Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.
Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.
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DOI：
10.1158/1078-0432.ccr-13-0027
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发表时间：
2013-07-15
期刊：
影响因子：
--
通讯作者：
Fuchs CS
中科院分区：
文献类型：
--
作者：
Ng K;Tabernero J;Hwang J;Bajetta E;Sharma S;Del Prete SA;Arrowsmith ER;Ryan DP;Sedova M;Jin J;Malek K;Fuchs CS
40-60% 的结直肠癌 (CRC) 患者中发现磷脂酰肌醇 3-激酶 (PI3K)/Akt/哺乳动物雷帕霉素靶点 (mTOR) 通路失调。依维莫司是一种口服 mTOR 抑制剂，在 I 期研究中证明对转移性 CRC (mCRC) 患者有效。在评估两种给药方案的连续 II 期研究中，对基于贝伐单抗、氟嘧啶、奥沙利铂和伊立替康的方案难治的 mCRC 患者接受依维莫司 70 mg/周 (N=99) 或 10 mg/d (N=100)。主要终点是疾病控制率（DCR）和客观缓解率；次要终点包括无进展生存期（PFS）、总生存期（OS）和缓解或疾病稳定持续时间（SD）。从所有患者身上收集肿瘤组织，用于预定义的探索性生物标志物分析。每个队列的每个方案集均包括 71 名患者。每周和每日计划中的 DCR 分别为 31.0% 和 32.4%（均为 SD）。每个队列中 SD 的中位持续时间为 3.9 个月。对于每周和每日计划，中位 PFS 和 OS 分别为 1.8 个月和 4.9 个月以及 1.8 个月和 5.9 个月。在探索性生物标志物分析中，与野生型 KRAS 患者相比，每日接受依维莫司治疗的患者中，KRAS 突变患者的中位 OS 显着缩短 (P = .008)，DCR 更低 (P = .035)。依维莫司 70 毫克/周或 10 毫克/天的耐受性良好，但对于经过大量治疗的转移性结直肠癌患者没有产生有意义的疗效。未来的研究可能会考虑评估依维莫司与其他药物联合使用或用于 PI3K/Akt/mTOR 通路失调的患者。
Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is seen in 40–60% of colorectal cancer (CRC) patients. Everolimus, an oral inhibitor of mTOR, demonstrated efficacy in metastatic CRC (mCRC) patients in phase I studies. In sequential phase II studies assessing 2 dosing schedules, mCRC patients refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/week (N=99) or 10 mg/d (N=100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses. 71 patients were included in the per protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 months and 4.9 months and 1.8 months and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = .008) and lower DCR (P = .035) compared with those with wild-type KRAS in exploratory biomarker analyses. Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.