Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX, USA.
J Natl Cancer Inst. 2023 Nov 8;115(11):1355-1363. doi: 10.1093/jnci/djad085.
National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice 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 predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat.
Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat.
Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (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), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports.
Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.
国家癌症研究所-儿童肿瘤组儿科分子分析治疗选择根据预先确定的遗传改变的检测，将 1-21 岁患有难治性实体瘤、脑肿瘤、淋巴瘤和组织细胞疾病的患者分配到分子靶向治疗的 II 期试验中。免疫组织化学检测到 EZH2 突变或 SMARCB1 或 SMARCA4 缺失的患者接受 EZH2 抑制剂 tazemetostat 治疗。
患者接受 tazemetostat 治疗 28 天周期，直至疾病进展或无法耐受毒性（最多 26 个周期）。主要终点是客观缓解率；次要终点包括无进展生存期和 tazemetostat 的耐受性。
20 名患者（中位年龄=5 岁）入组，均可评估反应和毒性。最常见的诊断是非典型畸胎样横纹肌样瘤（n=8）和恶性横纹肌样瘤（n=4）。可操作的改变包括 SMARCB1 缺失（n=16）、EZH2 突变（n=3）和 SMARCA4 缺失（n=1）。1 例非朗格汉斯细胞组织细胞增多症伴 SMARCA4 缺失患者出现 1 例客观缓解（26 个周期，1200mg/m2/剂量，每日 2 次）。4 例 SMARCB1 缺失患者的最佳反应为疾病稳定：上皮样肉瘤（n=2）、非典型畸胎样横纹肌样瘤（n=1）和肾髓质癌（n=1）。6 个月无进展生存率为 35%（95%置信区间[CI]：15.7%至 55.2%），6 个月总生存率为 45%（95%CI：23.1%至 64.7%）。治疗相关不良事件与先前的 tazemetostat 报告一致。
尽管 tazemetostat 在该难治性儿科肿瘤患者人群中未达到主要疗效终点（客观缓解率=5%，90%CI=1%至 20%），但 25%的多种组织学诊断患者经历了 6 个月及以上的延长稳定疾病（范围=9-26 个周期），提示 tazemetostat 可能对疾病稳定有一定作用。
