Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis

M Rimini; L Rimassa; K Ueshima; V Burgio; S Shigeo; T Tada; G Suda; C Yoo; J Cheon; D J Pinato; S Lonardi; M Scartozzi; M Iavarone; G G Di Costanzo; F Marra; C Soldà; E Tamburini; F Piscaglia; G Masi; G Cabibbo; F G Foschi; M Silletta; T Pressiani; N Nishida; H Iwamoto; N Sakamoto; B-Y Ryoo; H J Chon; F Claudia; T Niizeki; T Sho; B Kang; A D'Alessio; T Kumada; A Hiraoka; M Hirooka; K Kariyama; J Tani; M Atsukawa; K Takaguchi; E Itobayashi; S Fukunishi; K Tsuji; T Ishikawa; K Tajiri; H Ochi; S Yasuda; H Toyoda; C Ogawa; T Nishimur; T Hatanaka; S Kakizaki; N Shimada; K Kawata; T Tanaka; H Ohama; K Nouso; A Morishita; A Tsutsui; T Nagano; N Itokawa; T Okubo; T Arai; M Imai; A Naganuma; Y Koizumi; S Nakamura; K Joko; H Iijima; Y Hiasa; F Pedica; F De Cobelli; F Ratti; L Aldrighetti; M Kudo; S Cascinu; A Casadei-Gardini

doi:10.1016/j.esmoop.2022.100591

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis

ESMO Open. 2022 Dec;7(6):100591. doi: 10.1016/j.esmoop.2022.100591. Epub 2022 Oct 6.

Authors

M Rimini¹, L Rimassa², K Ueshima³, V Burgio¹, S Shigeo⁴, T Tada⁵, G Suda⁶, C Yoo⁷, J Cheon⁸, D J Pinato⁹, S Lonardi¹⁰, M Scartozzi¹¹, M Iavarone¹², G G Di Costanzo¹³, F Marra¹⁴, C Soldà¹⁵, E Tamburini¹⁶, F Piscaglia¹⁷, G Masi¹⁸, G Cabibbo¹⁹, F G Foschi²⁰, M Silletta²¹, T Pressiani²², N Nishida³, H Iwamoto⁴, N Sakamoto⁶, B-Y Ryoo⁷, H J Chon⁸, F Claudia⁹, T Niizeki⁴, T Sho⁶, B Kang⁸, A D'Alessio⁹, T Kumada²³, A Hiraoka²⁴, M Hirooka²⁵, K Kariyama²⁶, J Tani²⁷, M Atsukawa²⁸, K Takaguchi²⁹, E Itobayashi³⁰, S Fukunishi³¹, K Tsuji³², T Ishikawa³³, K Tajiri³⁴, H Ochi³⁵, S Yasuda³⁶, H Toyoda³⁶, C Ogawa³⁷, T Nishimur³⁸, T Hatanaka³⁹, S Kakizaki⁴⁰, N Shimada⁴¹, K Kawata⁴², T Tanaka²⁴, H Ohama³¹, K Nouso²⁶, A Morishita²⁷, A Tsutsui²⁹, T Nagano²⁹, N Itokawa²⁸, T Okubo²⁸, T Arai²⁸, M Imai³³, A Naganuma⁴³, Y Koizumi²⁵, S Nakamura⁵, K Joko³⁵, H Iijima³⁸, Y Hiasa²⁵, F Pedica⁴⁴, F De Cobelli⁴⁵, F Ratti⁴⁶, L Aldrighetti⁴⁶, M Kudo³, S Cascinu⁴⁷, A Casadei-Gardini⁴⁸

Affiliations

¹ IRCCS San Raffaele Scientific Institute Hospital, Department of Oncology, Vita-Salute San Raffaele University, Milan, Italy.
² Department of Biomedical Sciences, Humanitas University, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy.
³ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Higashi-Osaka, Japan.
⁴ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
⁵ Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.
⁶ Department of Gastroenterology and Hepatology, Hokkaido, Japan; University Graduate School of Medicine, Sapporo, Japan.
⁷ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁸ Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
⁹ Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK; Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy.
¹⁰ Oncology Unit 3, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹¹ Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy.
¹² Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
¹³ Department of Hepatology, Naples, Italy.
¹⁴ Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy.
¹⁵ Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁶ Department of Oncology and Palliative Care, Cardinale Hospital, Naples, Italy.
¹⁷ Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹⁸ Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
¹⁹ Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
²⁰ Internal Medicine, Infermi Hospital, Faenza (AUSL ROMAGNA), Ravenna, Italy.
²¹ Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy.
²² Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy.
²³ Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan.
²⁴ Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.
²⁵ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
²⁶ Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.
²⁷ Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan.
²⁸ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
²⁹ Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
³⁰ Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.
³¹ Premier Departmental Research of Medicine, Osaka Medical and Pharmaceutical University, Shinya Fukunishi, Osaka, Japan.
³² Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
³³ Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.
³⁴ Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.
³⁵ Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan.
³⁶ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
³⁷ Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan.
³⁸ Department of Internal medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan.
³⁹ Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan.
⁴⁰ Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴¹ Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.
⁴² Department of Hepatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁴³ Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.
⁴⁴ Department of Experimental Oncology, Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴⁵ School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
⁴⁶ Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴⁷ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
⁴⁸ Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy. Electronic address: [email protected].

Abstract

Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy.

Materials and methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population.

Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed.

Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Keywords: NAFLD; NASH; advanced HCC; atezolizumab; bevacizumab; lenvatinib; sorafenib.

MeSH terms

Bevacizumab / pharmacology
Bevacizumab / therapeutic use
Carcinoma, Hepatocellular* / drug therapy
Humans
Liver Neoplasms* / drug therapy
Non-alcoholic Fatty Liver Disease*
Propensity Score
Retrospective Studies
Sorafenib / pharmacology
Sorafenib / therapeutic use

Substances

Sorafenib
atezolizumab
lenvatinib
Bevacizumab