Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora, CO.
CS Mott Children's Hospital and University of Michigan, Ann Arbor, MI.
JCO Precis Oncol. 2024 Sep;8:e2400418. doi: 10.1200/PO-24-00418.
The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib.
Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival.
Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (, n = 11, , n = 2, , n = 6), with one tumor harboring two amplifications ( and ). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2).
The CDK4/6 inhibitor palbociclib at 75 mg/m orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.
国家癌症研究所-儿童肿瘤学组儿科分子分析治疗选择试验根据肿瘤中检测到的遗传改变，将 1-21 岁患有复发或难治性实体瘤、淋巴瘤和组织细胞疾病的患者分配到基于分子靶向治疗的 II 期治疗臂。肿瘤中存在 cyclinD-CDK4/6-INK4a-Rb 通路中具有完整 Rb 表达的预设基因组改变的患者被分配并接受 CDK4/6 抑制剂 palbociclib 治疗。
患者接受 palbociclib 口服，每天一次，28 天周期的 21 天，直至疾病进展、无法耐受毒性或最多 2 年。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。
23 名患者（中位年龄 15 岁；范围 8-21 岁）入组；20 名患者接受了方案治疗，并可评估毒性和反应。在可评估的患者中，最常见的诊断是骨肉瘤（n=9）和横纹肌肉瘤（n=6）。19 个肿瘤中发现了单个可操作基因扩增（n=11，n=2，n=6），1 个肿瘤有两个扩增（n=11，n=2，n=6）。血液学毒性是最常见的治疗相关事件。未观察到客观反应。2 名肿瘤中存在扩增（神经母细胞瘤和肉瘤）的患者，最佳反应为稳定疾病 6 个和 3 个周期。6 个月进展率为 10%（95%CI，1.7 至 27.2）。
在这个预处理过多的队列中，口服 75mg/m 的 CDK4/6 抑制剂 palbociclib 是可以耐受的。在这个组织学不可知的生物标志物选择的治疗耐药性实体瘤患者中，未观察到客观反应，表明通路改变本身不足以导致 palbociclib 单药治疗产生反应。
