【醒目】Rociletinib （CO1686）一期临床结果（ASCO2013全文）

First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of  EGFR T790M.
Meeting:2013 ASCO Annual Meeting Abstract No:2524
Citation:
J Clin Oncol 31, 2013 (suppl; abstr 2524)
Author(s): Lecia V. Sequist, Jean-Charles Soria, Shirish M. Gadgeel, Heather A. Wakelee, D. Ross Camidge, Andrea Varga, Panos Fidias, Antoinette J. Wozniak, Joel W. Neal, Robert Charles Doebele, Edward B. Garon, Sarah S. Jaw-Tsai, Jennifer C. Stern, Andrew R. Allen, Jonathan Wade Goldman; Massachusetts General Hospital, Boston, MA; Institut Gustave Roussy, Villejuif, France; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Stanford Cancer Institute, Stanford, CA; University of Colorado Cancer Center, Aurora, CO; University of California, Los Angeles, Santa Monica, CA; Clovis Oncology, Inc., San Francisco, CA; The David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, CA
Abstract:
Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 50% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition, compromises tolerability. CO-1686 is an orally active TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest maximal efficacy when trough plasma concentrations exceed 200ng/ml.
Methods: This is a first in human phase 1 (3+3) dose-finding study of oral CO-1686, administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. Endpoints include safety, pharmacokinetics (PK), and efficacy. All patients undergo a biopsy for genotyping before starting study drug.
Results: As of 18 Jan 2013, 35 patients (18/28 (64%) T790M+; 7 pending) have been treated with CO-1686. Dosing started at 150mg QD and escalated in steps to 900mg QD, 600mg BID and 400mg TID, with a maximum tolerated dose not yet reached. A recommended phase 2 dose is expected to be reached soon. Related AEs of grade 3 or higher were hypoglycaemia (n=1) and hyperglycaemia (n=1). AEs typical of WT-EGFR inhibition (rash, diarrhea) have not been observed. Dose-proportional PK was observed; plasma half-life was 4-5 hrs and at 900mg QD Cmax=3000ng/ml but trough concentrations were < 200ng/ml. At ≥300mg BID and TID dosing, trough concentrations can exceed 200ng/ml. At 900mg QD, 2 of 3 patients showed clinical benefit after 2 cycles of CO-1686 including one with clinically-relevant tumor shrinkage (18%) and a second with stabilization of a pleural effusion that had previously required repeat thoracenteses at ~10 day intervals. At 300mg BID, one patient (Del(19)/T790M+) with PK trough concentration >200ng/ml exhibited significant tumor shrinkage (29%) after 2 cycles. Further efficacy data from BID/TID cohorts and centrally-confirmed genotypes will be presented at the meeting. Conclusions: CO-1686 offers potential for improved activity and better tolerability over current EGFR TKIs, particularly in the treatment of T790M+ disease, an area of high unmet clinical need. Clinical trial information: NCT01526928.
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CO-1686耐药机理.pdf (1.3 MB, 下载次数: 146)

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背景：现有的表皮生长因子受体酪氨酸激酶抑制剂（TKIs）治疗非小细胞肺癌的效果受到继发耐药突变和耐受性的限制，约50％的患者会出现T790M突变，以及抑制野生型（WT）EGFR引起的明显的皮疹和腹泻。CO-1686是一种高效口服TKI，有效靶点是普通EGFR突变和T790M突变，同时不抑制野生EGFR。动物模型显示血药浓度超过200ng/ml时疗效最高。
方法：这是CO-1686口服药首次在人体进行（3+3）剂量探索1期临床研究，每21天为一个服药周期。入组非小细胞肺癌病人必须同时具备EGFR突变和EGFR TKI治疗史。研究终点包括安全性、药代动力学和疗效。所有患者在服药前都经过活检基因检测。
结果：截至2013年1月18日，一共有35个病人（其中18人有T790M突变，10人T790M阴性，7人未知）服用CO-1686。初始剂量为150mg每天一次，爬坡到900mg每天一次、600mg每天二次（共1200mg）和400mg每天三次（共1200mg），最大耐受剂量仍没有确定。2期临床推荐剂量将很快确定。3级以上的副作用包括低血糖（1人）和高血糖（1人）。研究中没有观察常见的与抑制野生EGFR靶点有关的副作用（皮疹和腹泻）。药物半衰期为 4-5小时，在900mg每天一次时，最高血药浓度为3000ng/ml，但最低血药浓度小于200ng/ml；在剂量高于300mg每天二次或者三次时，最低血药浓度大于200ng/ml。
在剂量高于300mg每天二次或者三次时，最低血药浓度大于200ng/ml。在900mg每天一次剂量组（共3名病人），经过二个服药周期（42天），有2名病人获得临床收益，其中一名肿瘤缩小18%，另外1名胸水受到控制（之前每隔10天进行胸水引流）。在300mg每天二次组，一名19突变合并T790M突变的病人经过二个服药周期（42天）肿瘤缩小了29%。更高剂量组的数据和具体的基因检测数据将在ASCO大会上公布。
结论：与现有的EGFR TKI相比，CO-1686活性更强，副作用更低，特别是对于T790M突变这一类有很高临床需求的病人。

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以下内容是我的个人推测：
CO-1686的动物试验剂量是WZ4002的4倍，参考1期临床结果，可以认为WZ4002的最低有效剂量是150mg每天，一天二次。
推荐剂量是200mg~300mg每天，一天二次。

最新进展啊，老马辛苦了，翻译得信达雅。

老马威武啊~~~~~~~~~~~

{:soso_e160:} 马老师辛苦 谢谢

马老师辛苦了。。。。

老马辛苦了。

有一个新药么？

还是看不懂 唉

看来效果不错。