University of Washington, SWOG Statistical Center, Seattle, WA98109., USA.
Clin Cancer Res. 2012 Feb 15;18(4):1129-37. doi: 10.1158/1078-0432.CCR-11-2488. Epub 2012 Jan 6.
Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.
This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.
On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.
The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.
致癌基因的激活突变导致信号通路的激活，这种情况发生在大多数黑色素瘤中，可以为治疗提供极好的靶点，但短期治疗成功受到内在和获得性耐药的限制。丝裂原活化蛋白激酶和磷酸肌醇 3-激酶/AKT/mTOR 途径在大多数皮肤黑色素瘤中被激活。本试验的目的是前瞻性评估两种未经治疗的转移性黑色素瘤患者的靶向药物联合治疗。
这项随机 II 期研究纳入了 2008 年 5 月至 2009 年 11 月间患有非眼部黑色素瘤、未接受过系统化疗且无脑转移病史的患者。A 组接受每日两次口服索拉非尼 200mg 联合静脉注射替西罗莫司 25mg 每周一次；B 组接受每日早晨口服索拉非尼 400mg，每晚口服索拉非尼 200mg，每日两次，联合口服替皮法尼 100mg，每日两次，每 4 周重复。主要目的是评估两种方案的无进展生存期（PFS）、客观缓解率和毒性。
在 A 组（63 例可评估患者）中，中位 PFS 为 2.1 个月，中位总生存期（OS）为 7 个月。3 例患者达到部分缓解（PR）。共入组 39 例可评估患者的 B 组在第一阶段入组后关闭，中位 PFS 为 1.8 个月，OS 为 7 个月，1 例患者达到 PR。
所测试的分子靶向药物联合治疗方案没有显示出足够的活性，不支持进一步使用。新的药物和通过对个体肿瘤的分子靶点进行特征分析来改善患者选择显示出巨大的潜力，应与适当的实验室相关性一起纳入未来的研究。
