#大药编#NEJM重磅:Larotrectinib靶向治疗TRK融合阳性肿瘤患者效果显著

在儿童和成人多种癌症中,发生三种原肌凝蛋白受体激酶(TRK)的融合。今年发表在《新英格兰医学杂志》上的研究评估了一种高度选择性的TRK抑制剂larotrectinib的有效性和安全性,在成人和儿童中都发现有这种基因融合。


来自美国的研究人员对患者进行了连续和前瞻性的TRK融合-阳性癌症识别,通过分子分析,在每个位点上进行常规的检测,进入三种流程中的一种:第一阶段涉及成人的研究,1 - 2阶段涉及儿童的研究,或涉及青少年和成人的第二阶段研究。综合分析的主要终点是独立审查的总体有效率。次要终点包括反应时间、无进展生存和安全。


共有55名患者被纳入研究,年龄从4个月到76岁不等。患者有17种独特的TRK -阳性肿瘤类型。根据独立机构评估,总体有效率为75%(95%  CI, 61 - 85),根据调查人员的评估,总体有效率为80% (95% CI, 67 - 90)。研究进行1年时,71%的患者持续有效,55%的患者保持无进展。反应的平均持续时间和无进展生存率尚未达到。在9.4个月的中位随访中,86%的患者(44名患者中有38名)继续接受治疗,或者接受了治疗。不良事件主要发生是1级,调查人员认为与larotrectinib相关的3级或4级不良事件没有发生在5%以上的患者身上。由于与药物有关的不良事件,没有患者停止使用larotrectinib。


这项临床试验表明,无论患者的年龄或肿瘤类型如何,Larotrectinib在TRK融合-阳性癌症患者中具有显著且持久的抗肿瘤活性,。

BACKGROUND

Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.


METHODS

We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.


RESULTS

A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.


CONCLUSIONS

Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.


Reference: 

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children



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