Petros Fessas1, Muntaha Naeem1, Matthias Pinter2, Thomas U Marron3, David Szafron4, Lorenz Balcar2, Anwaar Saeed5, Tomi Jun3, Sirish Dharmapuri3, Anuhya Gampa6, Yinghong Wang7, Uqba Khan8, Mahvish Muzaffar9, Musharraf Navaid9, Pei-Chang Lee10,11, Anushi Bulumulle9, Bo Yu12, Sonal Paul13, Neil Nimkar13, Dominik Bettinger14, Hannah Hildebrand5, Yehia I Abugabal15, Tiziana Pressiani16, Nicola Personeni16,17, Naoshi Nishida18, Masatoshi Kudo18, Ahmed Kaseb15, Yi-Hsiang Huang10,11, Celina Ang3, Anjana Pillai6, Lorenza Rimassa16,17, Abdul Rafeh Naqash19, Elad Sharon20, Alessio Cortellini1,21, David J Pinato1. 1. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom. 2. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Vienna Liver Cancer Study Group, AKH and Medical University of Vienna, Vienna, Austria. 3. Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Mount Sinai Hospital, New York, New York, USA. 4. Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA. 5. Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Westwood, Kansas, USA. 6. Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medicine, Chicago, Illinois, USA. 7. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 8. Division of Hematology and Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York, USA. 9. Division of Hematology/Oncology, East Carolina University, Greenville, North Carolina, USA. 10. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 11. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. 12. Lincoln Medical Center, New York, New York, USA. 13. New York Presbyterian Brooklyn Methodist Hospital, New York, New York, USA. 14. Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany. 15. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 16. Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Milan, Italy. 17. Department of Biomedical Sciences, Humanitas University, Milan, Italy. 18. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan. 19. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA. 20. National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, Maryland, USA. 21. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Abstract
BACKGROUND AND RATIONALE: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. METHODS: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within -30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. RESULTS: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). CONCLUSIONS: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.
BACKGROUND AND RATIONALE: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. METHODS: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within -30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. RESULTS: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). CONCLUSIONS: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.