新加坡国家癌症中心Pierce K H Chow团队比较了辅助阿特珠单抗联合贝伐单抗与主动监测治疗切除或消融的高危肝细胞癌患者的疗效与安全性。相关论文于2023年10月20日发表在《柳叶刀》杂志上。

对于治疗性切除或消融后仍有肝癌复发高风险的患者，目前尚未制定辅助治疗方案。该研究旨在评估辅助阿特珠单抗联合贝伐单抗与主动监测对高危肝细胞癌患者的疗效。

在这项全球开放标签3期IMbrave050研究中，课题组从世界卫生组织四个地区（欧洲地区、美洲地区、东南亚地区和西太平洋地区）26个国家的134家医院和医疗中心招募患有高风险手术切除或消融肝细胞癌的成年患者。通过交互式语音-网络响应系统以1:1的比例将患者随机分配，使用排列区块，区块大小为4，每3周静脉注射1200 mg 阿特珠单抗加15 mg/kg贝伐单抗，持续17个周期（12个月），或进行积极监测。主要终点是在意向治疗人群中通过独立审查设施评估的无复发生存率。

意向治疗人群包括在2019年12月31日至2021年11月25日期间随机分配的668名患者，接受阿特珠单抗加贝伐单抗治疗（n=334）或主动监测治疗（n=334）。在预先指定的中期分析中（2022年10月21日），中位随访时间为17.4个月。与主动监测（中位数，NE[21.4–NE]；危险比为0.72；p=0.012）相比，辅助阿特珠单抗联合贝伐单抗可显著提高无复发生存率（中位数，不可评估[NE]）。

332名接受阿特珠单抗联合贝伐单抗治疗的患者中有136名（41%）发生了3级或4级不良事件，330名主动监测组患者中有44名（13%）。阿特珠单抗联合贝伐单抗组有6名患者（2%，其中2名与治疗相关）发生5级不良事件，而主动监测组有1名患者（<1%）发生。29名接受阿特珠单抗联合贝伐单抗治疗的患者（9%）因不良事件而停药。

研究结果表明，在治疗性切除或消融后肝细胞癌复发风险较高的患者中，与积极监测相比，接受阿特珠单抗联合贝伐单抗治疗的患者无复发生存率有所提高。IMbrave050是第一个报告阳性结果的肝细胞癌辅助治疗的临床3期研究。然而，需要对无复发和总生存期进行更长时间的随访，以更全面地评估收益-风险状况。

附：英文原文

Title: 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

Author: Shukui Qin, Minshan Chen, Ann-Lii Cheng, Ahmed O Kaseb, Masatoshi Kudo, Han Chu Lee, Adam C Yopp, Jian Zhou, Lu Wang, Xiaoyu Wen, Jeong Heo, Won Young Tak, Shinichiro Nakamura, Kazushi Numata, Thomas Uguen, David Hsiehchen, Edward Cha, Stephen P Hack, Qinshu Lian, Ning Ma, Jessica H Spahn, Yulei Wang, Chun Wu, Pierce K H Chow, Alexander Thompson, Mark Danta, Pirooz Poursoltan, Andrew Kiberu, Renuka Chittajallu, Siddarth Sood, Rudolf Stauber, Matthias Pinter, Markus Peck-Radosavljevic, Jochen Decaestecker, Pieter-Jan Cuyle, Gontran Verset, Hans Van Vlierberghe, Sergio De Azevedo, Livia Andrade, Ademar Cunha Júnior, Luiza Faria, Cheng Tzu Yen, Leandro Colli, Jamil Asselah, Petr Kavan, Vladimir Marquez, Mayur Brahmania, Qiang Li, Baocai Xing, Yabing Guo, Zhendong Chen, Haitao Zhao, Tao Peng, Liming Wang, Lu Wang, Hongming Liu, Feixiang Wu, Lunxiu Qin, Qichang Zheng, Jieer Ying, Haitao Li, Tianfu Wen, Shukui Qin, Xiaoyu Wen, Yunpeng Liu, Minshan Chen, Boqing Wang, Yuxian Bai, Yifu He, Hong Zhao, Dong Zhou, Chaoliu Dai, Gaojun Teng, Shuzhong Cui, Yi Gao, Xizhi Zhang, Zheng Lu, Tao Yin, Youming Ding, Weidong Jia, Yongxiang Xia, Beicheng Sun, Qiang Xia, Yufeng Yuan, Huichuan Sun, Xuetao Shi, Adrián Guzmán, Luis Corrales, Zdenek Kral, Peter Priester, Eugen Kubala, Jean Frederic Blanc, Marc Bourliere, Jean Marie Peron, Christophe Borg, Jean-Pierre Bronowicki, Nathalie Ganne, Thomas Decaens, Thomas Uguen, Alexandra Heurgue, Joerg Trojan, Maria Angeles Gonzalez-Carmona, Christoph Roderburg, Thomas Ettrich, Clemens Schotten, Arne Kandulski, Thomas Yau, Lam Chan, Mario Scartozzi, Gianluca Masi, Silvia Fanello, Pier Maria Battezzati, Francesco Leonardi, Michele Ghidini, Kazushi Numata, Manabu Morimoto, Hisashi Hidaka, Kaoru Tsuchiya, Tatsuya Yamashita, Naoya Kato, Masatoshi Kudo, Atsushi Hagihara, Hironori Koga

Issue&Volume: 2023-10-20

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.

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

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01796-8/abstract