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Robert Mahn,1,&ast; Oscar André Glüer,1,&ast; Farsaneh Sadeghlar,1 Christian Möhring,1 Taotao Zhou,1 Thomas Anhalt,1 Malte Benedikt Monin,1 Alexander Kania,2 Tim R Glowka,2 Georg Feldmann,3 Peter Brossart,3 Joerg C Kalff,2 Ingo GH Schmidt-Wolf,4 Christian P Strassburg,1 Maria A Gonzalez-Carmona1 1Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany; 2Department of Surgery, University Hospital of Bonn, Bonn, Germany; 3Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany; 4Department of Integrated Oncology CIO Bonn, University Hospital of Bonn, Bonn, Germany&ast;These authors contributed equally to this workCorrespondence: Maria A Gonzalez-Carmona, Department of Internal Medicine I, University Hospital of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany, Tel +49 228 287 15216, Fax +49 228 287 14322, Email maria.gonzalez-carmona@ukbonn.deBackground and Aim: There are several existing systemic 1st- line therapies for advanced hepatocellular carcinoma (HCC), including atezolizumab/bevacizumab (Atez/Bev), sorafenib and lenvatinib. This study aims to compare the effectiveness of these three 1st-line systemic treatments in a real-world setting for HCC, focusing on specific patient subgroups analysis.Methods: A total of 177 patients with advanced HCC treated with Atez/Bev (n = 38), lenvatinib (n = 21) or sorafenib (n = 118) as 1st line systemic therapy were retrospectively analyzed and compared. Primary endpoints included objective response rate (ORR), progression-free survival (PFS) and 15-month overall survival (15-mo OS). Subgroups regarding liver function, etiology, previous therapy and toxicity were analyzed.Results: Atez/Bev demonstrated significantly longer median 15-month OS with 15.03 months compared to sorafenib with 9.43 months (p = 0.04) and lenvatinib with 8.93 months (p = 0.05). Similarly, it had highest ORR of 31.6% and longest median PFS with 7.97 months, independent of etiology. However, significantly superiority was observed only compared to sorafenib (ORR: 4.2% (p < 0.001); PFS: 4.57 months (p = 0.03)), but not comparing to lenvatinib (ORR: 28.6% (p = 0.87); PFS: 3.77 months (p = 0.10)). Atez/Bev also resulted in the longest PFS in patients with Child-Pugh A and ALBI 1 score and interestingly in those previously treated with SIRT. Contrary, sorafenib was non inferior in patients with impaired liver function.Conclusion: Atez/Bev achieved longest median PFS and 15-mo OS independent of etiology and particularly in patients with stable liver function or prior SIRT treatment. Regarding therapy response lenvatinib was non-inferior to Atez/Bev. Finally, sorafenib seemed to perform best for patients with deteriorated liver function.Keywords: HCC, first-line therapy, subgroups