Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201
Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201
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DOI：
10.1007/s11060-019-03271-3
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发表时间：
2019-10-01
影响因子：
3.9
通讯作者：
Mehta, Minesh P.
中科院分区：
文献类型：
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作者：
Chi, Andrew S.;Tarapore, Rohinton S.;Mehta, Minesh P.
背景：H3 k27m突变型弥漫性中线胶质瘤是一种致命的恶性肿瘤，目前尚无有效的药物治疗方法。这种疾病主要发生在儿童和年轻人身上。ONC201是多巴胺受体D2/3 （DRD2/3）的小分子选择性拮抗剂，具有特殊的安全性。在第一例接受ONC201 （NCT02525692）治疗的H3 k27m突变弥漫性中线胶质瘤患者出现持久应答后，开始了一项扩大准入计划。方法H3 k27m突变胶质瘤患者既往至少接受过放疗。排除脑脊膜轻散患者。所有患者每周口服一次开放标签ONC201。研究者至少每8周定期评估一次安全性、放射学评估和总生存率。截至2018年8月，共有18名H3 K27M-突变弥漫性中线胶质瘤或DIPG患者入组接受ONC201单患者扩展准入方案。在18例患者中：7例成人（20岁以下）和7例儿科（< 20岁）患者在疾病复发时开始ONC201治疗，4例儿科患者在放疗后但在疾病复发前开始ONC201治疗。结果：在开始ONC201治疗前的14例复发性疾病患者中，中位无进展生存期为14周，中位总生存期为17周。14例复发患者中有3例成人仍在接受无进展治疗，中位随访时间为49.6周（41-76.1周）。在放疗后开始辅助ONC201治疗的4例儿科患者中，2例DIPG患者至少在53周和81周内保持无进展。研究人员报告了一部分丘脑和脑桥胶质瘤患者的放射学消退，包括完全缓解，以及疾病相关神经系统症状的改善。这些患者的临床结果和影像学反应为ONC201靶向H3 k27m突变的弥漫性中线胶质瘤提供了初步和初步的临床概念证明，无论年龄或位置如何，都为该药物的有力临床试验提供了依据。
Background H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated.Methods Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M- mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence.Findings Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms.Interpretation The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.