Early Data Show EZH2 Inhibitor Active in Non-Hodgkin Lymphoma

The EZH2 inhibitor EPZ-6438 appears to be a well-tolerated drug and is showing early evidence of anti-lymphoma activity in patients with non-Hodgkin lymphoma of varying histology, according to early observations from a phase I clinical trial presented at the first ASH Meeting on Lymphoma Biology.

EZH2 is a histone methyltransferase that is implicated as an oncogenic driver of multiple human cancers, according to Robert A. Copeland, PhD, chief scientific officer of Epizyme, the developer of EPZ-6438.

“EZH2, and the protein methyltransferases in general, represent a novel target class with strong cancer associations,” Dr. Copeland told ASH Clinical News. “The compound EZP-6438 represents the first potent, selective, and orally bioavailable inhibitor of EZH2 to enter human clinical trials.”

To date, the ongoing phase I study has completed analysis of three cohorts of patients:

  • six patients enrolled at a dose of 100 mg twice daily
  • three patients at 200 mg twice daily
  • three patients at 400 mg twice daily

Enrollment of two additional cohorts testing doses of 800 mg and 1,600 mg is ongoing.

Among the 12 evaluable patients, four of whom have non-Hodgkin lymphoma of varying histology, the maximum tolerated dose had not been reached, and patients did not experience any dose-limiting toxicities or discontinue treatment due to adverse events.

Two patients with non-Hodgkin lymphoma achieved partial responses, one patient with relapsed transformed germinal center diffuse large B-cell lymphoma dosed at 100 mg and one patient with primary refractory mediastinal B-cell lymphoma receiving 200 mg of the drug. Both of these patients had wild-type EZH2. In addition, one patient with follicular lymphoma and the EZH2 mutation achieved stable disease at a 400 mg dose.

In preclinical testing, EPZ-6438 combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) showed increased potency and activity in cell lines, independent of EZH2-mutant status. Dr. Copeland and colleagues hypothesize that much of the synergy between these two treatments was due to prednisone, a glucocorticoid receptor agonist.

Based on the promising results seen in the phase I dose-escalation study, phase II studies testing EPZ-6438 alone and in combination with steroids in patients with germinal center diffuse large B-cell lymphoma, primary refractory mediastinal B-cell lymphoma, and follicular lymphoma with and without EZH2 mutations, will be initiated.

“If we continue to see objective responses in non-Hodgkin lymphoma patients in a fashion that is independent of EZH2 mutation, EZH2 inhibitors could have broad utility across a variety of B-cell lymphomas,” Dr. Copeland said.


    Copeland RA. Activity of the EZH2 inhibitor EPZ-6438 (E7438) in non-Hodgkin lymphoma: preclinical models and early clinical observations. Presented at: ASH Meeting on Lymphoma Biology; August 10-13; Colorado Springs, CO.