Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial
Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial
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DOI：
10.1200/jco.19.01307
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发表时间：
2020-01-20
影响因子：
45.3
通讯作者：
Cheng, Ann-Lii
中科院分区：
文献类型：
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作者：
Finn, Richard S.;Ryoo, Baek-Yeol;Cheng, Ann-Lii
目的 Pembrolizumab 在 II 期 KEYNOTE-224 试验中在既往接受过治疗的晚期肝细胞癌 (HCC) 患者中证明了抗肿瘤活性和安全性。 KEYNOTE-240 评估了派姆单抗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。既往接受过索拉非尼治疗的符合条件的晚期 HCC 患者以二比一的比例随机分配接受派姆单抗加最佳支持治疗 (BSC) 或安慰剂加 BSC 治疗。主要终点是总生存期 (OS) 和无进展生存期（PFS；单侧显着性阈值，分别为 P = .0174 [最终分析] 和 P = .002 [第一次中期分析]）。对所有接受≥1剂量研究药物的患者进行安全性评估。 结果 2016年5月31日至2017年11月23日期间，413名患者被随机分配。截至 2019 年 1 月 2 日，派姆单抗的中位随访时间为 13.8 个月，安慰剂的中位随访时间为 10.6 个月。派姆单抗的中位 OS 为 13.9 个月（95% CI，11.6 至 16.0 个月），而安慰剂为 10.6 个月（95% CI，8.3 至 13.5 个月）（风险比 [HR]，0.781；95% CI，0.611 至 0.998；P = 0.0238）。第一次中期分析时，派姆单抗的中位 PFS 为 3.0 个月（95% CI，2.8 至 4.1 个月），而安慰剂为 2.8 个月（95% CI，2.5 至 4.1 个月）（HR，0.775；95% CI，0.609 至 0.987；P = 0.0186）和 3.0 个月（95% CI，最终分析时为 2.8 至 4.1 个月）与 2.8 个月（95% CI，1.6 至 3.0 个月）（HR，0.718；95% CI，0.570 至 0.904；P = .0022）。与安慰剂组相比，派姆单抗组中有 147 名患者 (52.7%) 和 62 名患者 (46.3%) 发生了 3 级或以上不良事件；与治疗相关的那些分别发生在 52 名患者 (18.6%) 和 10 名患者 (7.5%) 中。未发现丙型肝炎或乙型肝炎耀斑。 结论 在本研究中，根据指定标准，OS 和 PFS 未达到统计学显着性。结果与 KEYNOTE-224 的结果一致，支持派姆单抗在该人群中具有有利的风险效益比。 (C) 2019 年美国临床肿瘤学会
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, P = .0174 [final analysis] and P = .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; P = .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; P = .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; P = .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. (C) 2019 by American Society of Clinical Oncology