Safety and efficacy of tazemetostat, an enhancer of zeste-homolog 2 inhibitor, in patients with relapsed or refractory malignant mesothelioma.

Abstract

9058 Background: Breast cancer gene 1 (BRCA1)-associated protein 1 (BAP1), a nuclear deubiquitinase, is commonly inactivated in malignant mesothelioma. Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of enhancer of zeste-homolog 2 (EZH2), a methyltransferase implicated as an oncogenic driver in this tumor. This study evaluated the safety and efficacy of tazemetostat (TAZ), a potent and selective EZH2 inhibitor, in relapsed/refractory (R/R) malignant mesothelioma with BAP1-inactivation. Methods: EZH-203 (NCT02860286) was a 2-part, open-label, phase 2 study that assessed the pharmacokinetics (PK), safety, and efficacy of TAZ in pts with R/R malignant mesothelioma. In part 1, pts received TAZ 800 mg QD on day 1 (D1) and 800 mg BID, beginning day 2 of cycle 1 (C1). In part 2, pts received 800 mg of TAZ BID on D1 of C1. A two-stage Green-Dahlberg design was used for part 2. Primary endpoints were PK profiling of TAZ in all pts (part 1), and disease control rate (DCR) at week 12 in pts with BAP1-deficient R/R malignant mesothelioma (part 2). Secondary endpoints included safety, overall response rate (ORR), progression-free survival, overall survival, and duration of response (DOR). Results: The study enrolled 74 pts with R/R malignant mesothelioma, 70 pts (95%) were centrally confirmed to be BAP1-deficient. Median prior lines of therapy were 2 (range, 1-9). Observed clinical data in the presence of CYP3A4 inhibitors and inducers suggest a low DDI potential of TAZ. The 12 week DCR was 47% (n = 35). The ORR per RECIST version 1.1 was 3% [complete response: 0%; partial response (PR): 3% (n = 2)]. Of the 2 patients with PR, 1 had a DOR of 21 weeks and the other is ongoing (15.3 weeks at data cut off). 47 pts (64%) and 21 pts (28%) had stable disease (SD) and progressive disease, respectively. Overall, 91% pts discontinued, either due to disease progression (n = 65), death (n = 5), or treatment discontinuation (n = 1). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in ≤5% of patients, most commonly anemia (5%) and dyspnea (4%). No pts discontinued due to TEAEs. There were no treatment related deaths. Conclusions: Based on disease control rate and stable disease, TAZ showed antitumor activity in pts with BAP1-deficient R/R malignant mesothelioma. TAZ monotherapy was generally well-tolerated. The current data support further clinical evaluation of TAZ in these pts. Furthermore, this trial presents an optimal paradigm for drug development in molecularly-enriched cohorts in mesothelioma. Clinical trial information: NCT02860286.

Topics & Concepts