Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
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DOI：
10.1016/s1470-2045(18)30119-0
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Hawkins DS
中科院分区：
文献类型：
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作者：
Laetsch TW;DuBois SG;Mascarenhas L;Turpin B;Federman N;Albert CM;Nagasubramanian R;Davis JL;Rudzinski E;Feraco AM;Tuch BB;Ebata KT;Reynolds M;Smith S;Cruickshank S;Cox MC;Pappo AS;Hawkins DS
涉及NTRK 1、NTRK 2或NTRK 3的基因融合（TRK融合）在广泛的儿科和成人恶性肿瘤中发现。Larotrectinib是一种高度选择性的TRK激酶小分子抑制剂，在临床前模型和携带TRK融合的肿瘤成人中表现出活性。本研究的主要目的是评估larotrectinib在儿科患者中的安全性。这项多中心、I期研究入组了年龄在1个月至21岁之间的婴儿、儿童和青少年，患有局部晚期或转移性实体瘤或中枢神经系统肿瘤，无论TRK融合状态如何。其他关键入选标准包括根据疾病特异性标准可评价和/或可测量的疾病、Karnofsky（≥16岁）或Lansky（<16岁）体能评分≥50、器官功能良好以及从所有既往抗癌治疗的急性毒性反应中完全恢复。Larotrectinib口服给药，每日两次（BID），连续28天，剂量水平递增，根据滚动六设计。第一阶段剂量递增部分的主要终点是larotrectinib在接受至少一剂larotrectinib治疗的晚期实体瘤或原发性中枢神经系统肿瘤儿科患者中的安全性，包括剂量限制毒性。次要终点包括用于进一步临床研究的最大耐受剂量或适当剂量的larotrectinib、药代动力学和抗肿瘤活性评估，包括客观缓解率（ORR）。此处报告的是已完成入组的I期剂量递增队列的患者。这些患者的随访和II期队列的入组正在根据本方案进行。本试验在ClinicalTrials.gov注册，编号为NCT 02637687。24名患者（17名患有TRK融合肿瘤，7名没有）的中位年龄为4.5岁（范围为0.1 -18岁），被招募到三个剂量队列。TRK融合癌患者被诊断为婴儿纤维肉瘤（n=8）、其他软组织肉瘤（n=7）和甲状腺乳头状癌（n=2）。不良事件主要为1级;最常见的是丙氨酸转氨酶和天冬氨酸转氨酶升高[各10例（42%）/24例]以及白细胞减少症和中性粒细胞计数降低[各5例（21%）/24例]。1例无TRK融合伴疾病进展的患者出现3级丙氨酸氨基转移酶升高，这是唯一的剂量限制性毒性，导致larotrectinib停药。没有其他患者因不良事件而停用larotrectinib。没有3级治疗相关不良事件发生在1例以上患者中，也没有观察到4级或5级治疗相关不良事件。观察到两起与larotrectinib相关的严重不良事件：在停用larotrectinib后的28天随访期间和在蒽环类药物治疗期间发生3级恶心和3级射血分数降低[各1例（4%）/24例]。未定义最大耐受剂量。基于药代动力学和抗肿瘤活性，将100 mg/m2（最大剂量为100 mg/剂）BID确定为推荐的II期剂量。根据实体瘤疗效评价标准（RECIST）v1.1，在TRK融合癌和可测量疾病患者中，客观缓解率（ORR）为93%（15例患者中的14例），其余不符合RECIST部分缓解标准的患者显示肿瘤消退。在未记录TRK融合癌的患者中，ORR为0%（0/7例患者）。TRK抑制剂larotrectinib在儿科患者中耐受良好。对于婴儿、儿童和青少年，无论年龄大小，推荐的II期剂量为100 mg/m2（上限为100 mg）。Larotrectinib在所有TRK融合阳性肿瘤患者中均表现出抗肿瘤活性。Loxo Oncology
Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had demonstrated activity in preclinical models and in adults with tumours harbouring TRK fusions. The primary aim of this study was to assess the safety of larotrectinib in paediatric patients. This multicentre, phase 1 study enrolled infants, children and adolescents aged 1 month to 21 years with locally advanced or metastatic solid or central nervous system tumours regardless of TRK fusion status. Other key inclusion criteria included evaluable and/or measurable disease according to disease specific criteria, Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance score of ≥50, adequate organ function, and full recovery from the acute toxic effects of all prior anticancer therapy. Larotrectinib was administered orally, twice daily (BID) on a continuous 28-day schedule, in increasing dose levels, according to a rolling six design. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose limiting toxicity, in paediatric patients with advanced solid or primary central nervous system tumours treated with at least one dose of larotrectinib. Secondary endpoints included the maximum tolerated dose or appropriate dose of larotrectinib for further clinical investigation, pharmacokinetics, and an assessment of antitumour activity including the objective response rate (ORR). Reported here are the patients enrolled to the phase 1 dose escalation cohort which has completed enrolment. Follow-up of these patients and enrolment to phase 2 cohorts are ongoing on this protocol. This trial is registered with ClinicalTrials.gov, number NCT02637687. Twenty-four patients (17 with tumours with TRK fusions, seven without) with a median age of 4·5 years (range 0·1–18) were enrolled to three dose cohorts. Patients with TRK fusion cancers had diagnoses of infantile fibrosarcoma (n=8), other soft tissue sarcomas (n=7) and papillary thyroid cancer (n=2). Adverse events were predominantly grade 1; the most common were increased alanine and aspartate aminotransferase [10 (42%) of 24 each] and leukopenia and decreased neutrophil count [5 (21%) of 24 each]. Grade 3 alanine aminotransferase elevation in a patient without a TRK fusion with progressive disease was the only dose limiting toxicity and resulted in larotrectinib discontinuation. No other patients discontinued larotrectinib for adverse events. No grade 3 treatment-related adverse events occurred in more than one patient and no grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines [1 (4%) of 24 each]. The maximum tolerated dose was not defined. A dose of 100 mg/m2 (maximum of 100 mg/dose) BID was determined to be the recommended phase 2 dose based on pharmacokinetics and antitumor activity. In patients with TRK fusion cancers and measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, the objective response rate (ORR) was 93% (14 of 15 patients), with the remaining patient that did not meet RECIST partial response criteria showing tumour regression. In patients without documented TRK fusion cancers, the ORR was 0% (0 of 7 patients). The TRK inhibitor larotrectinib was well tolerated in paediatric patients. A recommended phase 2 dose of 100mg/m2 (cap of 100 mg) was defined for infants, children, and adolescents, regardless of age. Larotrectinib demonstrated antitumour activity in all patients with TRK fusion-positive tumours. Loxo Oncology