BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.
In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.
And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.
The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.
“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.
The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.
The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.
All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.
E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).
‘Encouraging activity’
Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.
Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.
Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.
Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.
The patient with marginal zone lymphoma achieved stable disease and remains on study.
Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.
“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.
“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”
‘Little toxicity’
All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.
The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.
There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.
“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”
E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.
Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.
