激活丝裂原活化蛋白激酶通路改变的儿童和青年肿瘤患者中 Ulixertinib 的 II 期研究：国家癌症研究所-儿童肿瘤组儿科 MATCH 试验的 APEC1621J。
Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
机构信息
Department of Pediatrics, University of California, San Francisco School of Medicine, UCSF Benioff Children's Hospital, San Francisco, CA.
Frederick National Laboratory for Cancer Research, Frederick, MD.
出版信息
JCO Precis Oncol. 2024 Jun;8:e2400103. doi: 10.1200/PO.24.00103.
PURPOSE
The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.
METHODS
As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).
RESULTS
Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with -altered CNS tumors achieved stable disease >6 months.
CONCLUSION
Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
目的
国家癌症研究所-儿童肿瘤学组（NCI-COG）儿科MATCH 试验根据肿瘤中检测到的遗传改变，将 1-21 岁患有难治性恶性肿瘤的患者分配到分子靶向治疗的 II 期治疗臂。具有丝裂原活化蛋白激酶途径激活改变的患者接受了 ulixertinib 的治疗，ulixertinib 是一种细胞外信号调节激酶（ERK）1/2 抑制剂。
方法
由于没有以前的儿科数据，ulixertinib 首先在剂量递增队列中进行测试，以确定进行 II 期队列之前的推荐 II 期剂量（RP2D）。ulixertinib 以 260 mg/m/剂量口服，每日两次（剂量水平 1[DL1]，n = 15）或 350 mg/m/剂量口服，每日两次（DL2，n = 5）。主要终点是客观缓解率；次要终点包括安全性/耐受性和无进展生存期（PFS）。
结果
20 名患者（中位年龄 12 岁；范围，5-20）接受了治疗，所有患者均可评估反应。中枢神经系统肿瘤占 55%（11/20）的诊断，高级别胶质瘤和低级别胶质瘤最常见（各 5 例）。除 1 例外，所有中枢神经系统肿瘤均存在融合或 V600E 突变。横纹肌肉瘤（n = 5）是最常见的非中枢神经系统诊断。在剂量递增队列中，1 例患者在 DL1 时和 2 例患者在 DL2 时发生 1 周期的剂量限制毒性后，宣布 DL1 为 RP2D，包括疲劳、厌食、皮疹、恶心、呕吐、腹泻、脱水、低白蛋白血症和高钠血症。未观察到客观反应。6 个月 PFS 为 37%（95%CI，17 至 58）。3 例中枢神经系统肿瘤 - 改变的患者稳定疾病 >6 个月。
结论
ulixertinib 是一种新型靶向药物，没有以前的儿科数据，在国家精准医学篮子试验中成功进行了评估。ulixertinib 的儿科 RP2D 为 260 mg/m/剂量口服，每日两次。在生物标志物选择的难治性儿科肿瘤队列中观察到有限的单一药物疗效。
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