Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
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DOI：
10.1056/nejmoa1714448
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发表时间：
2018-02-22
期刊：
影响因子：
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通讯作者：
Hyman DM
中科院分区：
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作者：
Drilon A;Laetsch TW;Kummar S;DuBois SG;Lassen UN;Demetri GD;Nathenson M;Doebele RC;Farago AF;Pappo AS;Turpin B;Dowlati A;Brose MS;Mascarenhas L;Federman N;Berlin J;El-Deiry WS;Baik C;Deeken J;Boni V;Nagasubramanian R;Taylor M;Rudzinski ER;Meric-Bernstam F;Sohal DPS;Ma PC;Raez LE;Hechtman JF;Benayed R;Ladanyi M;Tuch BB;Ebata K;Cruickshank S;Ku NC;Cox MC;Hawkins DS;Hong DS;Hyman DM
涉及三种原肌球蛋白受体激酶（TRK）之一的融合发生在儿童和成人的各种癌症中。我们评估了Larotrectinib（一种高选择性TRK抑制剂）在患有这些融合肿瘤的成人和儿童中的疗效和安全性。我们招募了连续和前瞻性确定的TRK融合阳性癌症患者，通过在每个站点常规进行的分子分析检测到，进入三个方案之一：涉及成人的1期研究，涉及儿童的1-2期研究，或涉及青少年和成人的2期研究。综合分析的主要终点是根据独立审查的总体缓解率。次要终点包括反应持续时间、无进展生存期和安全性。共有55例患者入组并接受治疗，年龄从4个月至76岁不等。患者有17种独特的TRK融合阳性肿瘤类型。根据独立审查，总体缓解率为75%（95%置信区间[CI]，61 - 85），根据研究者评估，总体缓解率为80%（95% CI，67 - 90）。1年时，71%的缓解仍在进行中，55%的患者保持无进展。尚未达到中位缓解持续时间和无进展生存期。在中位随访9.4个月时，86%有反应的患者（44例患者中的38例）继续接受治疗或接受了旨在治愈的手术。不良事件主要为1级，研究者认为与larotrectinib相关的3级或4级不良事件发生率均未超过5%。没有患者因药物相关不良事件而停用larotrectinib。Larotrectinib在TRK融合阳性癌症患者中具有显著和持久的抗肿瘤活性，无论患者年龄或肿瘤类型如何。（由Loxo Oncology和其他人资助; ClinicalTrials.gov编号，NCT 02122913，NCT 02637687和NCT 02576431。
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. 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. 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. 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. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913, NCT02637687, and NCT02576431.)