响应率高达93%!这一“广谱”抗癌新药有望治疗多种儿童癌症

2018-04-02 绿谷生物 The Lancet Oncology
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Briana Ayala(左)和肿瘤学家Ted Laetsch博士(图片来源:UT Southwestern Medical Center)

近期,美国UT Southwestern's Simmons癌症中心的科学家们在《The Lancet Oncology》期刊发表文章揭示,larotrectinib在临床试验(phase 1/2)中取得喜人的成绩,93%的儿童患者得到积极响应。

一个月前,《New England Journal of Medicine》期刊就已经报道了larotrectinib的佳绩——17种不同癌症患者(年龄范围在4个月至76岁)的总体应答率为75%。

DOI: https://doi.org/10.1016/S1470-2045(18)30119-0

Larotrectinib:广谱抗癌药

Larotrectinib靶向特定的融合基因——TRK突变。所以它不同于传统的抗癌药物,不是针对某个器官、组织的肿瘤,而是针对特定分子标志物而界定治疗对象的“广谱抗癌药”。

TRK是原肌球蛋白受体激酶的简称。在一些癌症中,TRK基因的一部分与其他基因相连,且受控于同一套调控元件。这一融合现象的发生会导致TRK基因在本应关闭的时机被‘打开’,从而导致细胞生长失控。

Larotrectinib属于激酶抑制剂,通过抑制激酶活性而发挥疗效。这一选择性治疗策略意味着该药物不会引发与传统癌症治疗相关的严重副作用。同样重要的是,对于参与试验的大多数患者而言,这一治疗效果是持久的。

TRK融合突变存在于多种癌症中,包括肺癌、结肠癌、甲状腺癌、乳腺癌以及一些儿童肿瘤。2016年,larotrectinib获得FDA突破性疗法认定。

最新结果:93%的儿童癌症患者积极响应

虽然TRK基因融合突变发生于成年癌症的概率较低,但是它常常与一些罕见的儿童癌症有关,例如婴儿纤维肉瘤癌、细胞先天性中胚层肾瘤和乳头状甲状腺癌。

在由儿科助理教授Ted Laetsch领导的临床1期试验(2015年末至2017年4月)中,共24名儿童癌症患者参与了试验,其中17名患者携带有TRK融合突变。结果显示,每一个携带TRK融合基因突变的实体瘤患者在接受larotrectinib治疗之后,其肿瘤都缩小了。这种几近于普遍响应的疗效是前所未有的。

其中,有一名13岁的小患者Briana Ayala——2016年,她被诊断发现在其腹部生长有一种罕见的肿瘤,且包裹着身体内最大的主动脉。虽然美国德州大学西南医学中心的外科教授Stephen Megison对其进行里风险系数极高的外科外科手术,并成功切除部分主动脉以及大部分肿瘤组织,但是遗憾的是,残余的肿瘤组织再次开始扩增,且没有进一步的治疗对策。

Laetsch对其肿瘤样本进行了基因检测,发现这一罕见疾病与TRK融合有关。这意味着,larotrectinib新药或许有所帮助。于是,Briana Ayala参与了larotrectinib临床试验,每天服用2次药物。几周后,因癌症而引发的疼痛、腹部肿胀开始减缓和消退,扫描结果显示身体内的肿瘤明显减小。

治疗近2年后,Briana Ayala重返学校,恢复了正常的生活,且有机会实现她的梦想——当一名时装设计师。

这些结果表明,larotrectinib适用于携带TRK融合突变的癌症患者,且具有快速、有效、持久的治疗潜力。有学者认为,larotrectinib将会成为第一个在成人和儿童中同时开发和批准的治疗药物,且有望成为第一个上市的“广谱靶向药物”。

参考资料:

Pediatric cancer drug shows 93 percent response rate

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

Background 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 shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. Methods This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. Results Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3–13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 g per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. 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. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. Interpretation The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age.