PDF(Pubmed)
Abstract：
UNASSIGNED: Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas.
UNASSIGNED: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers.
UNASSIGNED: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects.
UNASSIGNED: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.
UNASSIGNED: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers.
UNASSIGNED: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects.
UNASSIGNED: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.
摘要：
■脑膜瘤发生在80％的神经纤维瘤病2（NF2）患者中，并导致显著的死亡率和发病率。然而，没有有效的药物治疗。NF2缺陷型肿瘤具有哺乳动物/机械性雷帕霉素靶（mTOR）的组成型激活，用mTORC1抑制剂治疗会导致少数肿瘤的生长停滞，与mTORC2/AKT途径的矛盾激活。我们研究了vistusertib的效果，双重mTORC1/mTORC2抑制剂，在NF2患有进行性或症状性脑膜瘤的患者中。
Vistusertib以125mg每日两次口服给药,每周连续2天。主要终点是靶脑膜瘤的影像学反应，定义为与基线相比体积减少20%。次要终点包括毒性，非靶肿瘤的成像反应，生活质量,和遗传生物标志物。
■18名参与者（13名女性），中位年龄41岁(范围，18-61）年，已注册。在目标脑膜瘤中，最佳反应是1/18肿瘤中的部分反应(PR)(6%)和17/18肿瘤中的稳定疾病(SD)(94%).对于所有测量的颅内脑膜瘤和前庭神经鞘瘤，最好的影像学反应是6/59个肿瘤中的PR(10%)和53个肿瘤中的SD(90%).治疗相关的3/4级不良事件发生在14名（78%）参与者中，9名参与者因副作用停止治疗。
■尽管研究未达到主要终点，vistusertib治疗与进展性NF2相关肿瘤的高SD发生率相关。然而,vistusertib的这种给药方案耐受性差.NF2的双重mTORC抑制剂的未来研究应集中在优化耐受性和评估参与者肿瘤稳定性的相关性上。
Vistusertib以125mg每日两次口服给药,每周连续2天。主要终点是靶脑膜瘤的影像学反应，定义为与基线相比体积减少20%。次要终点包括毒性，非靶肿瘤的成像反应，生活质量,和遗传生物标志物。
■18名参与者（13名女性），中位年龄41岁(范围，18-61）年，已注册。在目标脑膜瘤中，最佳反应是1/18肿瘤中的部分反应(PR)(6%)和17/18肿瘤中的稳定疾病(SD)(94%).对于所有测量的颅内脑膜瘤和前庭神经鞘瘤，最好的影像学反应是6/59个肿瘤中的PR(10%)和53个肿瘤中的SD(90%).治疗相关的3/4级不良事件发生在14名（78%）参与者中，9名参与者因副作用停止治疗。
■尽管研究未达到主要终点，vistusertib治疗与进展性NF2相关肿瘤的高SD发生率相关。然而,vistusertib的这种给药方案耐受性差.NF2的双重mTORC抑制剂的未来研究应集中在优化耐受性和评估参与者肿瘤稳定性的相关性上。
