BACKGROUND The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. METHODS Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). FINDINGS Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred. INTERPRETATION These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. FUNDING Bayer and Loxo Oncology.

中文翻译：

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Larotrectinib在TRK融合阳性实体瘤患者中的应用：3个1/2期临床试验的汇总分析。

背景技术基于55名患者的初步分析，选择性TRK抑制剂larotrectinib被批准用于患有晚期TRK融合阳性实体瘤的儿童和成人患者。我们的分析目的是探讨拉罗替尼在TRK融合阳性实体瘤患者中的疗效和长期安全性。方法在1期成人，1/2期儿科或2期青春期和成人试验中纳入患者并进行治疗。这些研究之间的某些资格标准有所不同。对于此汇总分析，符合条件的患者年龄为1个月或1个月以上，患有局部晚期或转移性非CNS原发性，TRK融合阳性实体瘤，如果可能的话，他们先前曾接受过标准治疗。该分析集包括接受larotrectinib批准的55例患者。以连续28天的时间表口服（胶囊或液体制剂）拉罗替尼（Larotrectinib），主要以每天两次100 mg的剂量对成年人和主要以100 mg / m2的剂量（最大100 mg）的儿科患者给药每天两次。主要终点是当地研究人员在意图治疗分析中评估的客观反应。参与试验已在ClinicalTrials.gov，NCT02122913（正在积极招募），NCT02637687（正在招募）和NCT02576431（正在招募）中注册。结果在2014年5月1日至2019年2月19日之间，接受159例TRK融合阳性癌症患者并接受larotrectinib治疗。年龄范围从不到1个月到84岁。根据研究者评估，具有客观反应的患者比例为153名可评估患者中的121名（79％，95％CI 72-85），有24位（16％）的回应完全。在260名接受TRK融合状态治疗的安全患者中，最常见的3或4级与larotrectinib相关的不良事件是丙氨酸转氨酶升高（260名患者中的8％[3％]），贫血（6％，2％）和嗜中性粒细胞减少（5 [2％]）。与larotrectinib相关的最常见严重不良事件是丙氨酸转氨酶升高（260例患者中的两个[<1％]），天冬氨酸转氨酶升高（两个[<1％]）和恶心（两个[<1％]）。没有发生与治疗有关的死亡。解释这些数据证实TRK融合蛋白定义了Larotrectinib具有高度活性的晚期实体瘤的独特分子亚组。安全性数据表明，长期使用larotrectinib是可行的。资助拜耳和Loxo肿瘤学。