Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors

Y Linda Wu; Grace van Hyfte; Umut Özbek; Marlene Reincke; Anuhya Gampa; Yehia I Mohamed; Naoshi Nishida; Brooke Wietharn; Suneetha Amara; Pei-Chang Lee; Bernhard Scheiner; Lorenz Balcar; Matthias Pinter; Arndt Vogel; Arndt Weinmann; Anwaar Saeed; Anjana Pillai; Lorenza Rimassa; Abdul Rafeh Naqash; Mahvish Muzaffar; Yi-Hsiang Huang; Ahmed O Kaseb; Masatoshi Kudo; David J Pinato; Celina Ang

doi:10.3389/fonc.2023.1128569

Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors

Front Oncol. 2023 Feb 14:13:1128569. doi: 10.3389/fonc.2023.1128569. eCollection 2023.

Authors

Y Linda Wu¹, Grace van Hyfte², Umut Özbek², Marlene Reincke³, Anuhya Gampa⁴, Yehia I Mohamed⁵, Naoshi Nishida⁶, Brooke Wietharn⁷, Suneetha Amara⁸, Pei-Chang Lee⁹, Bernhard Scheiner¹⁰, Lorenz Balcar¹⁰, Matthias Pinter¹⁰, Arndt Vogel¹¹, Arndt Weinmann¹², Anwaar Saeed⁷, Anjana Pillai⁴, Lorenza Rimassa^{13

14}, Abdul Rafeh Naqash¹⁵, Mahvish Muzaffar⁸, Yi-Hsiang Huang⁹, Ahmed O Kaseb⁵, Masatoshi Kudo⁶, David J Pinato¹⁶, Celina Ang¹

Affiliations

¹ Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
² Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
³ Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany.
⁴ Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medical Center, Chicago, IL, United States.
⁵ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
⁶ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
⁷ Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Kansas City, KS, United States.
⁸ Division of Hematology/Oncology, East Carolina University, Greenville, NC, United States.
⁹ Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
¹⁰ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
¹¹ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹² Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
¹³ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy.
¹⁴ Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Clinical and Research Hospital, Rozzano (Milan), Italy.
¹⁵ Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, United States.
¹⁶ Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London, United Kingdom.

Abstract

Background: In patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs).

Methods: We conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria.

Results: In our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510).

Conclusion: In this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.

Keywords: beta blocker; beta-adrenergic blockade; cancer immunotherapy; hepatocellular carcinoma; immune checkpoint inhibitors.

Copyright © 2023 Wu, van Hyfte, Özbek, Reincke, Gampa, Mohamed, Nishida, Wietharn, Amara, Lee, Scheiner, Balcar, Pinter, Vogel, Weinmann, Saeed, Pillai, Rimassa, Naqash, Muzaffar, Huang, Kaseb, Kudo, Pinato and Ang.

Grants and funding

DP is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and has received direct project funding by the NIHR Imperial Biomedical Research Center and ITMAT Push for Impact Grant Scheme 2019. Research reported in this publication was supported in part by the National Cancer Institute (Support Grant P30CA196521-01 awarded to the Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai) and used the Biostatistics Shared Resource Facility. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.