Department of Pediatrics, University of Michigan, Michigan Medicine, Ann Arbor, MI.
Department of Neurosurgery, University of Michigan, Michigan Medicine, Ann Arbor, MI.
J Natl Compr Canc Netw. 2024 Sep;22(7). doi: 10.6004/jnccn.2024.7045.
Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
在癌症治疗中，组织不可知的、分子靶向的治疗方法越来越普遍。在诊断时进行的深度肿瘤测序时代，某些肿瘤类别的分子驱动因素正在迅速被揭示。靶向治疗应该在细胞毒性化疗和放疗的框架内何时以及如何应用，目前尚未确定，因为其中许多药物在复发或难治性癌症患者的单臂研究中进行了研究。婴儿高级别神经胶质瘤（HGG）在生物学和临床上与较大儿童和成人 HGG 不同，分为 3 个分子亚组。第 1 组婴儿 HGG 由受体酪氨酸激酶融合驱动，最常见的是含有 ALK、ROS1、NTRK 或 MET 融合。拉罗替尼和恩曲替尼都是原肌球蛋白受体激酶抑制剂，具有组织不可知的批准，用于治疗携带有 NTRK 融合的实体瘤患者。本报告讨论了一名 11 个月大的女性，因婴儿痉挛发作就诊，发现无法切除的 NTRK 融合阳性婴儿 HGG。在诊断时发现 NTRK 融合后即开了拉罗替尼，迄今为止，没有其他干预措施，患者的病情稳定持续了>3 年。唯一经历的不良事件是 1 级天冬氨酸转氨酶和丙氨酸转氨酶升高。患者的神经系统检查正常，在所有领域（粗大运动、精细运动、认知、语言和社会情感）都按年龄正常发育。她不再服用抗癫痫药物。据我们所知，这是首例接受婴儿 HGG 靶向治疗作为一线治疗并获得长期稳定疾病的患者报告。一项针对新诊断婴儿 HGG 患者的拉罗替尼的前瞻性研究正在进行中，有望帮助回答关于反应持久性、是否需要额外治疗以及 TRK 抑制剂的长期毒性等问题。
