Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).
Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).
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DOI：
10.1158/2159-8290.cd-16-1237
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发表时间：
2017-04
期刊：
影响因子：
28.2
通讯作者：
De Braud FG
中科院分区：
文献类型：
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作者：
Drilon A;Siena S;Ou SI;Patel M;Ahn MJ;Lee J;Bauer TM;Farago AF;Wheler JJ;Liu SV;Doebele R;Giannetta L;Cerea G;Marrapese G;Schirru M;Amatu A;Bencardino K;Palmeri L;Sartore-Bianchi A;Vanzulli A;Cresta S;Damian S;Duca M;Ardini E;Li G;Christiansen J;Kowalski K;Johnson AD;Patel R;Luo D;Chow-Maneval E;Hornby Z;Multani PS;Shaw AT;De Braud FG
Entrectinib 是一种有效的口服酪氨酸激酶 TRKA/B/C、ROS1 和 ALK 抑制剂，在两项 1 期研究中对晚期或转移性实体瘤患者（包括患有活动性中枢神经系统疾病的患者）进行了评估。在此，我们总结了恩曲替尼在一组携带 NTRK1/2/3、ROS1 或 ALK 基因融合的肿瘤患者中的总体安全性并报告了恩曲替尼的抗肿瘤活性，这些患者之前未接受过针对特定基因的 TKI 治疗，并且接受了与 RP2D 一致的治疗暴露剂量的治疗。 Entrectinib 耐受性良好，主要为 1/2 级不良事件，通过剂量调整可逆转。在非小细胞肺癌、结直肠癌、乳腺类似分泌癌、黑色素瘤和肾细胞癌中观察到缓解，最早在开始治疗后 4 周，持续长达 2 年以上。值得注意的是，SQSTM1-NTRK1 重排肺癌患者实现了完全的 CNS 缓解。
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as > 2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.