In a phase II study reported in The Lancet Oncology, Zauderer et al found that the EZH2 inhibitor tazemetostat was active in patients with relapsed or refractory BRCA-associated protein 1 (BAP1)-inactivated malignant pleural mesothelioma.
As noted by the investigators, high expression of EZH2 has been identified in malignant pleural mesothelioma—particularly in association with loss of BAP1—and inactivation of BAP1 sensitizes tumor cells to EZH2 inhibition.
Study Details
In the study, 74 patients were enrolled from sites in France, the United Kingdom, and the United States between July 2016 and June 2017; 73 patients had BAP1-inactivated tumors. A total of 13 patients in part 1 of the study (evaluating pharmacokinetics) received 800 mg of tazemetostat once on day 1 and 800 mg twice daily thereafter. Part 2 consisted of 61 patients with BAP1-inactivated tumors who received tazemetostat at 800 mg twice daily. Treatment was given in 21-day cycles, up to approximately 17 cycles. The primary endpoint of part 2 was the disease control rate at week 12.
Disease Control Rate
After a median follow-up of 35.9 weeks (interquartile range = 20.6–85.9 weeks), disease control was observed in 33 (54%, 95% confidence interval [CI] = 42%–67%) of 61 patients at week 12. Partial response was observed in two patients, with responses persisting for 42 weeks in one and for 18 weeks at data cutoff in the other. At week 24, the disease control rate was 33% (95% CI = 21%–45%).
KEY POINTS
- Tazemetostat produced a disease control rate of 54% at 12 weeks.
- Tumor shrinkage was observed in 35% of evaluable patients.
Among all 74 patients, disease control was observed in 38 (51%, 95% CI = 40%–63%) at week 12. The disease control rate at week 24 was 28% (95% CI = 18%–39%). A reduction in tumor volume was observed in 24 (35%) of 69 evaluable patients. In the entire population, median progression-free survival was 18 weeks (95% CI = 12–24 weeks) and median overall survival was 36 weeks (95% CI = 29–61 weeks).
As noted by the investigators, EZH2 is an epigenetic regulator of gene expression implicated as an oncogenic driver that acts to increase H3K27me3. Among 10 patients with available data (not including the 2 patients with a partial response), H3K27me3 was reduced from baseline in 8 and increased in 2; all 8 patients with reductions had disease control at both week 12 and 24, whereas the 2 with decreased levels had progressive disease at week 12.
Adverse Events
Grade 3 or 4 adverse events occurred in 49% of the 74 patients, most commonly hyperglycemia (7%), hyponatremia (7%), and anemia (5%). Serious adverse events occurred in 34% of patients, most commonly pleural effusion, dyspnea, pericardial effusion, and sepsis (4% each). Death occurred in five patients (7%) while on study; none of the deaths was considered related to treatment.
The investigators concluded, “Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumors that are most likely to derive prolonged benefit or shrinkage from this therapy.”
Marjorie G. Zauderer, MD, of Memorial Sloan Kettering Cancer Center, and Dean A. Fennell, PhD, of the Leicester Cancer Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, are the corresponding authors for The Lancet Oncology article.
Disclosure: The study was funded by Epizyme. For full disclosures of the study authors, visit thelancet.com.
