Tazemetostat Results Signal the Utility of Biomarker-Driven Therapy for BAP1-Inactivated MPM

To identify patients with BAP1-inactivated malignant pleural mesothelioma (MPM) who may have prolonged benefit and tumor shrinkage from treatment with the EZH2 inhibitor, tazemetostat (Tazverik), biomarkers for the disease must be further defined, according to findings from a phase 2 study (NCT02860286).

“This multicenter, open-label, molecularly stratified, phase 2 trial extends novel preclinical findings, generating proof of concept related to the anti-tumor activity of EZH2 inhibition with tazemetostat in BAP1-inactivated, relapsed, or refractory malignant pleural mesothelioma, wrote the study authors lead by Marjorie G. Zauderer, MD, a medical oncologist and co-director of the MSK Mesothelioma Program at Memorial Sloan Kettering Cancer Center.

Currently, there are a limited number of therapies for patients with MPM. To date, no agents have been granted regulatory approval to treat relapsed MPM following disease progression after platinum-based chemotherapy. Tazemetostat has demonstrated anti-tumor activity in multiple hematologic malignancies and solid tumors. In the phase 2, multicenter, open-label, 2-part, single-arm, 2-stage study, the safety, and anti-tumor activity of tazemetostat in patients with relapsed or refractory malignant pleural mesothelioma with BAP1 loss of function.

The study was conducted at 16 hospitals across France, the United Kingdom, and the United States. Patients enrolled were those aged 18 years or older with an ECOG performance status of 0 or 1 and a life expectancy of over 3 months.

Patients in the study were administered tazemetostat 800 mg once daily on day 1 followed by twice daily thereafter. Treatment with tazemetostat lasted for 17, 21-day cycles. In part 1 of the study, investigators assessed pharmacokinetics as the primary end points in 12 patients, and in part 2, the co-primary end points were the disease control rate (DCR) and the incidence of treatment-emergent adverse events (TEAEs). Secondary end points explored in the study included objective response rate, progression-free survival (PFS), overall survival (OS), duration of response, and DCR.

The overall study population was made up of 74 patients with an average age of 68 years (range, 60-71). The population was 66% and 34% female, and the majority of patients had an ECOG performance status of 1 (74%) as opposed to a score of 0 (26%). All patients had been previously treated with systemic anticancer therapy with the majority (41%) having received 1 prior line of therapy. Only 38% of patients had prior radiotherapy. The majority of the cohort (82%) received therapy for advanced or metastatic disease vs neoadjuvant therapy (9%), adjuvant therapy (23%), palliation (5%), consolidation or maintenance (7%), or another therapy (4%).

The average time from last disease progression to entry was 2.17 months (range, 1.18-3.25). The primary tumor location was pleura for 92% of the population and peritoneum for 8%. Epithelioid was the most common histology among patients in the study (88%). Most patients had stage IV disease at the time of diagnosis.

Results showed that at 12 weeks, the DCR was 51% (95% CI, 40%-63%) and at 24 weeks, the DCR was 28% (95% CI, 18%-39%). The best response to tazemetostat in the study was a complete response (CR) observed in 2 patients. The most common response was stable disease, which occurred in 62% of patients. Responses to tazemetostat lasted for a median duration 30 weeks (95% CI, 24-30).

The median PFS observed with tazemetostat was 18 weeks (95% CI, 12-24). At the 12-week timepoint, the PFS rate was 60% (95% CI, 40%-70%), and at week 24, the PFS rate was 30% (95% CI, 20%-40%). The median OS was 36 weeks (95% CI, 29%-61%). At week 12, the OS rate observed with tazemetostat was 90% (95% CI, 80%-100%), and at week 24, the OS rate was 70% (95% CI, 60%-100%).

Tazemetostat treatment led to TEAEs in 99% of patients. The most common grade 1/2 TEAEs observed were fatigue (34%), decreased appetite (32%), dyspnea (30%), cancer pain (28%), and nausea (28%). Grade 3/4 TEAEs were observed in 49% of patient with the most common being hyperglycemia (7%), hyponatremia (7%), and anemia (5%). These events were consistent with those seen in prior studies of tazemetostat. Overall, the drug was tolerable, and few patients discontinued treatment.

“These results show the feasibility of molecularly stratified therapy for relapsed or refractory malignant pleural mesothelioma and, to our knowledge, provide the first evidence of antitumor activity and safety of an EZH2 inhibitor, tazemetostat, in BAP1-inactivated malignant pleural mesothelioma, thereby adding to the growing body of literature on the antitumor effects of this mechanistic approach. Our findings also underscore the importance of companion development of biomarkers of activity in parallel with the development of novel therapies,” wrote Zauderer et al.

_REFERENCE:

_{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; 23:758-767. doi: 10.1016/ S1470-2045(22)00277-7}