Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) or progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included objective response rate (ORR), assessed by BICR per RECIST v1.1, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.


中文翻译：

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Pembrolizumab 作为晚期肝细胞癌的二线治疗：3 期 KEYNOTE-240 试验的长期随访

简介：KEYNOTE-240 显示，在接受索拉非尼治疗的晚期肝细胞癌 (HCC) 患者中，派姆单抗与安慰剂相比具有良好的获益/风险特征；然而，最终分析时并未达到预先设定的总生存期（OS）或无进展生存期（PFS）优越性的统计显着性标准。报告基于额外 18 个月随访的结果。方法：接受索拉非尼治疗的晚期 HCC 成人患者以 2:1 的比例随机分配至帕博利珠单抗 200 mg（每 3 周静脉注射一次）或安慰剂组。双重主要终点是根据 RECIST v1.1 通过盲法独立中央审查 (BICR) 评估的 OS 和 PFS。次要终点包括根据 RECIST v1.1 由 BICR 评估的客观缓解率 (ORR) 和安全性。结果：413 名患者被随机分组​​（派姆单抗，n = 278；安慰剂，n = 135）。截至 2020 年 7 月 13 日，派姆单抗从随机化到数据截止的中位（范围）时间为 39.6（31.7-48.8）个月，安慰剂为 39.8（31.7-47.8）个月。36 个月时，派姆单抗的估计 OS 率 (95% CI) 为 17.7% (13.4–22.5%)，安慰剂为 11.7% (6.8–17.9%)。36 个月时，派姆单抗的估计 PFS 率 (95% CI) 为 8.9% (5.3-13.6%)，安慰剂为 0%。派姆单抗的 ORR (95% CI) 为 18.3% (14.0–23.4%)，安慰剂为 4.4% (1.6–9.4%)。免疫介导的肝炎事件并未随随访而增加。未报告病毒性肝炎突发事件。结论：通过延长随访，在接受索拉非尼治疗的晚期 HCC 患者中，派姆单抗继续保持 OS 和 PFS 的改善，并且与安慰剂相比，不良事件特征一致。尽管 KEYNOTE-240 在最终分析中未达到预先指定的统计显着性标准，但这些结果与 KEYNOTE-224 中观察到的二线派姆单抗的抗肿瘤活性以及二线派姆单抗在KEYNOTE-394 中观察到的来自亚洲的患者强化了派姆单抗在既往治疗的晚期 HCC 患者中的临床活性。