Author information

¹Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

²San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

³Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.

⁴Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

⁵Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

⁶Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

⁷Department of Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

⁸Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea.

⁹Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.

¹⁰Department of Medicine, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, South Korea.

¹¹Liver Unit-CHTMAD, Vila Real, Portugal.

¹²Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy.

¹³Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

¹⁴Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

¹⁵Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan.

¹⁶Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Division of Gastroenterology and Hepatology Milan, Milan, Italy.

¹⁷Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties PROMISE, University of Palermo, Palermo, Italy.

¹⁸Department of Internal Medicine, Ospedale di Faenza, Faenza, Italy.

¹⁹Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.

²⁰Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.

²¹Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan.

²²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

²³Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.

²⁴Department of Gastroenterology, Asahi General Hospital, Asahi, Japan.

²⁵Department of Gastroenterology, Osaka Medical and Pharmaceutical University, Osaka, Japan.

²⁶Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.

²⁷Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.

²⁸Department of Gastroenterology, Toyama University Hospital, Toyama, Japan.

²⁹Hepato-Biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan.

³⁰Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.

³¹Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan.

³²Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo Medical University, Nishinomiya, Japan.

³³Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan.

³⁴Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.

³⁵Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan.

³⁶Department of Hepatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

³⁷Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan.

³⁸Department of Surgery, Kansai Medical University, Osaka, Japan.

³⁹Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan.

⁴⁰Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy.

⁴¹SC Oncologia-Ematologia PO San Martino Oristano, Oristano, Italy.

⁴²Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Abstract

Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients.

Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies.

Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups.

Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.