Tazemetostat Reduces EZH2 Activity in Patients with Malignant Mesothelioma

Treatment with tazemetostat reduces EZH2 activity and B-cell infiltration in patients with relapsed or refractory BAP1-inactivated malignant pleural mesothelioma, according to results of a phase 2 study.

“Tazemetostat, a potent, selective, oral EZH2 inhibitor, has shown antitumour activity in several tumour types in preclinical studies,” wrote Marjorie Zauderer, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues.

The open-label, single-arm phase 2 study of 74 patients (13 in part 1 and 61 in part 2) administered 800 mg of oral tazemetostat to patients once on day 1 and twice daily every day of treatment thereafter. Patients in part 2 received tazemetostat twice daily from day 1 onward, in a 2-stage Green-Dahlberg design. Both parts administered tazemetostat in approximately 17 21-day cycles.

The primary end point of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 of cycle 1. In part 1, patients reported a mean maximum serum concentration of 829 ng/mL and a median time to maximum serum concentration of 2 hours.

The primary end point of part 2 was the disease control rate of patients with malignant pleural mesothelioma at week 12. After 12 weeks, the disease control rate in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% confidence interval [CI], 42 to 67; 33 of 61 patients).

No participants experienced a confirmed complete response. More than one-third (25 [34%] of 74) of participants experienced serious adverse events (AEs). Treatment-emergent AEs included hyperglycaemia (5 [7%] patients), hyponatraemia (5 [7%]), and anaemia (4 [5%]).

“These results show the feasibility of molecularly stratified therapy for relapsed or refractory malignant pleural mesothelioma,” explained Dr Zauderer et al, concluding, “further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.”

Source:

Zauderer MG, Szlosarek PW, Le Moulec S, et al. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2022;23(6):758-767. doi:10.1016/S1470-2045(22)00277-7