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阿替利珠单抗联合贝伐珠单抗对比主动监测用于治疗接受手术切除或消融治疗的高风险肝细胞癌患者(IMbrave050):一项随机、开放标签、多中心、III 期临床试验。

Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial.

机构信息

Jinling Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Sun Yat-sen University Cancer Center, Guangzhou, China.

出版信息

Lancet. 2023 Nov 18;402(10415):1835-1847. doi: 10.1016/S0140-6736(23)01796-8. Epub 2023 Oct 20.


DOI:10.1016/S0140-6736(23)01796-8
PMID:37871608
Abstract

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.

摘要

背景:对于根治性切除或消融后仍存在肝细胞癌复发高风险的患者,尚无辅助治疗方法。我们旨在评估辅助阿替利珠单抗联合贝伐珠单抗与主动监测在高危肝细胞癌患者中的疗效。

方法:在全球、开放标签、III 期 IMbrave050 研究中,从四个世界卫生组织区域(欧洲区域、美洲区域、东南亚区域和西太平洋区域)的 26 个国家的 134 家医院和医疗中心招募了接受高风险手术切除或消融的肝细胞癌的成年患者。患者通过交互式语音网络应答系统以 1:1 的比例随机分配,使用大小为 4 的置换块,接受静脉注射 1200mg 阿替利珠单抗联合 15mg/kg 贝伐珠单抗,每 3 周一次,共 17 个周期(12 个月)或接受主动监测。主要终点是意向治疗人群中独立审查机构评估的无复发生存率。这项试验在 ClinicalTrials.gov 上注册,NCT04102098。

结果:意向治疗人群包括 2019 年 12 月 31 日至 2021 年 11 月 25 日期间随机分配至阿替利珠单抗联合贝伐珠单抗组(n=334)或主动监测组(n=334)的 668 名患者。在预设的中期分析(2022 年 10 月 21 日)时,中位随访时间为 17.4 个月(IQR 13.9-22.1)。与主动监测相比,辅助阿替利珠单抗联合贝伐珠单抗显著改善了无复发生存率(中位无复发生存期,不可评估[NE];[95%CI 22.1-NE])。与主动监测组(中位 NE[21.4-NE];风险比,0.72[调整后 95%CI 0.53-0.98];p=0.012)相比,接受阿替利珠单抗联合贝伐珠单抗治疗的患者无复发生存期显著延长。接受阿替利珠单抗联合贝伐珠单抗治疗的 332 名患者中有 136 名(41%)和主动监测组的 330 名患者中有 44 名(13%)发生 3 级或 4 级不良事件。阿替利珠单抗联合贝伐珠单抗组有 6 名患者(2%,其中 2 例与治疗相关)发生 5 级不良事件,主动监测组有 1 名患者(<1%)发生 5 级不良事件。因不良事件,阿替利珠单抗联合贝伐珠单抗组有 29 名患者(9%)停止使用阿替利珠单抗联合贝伐珠单抗。

解释:在根治性切除或消融后仍存在肝细胞癌复发高风险的患者中,与主动监测相比,接受阿替利珠单抗联合贝伐珠单抗治疗可改善无复发生存率。据我们所知,IMbrave050 是第一项报告肝细胞癌辅助治疗阳性结果的 III 期研究。然而,需要更长时间的无复发生存期和总生存期随访,以更全面地评估获益风险特征。

资金:罗氏/基因泰克公司资助。

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