Selective RET kinase inhibition for patients with RET-altered cancers.
Selective RET kinase inhibition for patients with RET-altered cancers.
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DOI：
10.1093/annonc/mdy137
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发表时间：
2018-08-01
期刊：
影响因子：
--
通讯作者：
Drilon A
中科院分区：
文献类型：
--
作者：
Subbiah V;Velcheti V;Tuch BB;Ebata K;Busaidy NL;Cabanillas ME;Wirth LJ;Stock S;Smith S;Lauriault V;Corsi-Travali S;Henry D;Burkard M;Hamor R;Bouhana K;Winski S;Wallace RD;Hartley D;Rhodes S;Reddy M;Brandhuber BJ;Andrews S;Rothenberg SM;Drilon A
涉及RET激酶的改变与肺癌、甲状腺癌和其他癌症的发病机制有关。然而，具有抗RET活性的多激酶抑制剂（MKI）在RET改变的患者中的临床活性似乎有限，这使得靶向RET的治疗潜力受到质疑。LOXO-292是一种选择性RET抑制剂，旨在抑制多种RET融合、激活突变和获得性耐药突变。使用多种体外和体内RET依赖性肿瘤模型在临床前证实了有效的抗RET活性、高选择性和中枢神经系统覆盖。由于临床紧迫性，2例RET改变的MKI耐药癌症患者接受了LOXO-292治疗，采用实时药代动力学评估指导的快速剂量滴定，以安全、快速地实现有意义的临床暴露。LOXO-292对具有内源性RET基因改变的人癌细胞系表现出强效和选择性的临床前抗RET活性;经工程改造以表达KIF 5 B-RET融合蛋白−/+ RET V804 M看门人抗性突变或常见RET激活突变M918 T的细胞;和RET改变的人癌细胞系和患者来源的异种移植物，包括原位注射到脑中的患者来源的RET融合阳性异种移植物。1例RET M918 T突变型甲状腺髓样癌肝转移和获得性RET V804 M看门人耐药突变患者，既往接受过6种MKI方案治疗，肿瘤降钙素、CEA和游离DNA迅速降低，疼痛性肝肿大和肿瘤相关腹泻消退，并确认肿瘤缓解。第2例KIF 5 B-RET融合阳性肺癌患者对alectinib获得性耐药，并出现症状性脑转移，其脑部出现显著缓解，症状消退。这些结果为RET改变的临床有效性提供了概念验证，并确定LOXO-292的选择性RET抑制作用是一种有前景的治疗方法，可用于接受过大量预治疗、经历过多激酶受体的多种RET改变肿瘤患者。
Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein −/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
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影响因子：
51.1
作者：
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作者：
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影响因子：
11.5
作者：
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影响因子：
64.5
作者：
TAKAHASHI, M;RITZ, J;COOPER, GM
通讯作者：
COOPER, GM