A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor
A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor
复制标题
DOI：
10.1038/bjc.2017.10
复制
发表时间：
2017-02-28
影响因子：
8.8
通讯作者：
Patnaik, Amita
中科院分区：
文献类型：
--
作者：
Bendell, Johanna C.;Javle, Milind;Patnaik, Amita
Binimetinib（MEK 162; ARRY-438162）是一种有效和选择性的口服MEK 1/2抑制剂。这项1期研究确定了最大耐受剂量（MTD），安全性，药代动力学和药效学特征，并在晚期实体瘤患者的初步抗肿瘤活性的binimetinib，与胆管癌或KRAS或BRAF突变的结直肠癌患者的扩展队列。按照3+ 3剂量递增设计，在MTD确定后入组扩展队列。从血浆样品测定药代动力学特性。评估肿瘤样品中RAS、RAF和其他相关基因的突变。在血清和皮肤穿刺活检samples.Results的药效学特性进行了评价：93例患者接受比尼替尼（剂量递增阶段，19;扩展，74）。MTD为60 mg，每日两次，剂量限制性不良事件（AE）为痤疮样皮炎和脉络膜视网膜病变。由于MTD时治疗相关眼毒性的发生频率，扩展患者的剂量随后降至45 mg每日两次。所有剂量水平的常见AE包括皮疹（81%）、恶心（56%）、呕吐（52%）、腹泻（51%）、外周水肿（46%）和疲乏（43%）;大多数为1/2级。观察到比尼替尼暴露量呈剂量比例增加，在血清和皮肤穿刺活检样本中证实了靶点抑制。三例胆道癌患者有客观的反应（一个完全和两个部分）。结论：Binimetinib表现出可管理的安全性，目标抑制，剂量成比例的暴露。45 mg每日两次剂量被确定为推荐的II期剂量。胆道癌患者的3个客观缓解令人鼓舞，并支持在该人群中进行进一步评价。
Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS-or BRAF-mutant colorectal cancer.Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.