Abstract：
BACKGROUND: NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.
METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.
RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.
CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children\'s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).
METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.
RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.
CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children\'s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).
摘要：
背景：NF2相关神经鞘瘤病（NF2-SWN，以前称为神经纤维瘤病2型）是一种肿瘤易感性综合征，表现为多发性前庭神经鞘瘤，非前庭神经鞘瘤,脑膜瘤,和室管膜瘤.这种情况无情地进展，没有批准的疗法。根据Brigatinib（多种酪氨酸激酶抑制剂）在NF2驱动的非前庭神经鞘瘤和脑膜瘤中的临床前活性，对于患有多种类型的进展性NF2-SWN肿瘤的患者,需要使用布格替尼的数据.
方法：在带有篮子设计的第2阶段平台试验中，12岁或以上的NF2-SWN患者和进展性肿瘤患者接受每日180mg口服布格替尼治疗.中央审查委员会评估了每位患者的一个目标肿瘤和最多五个非目标肿瘤。主要结果是靶肿瘤的影像学反应。关键次要结果是安全性，所有肿瘤的反应率，听力反应,和患者报告的结果。
结果：共有40名患者（中位年龄，26年）进行性靶肿瘤（10例前庭神经鞘瘤，8个非前庭神经鞘瘤，20个脑膜瘤，和2个室管膜瘤）接受布格替尼治疗。在中位随访10.4个月后，有影像学反应的肿瘤百分比为10%(95%置信区间[CI]，目标肿瘤为3至24），所有肿瘤为23％（95％CI，16至30）；脑膜瘤和非前庭神经鞘瘤的益处最大。治疗期间，所有肿瘤类型的年化增长率均降低。35％（95％CI，20至53）的合格耳朵听力改善。探索性分析表明，治疗期间自我报告的疼痛严重程度降低（每月-0.013单位；95％CI，-0.002至-0.029），评分从0（无疼痛）到3（严重疼痛）。未报告4级或5级治疗相关不良事件。
结论：Brigatinib治疗导致多种肿瘤类型的影像学反应，并在NF2-SWN患者的大量预处理队列中获得临床益处。（由儿童肿瘤基金会等资助；INTUITT-NF2ClinicalTrials.gov编号，NCT04374305。).
方法：在带有篮子设计的第2阶段平台试验中，12岁或以上的NF2-SWN患者和进展性肿瘤患者接受每日180mg口服布格替尼治疗.中央审查委员会评估了每位患者的一个目标肿瘤和最多五个非目标肿瘤。主要结果是靶肿瘤的影像学反应。关键次要结果是安全性，所有肿瘤的反应率，听力反应,和患者报告的结果。
结果：共有40名患者（中位年龄，26年）进行性靶肿瘤（10例前庭神经鞘瘤，8个非前庭神经鞘瘤，20个脑膜瘤，和2个室管膜瘤）接受布格替尼治疗。在中位随访10.4个月后，有影像学反应的肿瘤百分比为10%(95%置信区间[CI]，目标肿瘤为3至24），所有肿瘤为23％（95％CI，16至30）；脑膜瘤和非前庭神经鞘瘤的益处最大。治疗期间，所有肿瘤类型的年化增长率均降低。35％（95％CI，20至53）的合格耳朵听力改善。探索性分析表明，治疗期间自我报告的疼痛严重程度降低（每月-0.013单位；95％CI，-0.002至-0.029），评分从0（无疼痛）到3（严重疼痛）。未报告4级或5级治疗相关不良事件。
结论：Brigatinib治疗导致多种肿瘤类型的影像学反应，并在NF2-SWN患者的大量预处理队列中获得临床益处。（由儿童肿瘤基金会等资助；INTUITT-NF2ClinicalTrials.gov编号，NCT04374305。).
