Disease Etiology Impact on Outcomes of Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab: A Real-World, Multicenter Study
Authors: Rossari Federico , Tada Toshifumi , Suda Goki , Shimose Shigeo , Kudo Masatoshi , Yoo Changhoon , Cheon Jaekyung , Finkelmeier Fabian , Lim Ho Yeong , Presa José , Masi Gianluca , Bergamo Francesca , Amadeo Elisabeth , Vitiello Francesco , Kumada Takashi , Sakamoto Naoya , Iwamoto Hideki , Aoki Tomoko , Chon Hong Jae , Himmelsbach Vera , Iavarone Massimo , Cabibbo Giuseppe , Montes Margarida , Foschi Francesco Giuseppe , Vivaldi Caterina , Soldà Caterina , Sho Takuya , Niizeki Takashi , Nishida Naoshi , Steup Christoph , Hirooka Masashi , Kariyama Kazuya , Tani Joji , Atsukawa Masanori , Takaguchi Koichi , Itobayashi Ei , Fukunishi Shinya , Tsuji Kunihiko , Ishikawa Toru , Tajiri Kazuto , Ochi Hironori , Yasuda Satoshi , Toyoda Hidenori , Ogawa Chikara , Nishimura Takashi , Hatanaka Takeshi , Kakizaki Satoru , Shimada Noritomo , Kawata Kazuhito , Hiraoka Atsushi , Tada Fujimasa , Ohama Hideko , Nouso Kazuhiro , Morishita Asahiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Okubo Tomomi , Imai Michitaka , Kosaka Hisashi , Naganuma Atsushi , Koizumi Yohei , Nakamura Shinichiro , Kaibori Masaaki , Iijima Hiroko , Hiasa Yoichi , Persano Mara , Foti Silvia , Camera Silvia , Stefanini Bernardo , Scartozzi Mario , Cascinu Stefano , Casadei-Gardini Andrea , Rimini Margherita 
Published: April 2024

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.