JHEP Reports (Feb 2024)
A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma
- Lorenz Balcar,
- Bernhard Scheiner,
- Claudia Angela Maria Fulgenzi,
- Antonio D’Alessio,
- Katharina Pomej,
- Marta Bofill Roig,
- Elias Laurin Meyer,
- Jaekyung Che,
- Naoshi Nishida,
- Pei-Chang Lee,
- Linda Wu,
- Celina Ang,
- Anja Krall,
- Anwaar Saeed,
- Bernardo Stefanini,
- Antonella Cammarota,
- Tiziana Pressiani,
- Yehia I. Abugabal,
- Shadi Chamseddine,
- Brooke Wietharn,
- Alessandro Parisi,
- Yi-Hsiang Huang,
- Samuel Phen,
- Caterina Vivaldi,
- Francesca Salani,
- Gianluca Masi,
- Dominik Bettinger,
- Arndt Vogel,
- Johann von Felden,
- Kornelius Schulze,
- Marianna Silletta,
- Michael Trauner,
- Adel Samson,
- Henning Wege,
- Fabio Piscaglia,
- Peter R. Galle,
- Rudolf Stauber,
- Masatoshi Kudo,
- Amit G. Singal,
- Aleena Itani,
- Susanna V. Ulahannan,
- Neehar D. Parikh,
- Alessio Cortellini,
- Ahmed Kaseb,
- Lorenza Rimassa,
- Hong Jae Chon,
- David J. Pinato,
- Matthias Pinter
Affiliations
- Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Claudia Angela Maria Fulgenzi
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
- Antonio D’Alessio
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Marta Bofill Roig
- Section for Medical Statistics, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria
- Elias Laurin Meyer
- Section for Medical Statistics, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria; Berry Consultants, Vienna, Austria
- Jaekyung Che
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
- Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Linda Wu
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
- Celina Ang
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
- Anja Krall
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Anwaar Saeed
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh (UPMC), Pittsburgh, PA, USA
- Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Antonella Cammarota
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
- Yehia I. Abugabal
- Dept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Shadi Chamseddine
- Dept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Brooke Wietharn
- Division of Medical Oncology, Department of Medicine, University of Kansas Cancer Center, Westwood, KS, USA
- Alessandro Parisi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy
- Yi-Hsiang Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan; Healthcare and Services Center, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
- Samuel Phen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Caterina Vivaldi
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Francesca Salani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Dominik Bettinger
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Centre, Freiburg, Germany
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Kornelius Schulze
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Marianna Silletta
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Adel Samson
- Leeds Institute of Medical Research at St. James's (LIMR), School of Medicine, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Leeds, UK
- Henning Wege
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Peter R. Galle
- I. Medical Department, University Medical Centre Mainz, Mainz, Germany
- Rudolf Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
- Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Aleena Itani
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Susanna V. Ulahannan
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Neehar D. Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Alessio Cortellini
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, Italy
- Ahmed Kaseb
- Dept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
- Hong Jae Chon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
- David J. Pinato
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel.: +43 1 40400 47440, fax: +43 1 40400 47350. (M. Pinter), or Division of Cancer, Department of Surgery and Cancer, Imperial College London, Du Cane Road, W12 0HS, London, UK. (D.J. Pinato)
- Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel.: +43 1 40400 47440, fax: +43 1 40400 47350. (M. Pinter), or Division of Cancer, Department of Surgery and Cancer, Imperial College London, Du Cane Road, W12 0HS, London, UK. (D.J. Pinato)
- Journal volume & issue
-
Vol. 6,
no. 2
p. 100982
Abstract
Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.
