Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer
Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer
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DOI：
10.1056/nejmoa1413654
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发表时间：
2015-04-30
影响因子：
158.5
通讯作者：
Camidge, D. R.
中科院分区：
文献类型：
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作者：
Sequist, L. V.;Soria, J-C;Camidge, D. R.
表皮生长因子受体（EGFR）编码基因突变的非小细胞肺癌（NSCLC）对批准的EGFR抑制剂敏感，但在大多数情况下，由T790 M EGFR突变介导的耐药性发展。Rociletinib（CO-1686）是一种EGFR抑制剂，在EGFR突变的非小细胞肺癌（NSCLC）的临床前模型中具有活性，无论是否伴有T790 M。方法在这项1-2期研究中，我们对EGFR突变的非小细胞肺癌（NSCLC）患者给予了Rociletinib，这些患者在既往接受EGFR抑制剂治疗期间发生了疾病进展。在研究的扩展（2期）部分，T790 M阳性疾病患者接受了500 mg每日两次、625 mg每日两次或750 mg每日两次的rociletinib治疗。主要目的是评估rociletinib的安全性、副作用特征、药代动力学和初步抗肿瘤活性。在筛选期间进行肿瘤活检以鉴定T790 M。治疗以连续21天为周期，共纳入130例患者。入选的前57名患者接受了游离碱形式的rociletinib（150 mg每日一次至900 mg每日两次）。其余患者接受溴化氢盐（HBr）形式（500 mg每日两次至1000 mg每日两次）。未确定最大耐受剂量（与剂量限制性毒性作用发生率小于33%相关的最高剂量）。唯一常见的剂量限制性不良事件是高血糖症。在一项疗效分析中，包括接受900 mg每日两次游离碱rociletinib或任何剂量HBr形式的患者，46例可评价的T790 M阳性疾病患者的客观缓解率为59%（95%置信区间[CI]，45 - 73），17例T790 M阴性疾病患者中可评估的比率为29%结论：SRociletinib对T790 M耐药突变相关的EGFR突变NSCLC患者有效。
BACKGROUNDNon-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.METHODSIn this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.RESULTSA total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).CONCLUSIONSRociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation.