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

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 hepatoc...

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Published in:	The Lancet (British edition) Vol. 402; no. 10415; pp. 1835 - 1847
Main Authors:	Qin, Shukui, Chen, Minshan, Kudo, Masatoshi, Yopp, Adam C, Wang, Lu, Tak, Won Young, Lian, Qinshu, Spahn, Jessica H, Wang, Yulei, Chow, Pierce K H, Poursoltan, Pirooz, Kiberu, Andrew, Chittajallu, Renuka, Sood, Siddarth, Stauber, Rudolf, Peck-Radosavljevic, Markus, Decaestecker, Jochen, Verset, Gontran, Cunha Júnior, Ademar, Faria, Luiza, Asselah, Jamil, Brahmania, Mayur, Li, Qiang, Chen, Zhendong, Zhao, Haitao, Liu, Hongming, Wu, Feixiang, Zheng, Qichang, Li, Haitao, Wen, Tianfu, Liu, Yunpeng, Bai, Yuxian, Zhao, Hong, Yin, Tao, Ding, Youming, Jia, Weidong, Xia, Yongxiang, Xia, Qiang, Guzmán, Adrián, Corrales, Luis, Kubala, Eugen, Blanc, Jean Frederic, Borg, Christophe, Decaens, Thomas, Uguen, Thomas, Heurgue, Alexandra, Trojan, Joerg, Gonzalez-Carmona, Maria Angeles, Schotten, Clemens, Kandulski, Arne, Yau, Thomas, Scartozzi, Mario, Leonardi, Francesco, Ghidini, Michele, Koga, Hironori, Kawamura, Yusuke, Hasegawa, Kiyoshi, Marusawa, Hiroyuki, Hayashi, Hiromitsu, Lee, Han Chu, Paik, Seung Woon, Kim, Do Young, Jeong, Sook-Hyang, Kim, Hyeyeong, Yoon, Seung Kew, Yoon, Jung-Hwan, Villalobos, Ricardo, Martinez Rodriguez, Jorge Luis, Oyervides Juarez, Victor, Hernández, Carlos Alberto, de Vos-Geelen, Judith, Gane, Edward, Torres Mattos, Cesar, Alyasova, Anna, Sekacheva, Marina, Ledin, Evgeny, Toh, Han Chong, Lopez Lopez, Carlos, Muñoz Martin, Andres Jesus, Reig Monzón, Maria, Delgado Mingorance, Ignacio, Minguez Rosique, Beatriz, Huang, Yi-Hsiang, Huang, Jee-Fu, Su, Wei-Wen, Maneenil, Kunlatida, Harputluoglu, Hakan, Buchschacher, Gary, Xiong, Henry, Patel, Mital, Li, Daneng, Brooks, Gabriel, Patel, Reema, Kardosh, Adel, Shah, Ashesh, Burris III, Howard, Hsiehchen, David
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 18-11-2023 Elsevier Limited
Subjects:	Ablation Adult Adverse events Antineoplastic Combined Chemotherapy Protocols Bevacizumab Bevacizumab - therapeutic use Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - surgery Clinical medicine Health care facilities Health services Hepatitis B Hepatocellular carcinoma Humans Immunotherapy Labels Ligands Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - surgery Monoclonal antibodies Patients Risk assessment Surveillance Survival Targeted cancer therapy Vascular endothelial growth factor Watchful Waiting South Korea Japan
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Summary:	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. 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. 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. 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. F Hoffmann-La Roche/Genentech.
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ISSN:	0140-6736 1474-547X
DOI:	10.1016/S0140-6736(23)01796-8