Tazemetostat Safe, Effective for Relapsed/Refractory Malignant Mesothelioma

In a phase 2 study, tazemetostat was well-tolerated and demonstrated anti-tumor activity in patients with BAP1-deficient relapsed or refractory malignant mesothelioma (J Clin Onco. 2020;38(suppl; abstr 9058).

“Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of [EZH2],” wrote Marjorie Glass Zauderer, MD, Memorial Sloan Kettering Cancer Center, New York, and colleagues.

In the open-label, 2-part EZH-203 clinical trial, Dr Zauderer and colleagues assessed the safety, efficacy, and pharmacokinetics of tazemetostat in patients with relapsed or refractory malignant mesothelioma with BAP1-inactivation.

During part 1 of EZH-203, patients were given tazemetostat 800 mg once daily on day 1 and 800 mg twice daily starting on day 2 of cycle 1. In part 2 of the study, patients received tazemetostat 800 mg twice daily on day 1 of cycle 1.

Of note, Dr Zauderer et al used a 2-stage Green-Dahlberg design for part 2 of the study.

The primary end points of the study were pharmacokinetic profiling of tazemetostat in all patients (part 1), and disease control rate at week 12 amogn patients with BAP1-deficient, relapsed or refractory disease (part 2).

The secondary end points of the trial included safety, overall response rate (ORR), progression-free survival, overall survival, and response duration.

A total of 74 patients (median prior lines of therapy, 2) with relapsed or refractory malignant mesothelioma were enrolled in the study. Of these patients, 70 (95%) were BAP1-deficient.

The disease control rate at 12 weeks was 47%, and the ORR was 3%, including complete and partial responses 0% and 3%, respectively). One of the 2 patients who had partial responses had a 21-week response duration and the other has a response rate that is ongoing (15.3 weeks as of data cut off).

Stable and progressive disease were reported in 47 (64%) and 21 (28%) patients, respectively, and 91% of patients discontinued therapy because of disease progression (n = 65) or death (n = 5).

Treatment-emergent adverse events grade ≥3 were reported in ≤5% of patients, with the most common being anemia (5%) and dyspnea (4%).

There were no reports of patients discontinuing therapy because of treatment-emergent adverse events, and there were no treatment-related deaths.

“Based on disease control rate and stable disease, tazemetostat showed antitumor activity in pts with BAP1-deficient relapsed or refractory malignant mesothelioma,” Dr Zauderer and co-investigators said.

“Tazemetostat monotherapy was generally well-tolerated. The current data support further clinical evaluation of tazemetostat in these patients. Furthermore, this trial presents an optimal paradigm for drug development in molecularly-enriched cohorts in mesothelioma,” they concluded.—Hina M. Porcelli