Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA.
University of Texas Southwestern, Dallas, TX.
JCO Precis Oncol. 2024 Sep;8:e2400258. doi: 10.1200/PO.24.00258.
Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.
Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.
A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.
This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.
患有复发性或难治性实体瘤和中枢神经系统肿瘤的 1-21 岁患者被分配到国家癌症研究所-儿童肿瘤学组（NCI-COG）儿科分子分析治疗选择（MATCH）试验的分子靶向治疗 II 期研究。肿瘤中存在磷酸肌醇 3-激酶（PI3K）/雷帕霉素（mTOR）通路中预先定义的遗传改变且缺乏丝裂原激活蛋白激酶通路激活改变的患者接受 PI3K/mTOR 抑制剂索拉非尼治疗。
患者以 28 天为一个周期，每天接受两次索拉非尼治疗，直到疾病进展或无法耐受毒性。由于据我们所知，这是首次在儿科中研究索拉非尼，因此进行了滚动 6 个有限剂量递增。主要终点是客观缓解率；次要终点包括无进展生存期（PFS）和儿童索拉非尼的推荐 II 期剂量和毒性。
共有 3.4%（41/1,206）的经中心检测的患者符合该治疗组。共治疗了 17 名患者。在接受治疗的患者中，最常见的诊断包括骨肉瘤（n = 6）和高级别胶质瘤（n = 5），这些患者存在磷酸酶和张力蛋白同源物（n = 6）、（n = 5）、和结节性硬化症 2（n = 3）的改变。未观察到客观缓解或持久稳定的疾病。3 个月的 PFS 为 12%（95%CI，2 至 31）。有 2 名患者发生剂量限制毒性（黏膜炎和肺炎）。确定儿童索拉非尼的推荐 II 期剂量为 2 级（115mg/m/剂量，每日两次）。
这项全国性研究成功地确定了患者，并以组织学不可知的方式评估了针对罕见分子亚组患者的分子靶向治疗的疗效。不幸的是，索拉非尼对具有 PI3K/mTOR 通路改变的肿瘤没有活性。需要进行 NCI-COG 儿科 MATCH 等前瞻性试验，以评估分子靶向治疗的疗效，因为它们在临床实践中的使用越来越多。
