Abstract
BACKGROUND: NCI-COG Pediatric MATCH assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of pre-defined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. METHODS: Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and tolerability of tazemetostat. RESULTS: Twenty patients (median age, 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (ATRT; n = 8) and malignant rhabdoid tumor (MRT; n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), ATRT (n = 1), renal medullary carcinoma (n = 1). Six-month PFS was 35% (95% CI: 15.7%, 55.2%) and six-month OS, 45% (95% CI 23.1, 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. CONCLUSION: Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (ORR: 5%, 90% CI 1%, 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of > 6 months (range: 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization. For permissions, please email: journals.permissions@oup.com.
