Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population

Andrea Casadei-Gardini¹, Margherita Rimini², Toshifumi Tada³, Goki Suda⁴, Shigeo Shimose⁵, Masatoshi Kudo⁶, Jaekyung Cheon⁷, Fabian Finkelmeier⁸, Ho Yeong Lim⁹, Lorenza Rimassa¹⁰, José Presa¹¹, Gianluca Masi¹², Changhoon Yoo¹³, Sara Lonardi¹⁴, Francesco Tovoli¹⁵, Takashi Kumada¹⁶, Naoya Sakamoto⁴, Hideki Iwamoto⁵, Tomoko Aoki⁶, Hong Jae Chon⁷, Vera Himmelsbach⁸, Tiziana Pressiani¹⁷, Margarida Montes¹¹, Caterina Vivaldi¹², Caterina Soldà¹⁴, Fabio Piscaglia¹⁵, Atsushi Hiraoka¹⁸, Takuya Sho⁴, Takashi Niizeki⁵, Naoshi Nishida⁶, Christoph Steup⁸, Massimo Iavarone¹⁹, Giovanni Di Costanzo²⁰, Fabio Marra²¹, Mario Scartozzi²², Emiliano Tamburini²³, Giuseppe Cabibbo²⁴, Francesco Giuseppe Foschi²⁵, Marianna Silletta²⁶, Masashi Hirooka²⁷, Kazuya Kariyama²⁸, Joji Tani²⁹, Masanori Atsukawa³⁰, Koichi Takaguchi³¹, Ei Itobayashi³², Shinya Fukunishi³³, Kunihiko Tsuji³⁴, Toru Ishikawa³⁵, Kazuto Tajiri³⁶, Hironori Ochi³⁷, Satoshi Yasuda³⁸, Hidenori Toyoda³⁸, Chikara Ogawa³⁹, Takashi Nishimura⁴⁰, Takeshi Hatanaka⁴¹, Satoru Kakizaki⁴², Noritomo Shimada⁴³, Kazuhito Kawata⁴⁴, Fujimasa Tada¹⁸, Hideko Ohama¹⁸, Kazuhiro Nouso²⁸, Asahiro Morishita²⁹, Akemi Tsutsui³¹, Takuya Nagano³¹, Norio Itokawa³⁰, Tomomi Okubo³⁰, Taeang Arai³⁰, Michitaka Imai³⁵, Hisashi Kosaka⁴⁵, Atsushi Naganuma⁴⁶, Yohei Koizumi²⁸, Shinichiro Nakamura³, Masaki Kaibori⁴⁵, Hiroko Iijima⁴⁰, Yoichi Hiasa²⁷, Valentina Burgio², Mara Persano²², Angelo Della Corte⁴⁷, Francesca Ratti⁴⁸, Francesco De Cobelli⁴⁷, Luca Aldrighetti⁴⁸, Stefano Cascinu⁴⁹, Alessandro Cucchetti⁵⁰

Affiliations

¹ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy. Electronic address: casadeigardini@gmail.com.
² Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy.
³ Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.
⁴ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
⁵ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
⁶ Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Japan.
⁷ Department of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea.
⁸ Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt Am Main, Germany.
⁹ Department of Medicine, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, South Korea.
¹⁰ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
¹¹ Liver Unit-CHTMAD, Vila Real, Portugal.
¹² Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
¹³ Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
¹⁴ Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁵ Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15 Bologna- Italy.
¹⁶ Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan.
¹⁷ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
¹⁸ Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.
¹⁹ Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
²⁰ Department of Hepatology, Naples, 80131, Italy.
²¹ Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy.
²² Azienda Ospedaliera Universitaria (AOU) Cagliari, University Hospital and University of Cagliari, Cagliari, Italy.
²³ Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy.
²⁴ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
²⁵ Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza, Italy.
²⁶ Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy.
²⁷ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
²⁸ Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.
²⁹ Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan.
³⁰ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
³¹ Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
³² Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.
³³ Department of Gastroenterology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
³⁴ Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
³⁵ Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.
³⁶ Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.
³⁷ Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan.
³⁸ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
³⁹ Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan.
⁴⁰ Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo Medical University, Nishinomiya, Japan.
⁴¹ Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan.
⁴² Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴³ Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.
⁴⁴ Department of Hepatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁴⁵ Department of Surgery, Kansai Medical University, Osaka, Japan.
⁴⁶ Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴⁷ Department of Radiology, IRCCS San Raffaele Hospital, Milan, Italy; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Universita Vita-Salute San Raffaele, Milan, Italy.
⁴⁸ Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, Milan, Italy.
⁴⁹ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁵⁰ Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum - Univeristy of Bologna, Bologna, Italy.

PMID: 36527976
DOI: 10.1016/j.ejca.2022.11.017

Randomized Controlled Trial

Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population

Andrea Casadei-Gardini et al. Eur J Cancer. 2023 Feb.

. 2023 Feb:180:9-20.

doi: 10.1016/j.ejca.2022.11.017. Epub 2022 Nov 25.

Authors

Affiliations

¹ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy. Electronic address: casadeigardini@gmail.com.
² Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy.
³ Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.
⁴ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
⁵ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
⁶ Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Japan.
⁷ Department of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea.
⁸ Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt Am Main, Germany.
⁹ Department of Medicine, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, South Korea.
¹⁰ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
¹¹ Liver Unit-CHTMAD, Vila Real, Portugal.
¹² Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
¹³ Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
¹⁴ Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁵ Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15 Bologna- Italy.
¹⁶ Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan.
¹⁷ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.
¹⁸ Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.
¹⁹ Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
²⁰ Department of Hepatology, Naples, 80131, Italy.
²¹ Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy.
²² Azienda Ospedaliera Universitaria (AOU) Cagliari, University Hospital and University of Cagliari, Cagliari, Italy.
²³ Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy.
²⁴ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
²⁵ Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza, Italy.
²⁶ Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy.
²⁷ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
²⁸ Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.
²⁹ Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan.
³⁰ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
³¹ Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
³² Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.
³³ Department of Gastroenterology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
³⁴ Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
³⁵ Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.
³⁶ Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.
³⁷ Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan.
³⁸ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
³⁹ Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan.
⁴⁰ Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo Medical University, Nishinomiya, Japan.
⁴¹ Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan.
⁴² Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴³ Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.
⁴⁴ Department of Hepatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁴⁵ Department of Surgery, Kansai Medical University, Osaka, Japan.
⁴⁶ Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴⁷ Department of Radiology, IRCCS San Raffaele Hospital, Milan, Italy; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Universita Vita-Salute San Raffaele, Milan, Italy.
⁴⁸ Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, Milan, Italy.
⁴⁹ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁵⁰ Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum - Univeristy of Bologna, Bologna, Italy.

PMID: 36527976
DOI: 10.1016/j.ejca.2022.11.017

Abstract

Background and aims: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario.

Methods: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point.

Results: The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events.

Conclusion: Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.

Keywords: Advanced HCC; Atezolizumab; Bevacizumab; Lenvatinib; NAFLD; NASH; RWD.

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Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. L Rimassa has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. A.C.G. has received grants and personal fees from MSD, Eisai, Bayer, and is an advisor for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb; has received grants and personal fees from MSD, Eisai, and Bayer, and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly and ONO Pharmaceutical. F.P. has received consulting or lecture fees from Consulting or lecture fees in the last two years from: Astrazeneca, Bayer, Bracco, EISAI, ESAOTE, Exact Sciences, IPSEN; MSD; Roche, Samsung, Tiziana Life Sciences. F.F received speaker honoraria and consultant fees from Abbvie, Eisai and CSL Behring and received travel support from Ipsen. T.P. consults for and received grants from Bayer. She also received grants from Lilly and Roche. There are no conflicts of interest among the other authors.

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Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population

Affiliations

Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources

Medical