University of Colorado, Denver, Colorado.
MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2018 Sep 15;78(18):5398-5407. doi: 10.1158/0008-5472.CAN-18-0316. Epub 2018 Jul 24.
MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in -mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program-approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib "run-in" to evaluate FZD2 biomarker upregulation and -WT and -MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. stratification did not identify any differences in response between -WT and -MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation. These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. .
MEK 抑制在癌症药物开发中很有意义，但在转移性结直肠癌（mCRC）中的临床活性有限。临床前研究表明，在对 MEK 抑制剂 selumetinib 耐药的 -突变细胞系中，Wnt 通路过表达。selumetinib 与环孢素 A（一种非典型 Wnt 通路调节剂）的联合在 mCRC 患者来源的异种移植模型中显示出抗肿瘤活性。为了转化这些结果，我们进行了一项 NCI 癌症治疗评估计划批准的多中心 I/IB 期临床试验（NCT02188264），研究 selumetinib 与环孢素 A 的联合用药。晚期实体恶性肿瘤患者在剂量递增阶段接受口服 selumetinib 和环孢素 A 的联合治疗，随后是对伊立替康和奥沙利铂耐药的 mCRC 扩展队列。扩展队列采用单一药物 selumetinib“先导期”来评估 FZD2 生物标志物上调和 -WT 和 -MT 分层，以确定任何潜在的疗效预测因素。分别有 20 名和 19 名患者入组剂量递增和扩展阶段。最常见的不良反应和 3/4 级毒性为皮疹、高血压和水肿。报告了 3 例剂量限制性毒性（3 级高血压、皮疹和肌酐升高）。MTD 为 selumetinib 每天两次 75 mg 和环孢素 A 每天两次 2 mg/kg，每 28 天为一个周期。-WT 和 -MT 癌症之间的反应没有分层差异。观察到 2 例部分缓解、18 例稳定疾病和 10 例疾病进展。selumetinib 联合环孢素 A 耐受性良好，在 mCRC 中显示出活性。未来的概念开发策略包括确定更好的疗效预测因素和改善 Wnt 通路调节。这些发现将 selumetinib 和环孢素的临床前研究转化为一项在晚期实体恶性肿瘤患者中进行的此类联合治疗的 I 期首次人体临床试验。
