Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial.

IF 11.6 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver Cancer Pub Date : 2023-02-14 eCollection Date: 2023-09-01 DOI:10.1159/000529636

Philippe Merle, Masatoshi Kudo, Julien Edeline, Mohamed Bouattour, Ann-Lii Cheng, Stephen L Chan, Thomas Yau, Marcelo Garrido, Jennifer Knox, Bruno Daniele, Valeriy Breder, Ho Yeong Lim, Sadahisa Ogasawara, Stéphane Cattan, Yee Chao, Abby B Siegel, Iván Martinez-Forero, Ziwen Wei, Chih-Chin Liu, Richard S Finn

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引用次数: 0

Abstract

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) and 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 per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, 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.

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Pembrolizumab作为晚期肝癌的二线治疗：KEYNOTE-240 3期试验的长期随访。

引言：KEYNOTE-240显示，在索拉非尼治疗的晚期肝细胞癌（HCC）患者中，pembrolizumab与安慰剂相比具有良好的获益/风险状况；然而，在最终分析中，未达到预先指定的总生存率（OS）和无进展生存率（PFS）优势的统计学显著性标准。报告了基于额外18个月随访的结果。方法：索拉非尼治疗晚期HCC的成年人以2:1的比例随机接受每3周静脉注射200 mg pembrolizumab或安慰剂。双主要终点是根据RECIST v1.1通过盲法独立中心评审（BICR）评估OS和PFS。次要终点包括BICR根据RECIST v1.1评估的客观有效率（ORR）和安全性。结果：413名患者被随机分组（pembrolizumab，n=278；安慰剂，n=135）。截至2020年7月13日，pembrolizumab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，pembrolizumab和安慰剂的估计OS发生率（95%CI）分别为17.7%（13.4-2.5%）和11.7%（6.8-17.9%）。36个月时，pembrolizumab的估计PFS率（95%CI）为8.9%（5.3-13.6%），安慰剂为0%。pembrolizumab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没有随着随访而增加。未报告病毒性肝炎突发事件。结论：在索拉非尼治疗的晚期HCC患者中，随着随访时间的延长，pembrolizumab在OS和PFS方面继续保持改善，并且与安慰剂相比，不良事件发生率一致。尽管KEYNOTE-240在最终分析时不满足预先指定的统计学显著性标准，这些结果与KEYNOTE-224中观察到的二线pembrolizumab的抗肿瘤活性以及KEYNOTE-394中观察到在亚洲患者中二线pembrulizumab具有统计学意义和临床意义的OS和PFS益处一起，加强了pembrolizhumab在先前治疗的晚期HCC患者中的临床活性。

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来源期刊

Liver Cancer Medicine-Oncology

CiteScore

20.80

自引率

7.20%

发文量

审稿时长

16 weeks

期刊介绍： Liver Cancer is a journal that serves the international community of researchers and clinicians by providing a platform for research results related to the causes, mechanisms, and therapy of liver cancer. It focuses on molecular carcinogenesis, prevention, surveillance, diagnosis, and treatment, including molecular targeted therapy. The journal publishes clinical and translational research in the field of liver cancer in both humans and experimental models. It publishes original and review articles and has an Impact Factor of 13.8. The journal is indexed and abstracted in various platforms including PubMed, PubMed Central, Web of Science, Science Citation Index, Science Citation Index Expanded, Google Scholar, DOAJ, Chemical Abstracts Service, Scopus, Embase, Pathway Studio, and WorldCat.