From Massachusetts General Hospital (L.V.S., R.S.H., J.L., Z.P.), Harvard Medical School (L.V.S., G.R.O., R.S.H., Z.P.), and Dana-Farber Cancer Institute (G.R.O.) - all in Boston; the Drug Development Department, Université Paris-Sud, Gustave Roussy Cancer Campus (J.-C.S.), and Institut Gustave Roussy (A.V.), Villejuif - both in France; the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.W.G., E.B.G., M.A.M., S.N.), and Stanford Cancer Institute, Stanford University, Stanford (H.A.W., J.W.N.) - both in California; the Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit (S.M.G., C.G., A.J.W.); University of Texas M.D. Anderson Cancer Center, Houston (V.P.); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); the Medical University of Gdansk, Gdansk, Poland (R.D.); the University of Colorado (D.L.A., D.R.C.) and University of Colorado Cancer Center (R.C.D.) - both in Aurora; and Clovis Oncology, San Francisco (M.R., C.A.K., S.J.-T., S.L.M., A.R.A.), Boulder, CO (J.I., D.D.), and Cambridge, United Kingdom (L.R.).
N Engl J Med. 2015 Apr 30;372(18):1700-9. doi: 10.1056/NEJMoa1413654.
Non-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.
In 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.
A 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).
Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).
表皮生长因子受体（EGFR）基因突变的非小细胞肺癌（NSCLC）对已批准的 EGFR 抑制剂敏感，但大多数情况下，耐药性是由 T790M EGFR 突变介导的。 Rociletinib（CO-1686）是一种在有或没有 T790M 的 EGFR 突变的 NSCLC 临床前模型中具有活性的 EGFR 抑制剂。
在这项 1-2 期研究中，我们对先前接受过现有 EGFR 抑制剂治疗的 EGFR 突变型 NSCLC 患者给予 Rociletinib。在研究的扩展（2 期）部分，T790M 阳性疾病患者接受 Rociletinib 500mg 每日两次、625mg 每日两次或 750mg 每日两次的剂量。主要目标是评估 Rociletinib 的安全性、副作用谱、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确定 T790M。治疗以连续 21 天周期给药。
共纳入 130 例患者。前 57 例入组患者接受 Rociletinib 游离碱形式（150mg 每日一次至 900mg 每日两次）。其余患者接受氢溴酸盐（HBr）形式（500mg 每日两次至 1000mg 每日两次）。未确定最大耐受剂量（与低于 33%的剂量限制毒性发生率相关的最高剂量）。唯一常见的剂量限制不良事件是高血糖症。在包括接受 Rociletinib 游离碱 900mg 每日两次或任何剂量 HBr 形式的 46 例 T790M 阳性疾病患者的疗效分析中，可评估患者的客观缓解率为 59%（95%置信区间[CI]，45 至 73），17 例 T790M 阴性疾病患者的缓解率为 29%（95%CI，8 至 51）。
Rociletinib 对伴有 T790M 耐药突变的 EGFR 突变型 NSCLC 患者有效。（由 Clovis Oncology 资助；ClinicalTrials.gov 编号，NCT01526928）。
