University of California, Los Angeles, Los Angeles, CA.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
J Clin Oncol. 2020 Jan 20;38(3):193-202. doi: 10.1200/JCO.19.01307. Epub 2019 Dec 2.
PURPOSE: Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS: This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, = .0174 [final analysis] and = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS: Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION: In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.
目的：在先前接受过治疗的晚期肝细胞癌（HCC）患者中，帕博利珠单抗在 II 期 KEYNOTE-224 试验中显示出抗肿瘤活性和安全性。KEYNOTE-240 评估了 pembrolizumab 在该人群中的疗效和安全性。
患者和方法：这项随机、双盲、III 期研究在 27 个国家的 119 个医疗中心进行。先前接受过索拉非尼治疗的晚期 HCC 患者符合入选条件，他们以 2:1 的比例随机分配接受 pembrolizumab 联合最佳支持治疗（BSC）或安慰剂联合 BSC。主要终点为总生存期（OS）和无进展生存期（PFS；单侧显著性阈值分别为 =.0174（最终分析）和 =.002（第一次中期分析）。所有接受至少一剂研究药物的患者均进行安全性评估。
结果：2016 年 5 月 31 日至 2017 年 11 月 23 日期间，共有 413 名患者被随机分配。截至 2019 年 1 月 2 日，pembrolizumab 组的中位随访时间为 13.8 个月，安慰剂组为 10.6 个月。pembrolizumab 组的中位 OS 为 13.9 个月（95%CI，11.6 至 16.0 个月），安慰剂组为 10.6 个月（95%CI，8.3 至 13.5 个月）（HR，0.781；95%CI，0.611 至 0.998； =.0238）。在第一次中期分析时，pembrolizumab 组的中位 PFS 为 3.0 个月（95%CI，2.8 至 4.1 个月），安慰剂组为 2.8 个月（95%CI，2.5 至 4.1 个月）（HR，0.775；95%CI，0.609 至 0.987； =.0186），在最终分析时，pembrolizumab 组的中位 PFS 为 3.0 个月（95%CI，2.8 至 4.1 个月），安慰剂组为 2.8 个月（95%CI，1.6 至 3.0 个月）（HR，0.718；95%CI，0.570 至 0.904； =.0022）。pembrolizumab 组发生 3 级或更高级别的不良事件的患者为 147 例（52.7%），安慰剂组为 62 例（46.3%）；与治疗相关的不良事件分别发生在 52 例（18.6%）和 10 例（7.5%）患者中。未发现丙型肝炎或乙型肝炎病毒复发。
结论：在这项研究中，OS 和 PFS 未达到规定的统计学标准。这些结果与 KEYNOTE-224 一致，支持 pembrolizumab 在该人群中具有良好的风险效益比。
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