

The median progression-free survival was 13.8 months in those with the mutation and 11.8 months in the wild-type cohort. These data demonstrate a clear benefit in both subgroups, said Dr Morschhauser, although the benefit was slightly better in the EZH2 mutation subgroup.

The median overall survival was also impressive and has not been reached in either cohort, he noted.

Finally, the response rates in deemed higher-risk subgroups were also notable. The data were consistent with responses in all patients, said Dr Morschhauser, with 64% of patients with refractory disease and 63% of the POD24 subgroup achieving an objective response in the mutation-positive 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 who are relapsed or refractory after one line of therapy,” he noted.

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