二线派姆单抗治疗晚期HCC: III期KEYNOTE-240和KEYNOTE-394研究的meta分析

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports Pub Date : 2025-02-04 DOI:10.1016/j.jhepr.2025.101350

Richard S. Finn , Kangsheng Gu , Xi Chen , Philippe Merle , Kyung-Hun Lee , Mohamed Bouattour , Peiguo Cao , Wei Wang , Ann-Lii Cheng , Liangjun Zhu , Ho Yeong Lim , Masatoshi Kudo , Yueyin Pan , Ting-Tsung Chang , Julien Edeline , Wei Li , Ping Yang , Chen Li , Jianfeng Li , Abby B. Siegel , Shukui Qin

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引用次数: 0

摘要

背景,我们对KEYNOTE-240和KEYNOTE-394研究的数据进行了荟萃分析，以更精确地估计派姆单抗对既往治疗过的晚期肝细胞癌（HCC）患者的治疗效果。方法：经索拉非尼或奥沙利铂为基础的化疗（KEYNOTE-394）治疗后确诊HCC，疾病进展或不耐受，巴塞罗那临床肝癌C期或B期疾病不适应或难以局部治疗，根据实体瘤反应评价标准（RECIST） 1.1版有一个或多个可测量病变的患者随机分配为2:1，接受派姆单抗或安慰剂治疗≤35个周期。KEYNOTE-240和KEYNOTE-394意向治疗人群的数据汇总，分别评估派姆单抗和安慰剂的治疗效果。结果共有578名和288名接受派姆单抗和安慰剂治疗的患者被纳入本分析。与安慰剂相比，派姆单抗改善了总生存期（风险比0.79,95% CI 0.67-0.93）、无进展生存期(根据RECIST v1.1的盲法独立中心评价[BICR]；风险比0.76,95% CI 0.64-0.89)和客观缓解率(根据BICR的RECIST v1.1；15.4%对2.8%，估计治疗差异为12.5%；95% ci 8.8-16.2)。亚组分析显示，pembrolizumab的治疗效果在基线参与者特征中大致相似，包括病毒状态、巴塞罗那诊所肝癌分期和地理区域。KEYNOTE-240和KEYNOTE-394的meta分析显示，派姆单抗在总生存期、无进展生存期和客观缓解率方面具有临床意义的改善。该分析扩展了每项研究的结果，并提供了进一步的证据，证明派姆单抗作为治疗晚期HCC的二线治疗，在先前的索拉非尼或奥沙利铂为基础的治疗之后，具有全球益处。为了更准确地估计派姆单抗对既往治疗过的晚期肝细胞癌患者的治疗效果，我们使用KEYNOTE-240和KEYNOTE-394 III期研究的合并参与者数据进行了疗效荟萃分析。亚组分析显示，pembrolizumab的治疗效果在基线特征（包括病毒状态、巴塞罗那诊所肝癌分期和地理区域）中大致相似。这项荟萃分析进一步证明了派姆单抗作为晚期肝细胞癌二线治疗的全球益处。临床试验注册：在ClinicalTrials.gov注册NCT02702401 （KEYNOTE-240）和NCT03062358 （KEYNOTE-394）。

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Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies

Background & Aims

We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC).

Methods

Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer stage C or B disease not amenable to or refractory to locoregional therapy, and one or more measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for ≤35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately.

Results

In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (hazard ratio 0.79, 95% CI 0.67–0.93), progression-free survival (per RECIST v1.1 by blinded independent central review [BICR]; hazard ratio 0.76, 95% CI 0.64–0.89), and objective response rate (per RECIST v1.1 by BICR; 15.4% vs. 2.8%, for an estimated treatment difference of 12.5%; 95% CI 8.8–16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region.

Conclusions

Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in overall survival, progression-free survival, and objective response rate. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy.

Impact and implications

To obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma, we performed a meta-analysis of efficacy using pooled participant data from the phase III KEYNOTE-240 and KEYNOTE-394 studies. Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. This meta-analysis provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced hepatocellular carcinoma.

Clinical Trials Registration

Registered at ClinicalTrials.gov NCT02702401 (KEYNOTE-240) and NCT03062358 (KEYNOTE-394).

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来源期刊

JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

12.40

自引率

2.40%

发文量

161

审稿时长

36 days

期刊介绍： JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.