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, Hokkaido, Japan.

⁵Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 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, Korea.

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

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

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

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

⁴¹Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Abstract

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.