Abstract：
OBJECTIVE: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel.
METHODS: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level.
RESULTS: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved.
CONCLUSIONS: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.
METHODS: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level.
RESULTS: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved.
CONCLUSIONS: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.
摘要：
目的：MAPK通路在葡萄膜黑色素瘤（UM）中被组成型激活。塞马替尼（AZD6244，ARRY-142886），MEK抑制剂，在转移性UM中作为单一疗法显示出有限的活性。临床前研究支持MEK抑制剂与紫杉烷类的协同细胞毒活性，在此,我们试图评估司美替尼和紫杉醇联合应用的临床疗效.
方法：77例未接受过化疗的转移性UM患者被随机分配到单独使用司美替尼，或与紫杉醇联合使用，在紫杉醇前两天中断或不中断使用司美替尼。主要终点是无进展生存期（PFS）。修改后,将组合方组合并进行分析,并对样本量进行调整,以检测风险比(HR):0.55,1侧5%显著性水平下的80%功效.
结果：联合治疗组的中位PFS为4.8个月（95％CI：3.8-5.6），而司米替尼组的中位PFS为3.4个月（2.0-3.9）（HR0.62[90％CI0.41-0.92]，1侧p值=0.022)。组合和单一疗法组的ORR分别为14%和4%。联合用药的中位OS为9个月，与单独的司美替尼（10个月）无显著差异，HR为0.98[90%CI0.58-1.66]，1侧p值=0.469。毒性与所涉及的试剂的已知概况一致。
结论：SelPac达到了主要终点，显示司美替尼和紫杉醇联合用药的PFS改善。没有观察到OS的改善，PFS的适度改善并没有改变实践。
方法：77例未接受过化疗的转移性UM患者被随机分配到单独使用司美替尼，或与紫杉醇联合使用，在紫杉醇前两天中断或不中断使用司美替尼。主要终点是无进展生存期（PFS）。修改后,将组合方组合并进行分析,并对样本量进行调整,以检测风险比(HR):0.55,1侧5%显著性水平下的80%功效.
结果：联合治疗组的中位PFS为4.8个月（95％CI：3.8-5.6），而司米替尼组的中位PFS为3.4个月（2.0-3.9）（HR0.62[90％CI0.41-0.92]，1侧p值=0.022)。组合和单一疗法组的ORR分别为14%和4%。联合用药的中位OS为9个月，与单独的司美替尼（10个月）无显著差异，HR为0.98[90%CI0.58-1.66]，1侧p值=0.469。毒性与所涉及的试剂的已知概况一致。
结论：SelPac达到了主要终点，显示司美替尼和紫杉醇联合用药的PFS改善。没有观察到OS的改善，PFS的适度改善并没有改变实践。
