Doz François, van Tilburg Cornelis M, Geoerger Birgit, Højgaard Martin, Øra Ingrid, Boni Valentina, Capra Michael, Chisholm Julia, Chung Hyun Cheol, DuBois Steven G, Gallego-Melcon Soledad, Gerber Nicolas U, Goto Hiroaki, Grilley-Olson Juneko E, Hansford Jordan R, Hong David S, Italiano Antoine, Kang Hyoung Jin, Nysom Karsten, Thorwarth Anne, Stefanowicz Joanna, Tahara Makoto, Ziegler David S, Gavrilovic Igor T, Norenberg Ricarda, Dima Laura, De La Cuesta Esther, Laetsch Theodore W, Drilon Alexander, Perreault Sebastien
SIREDO Oncology Center (Care, Innovation and Research for Children and AYA with Cancer), Institut Curie and Université de Paris, Paris, France.
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Neuro Oncol. 2022 Jun 1;24(6):997-1007. doi: 10.1093/neuonc/noab274.
Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.
Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).
As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified.
In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.
拉罗替尼是首个同类的、高度选择性的原肌球蛋白受体激酶（TRK）抑制剂，被批准用于治疗TRK融合阳性癌症的成人和儿童患者。本研究的目的是评估拉罗替尼在TRK融合阳性原发性中枢神经系统（CNS）肿瘤患者中的疗效和安全性。
从两项临床试验（NCT02637687，NCT02576431）中确定TRK融合阳性原发性CNS肿瘤患者。主要终点是研究者评估的客观缓解率（ORR）。
截至2020年7月，确定了33例TRK融合阳性CNS肿瘤患者（中位年龄：8.9岁；范围：1.3 - 79.0岁）。最常见的组织学类型是高级别胶质瘤（HGG；n = 19）和低级别胶质瘤（LGG；n = 8）。所有患者的ORR为30%（95%置信区间[CI]：16 - 49）。24周疾病控制率为73%（95% CI：54 - 87）。28例可测量疾病患者中有23例（82%）肿瘤缩小。缓解持续时间、无进展生存期和总生存期的12个月率分别为75%（95% CI：45 - 100）、56%（95% CI：38 - 74）和85%（95% CI：71 - 99）。中位缓解时间为1.9个月（范围1.0 - 3.8个月）。治疗持续时间为1.2 - 31.3 +个月。20例患者报告了与治疗相关的不良事件，3例为3 - 4级。未发现新的安全信号。
在TRK融合阳性CNS肿瘤患者中，拉罗替尼显示出快速且持久的反应、高疾病控制率和良好的安全性。
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