L Derosa1, M D Hellmann2, M Spaziano3, D Halpenny4, M Fidelle1, H Rizvi5, N Long4, A J Plodkowski4, K C Arbour6, J E Chaft7, J A Rouche8, L Zitvogel9, G Zalcman10, L Albiges11, B Escudier12, B Routy13. 1. Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015; Equipe Labellisée-Ligue Nationale Contre le Cancer, Villejuif, France; Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France. 2. Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, USA; Parker Institute for Cancer Immunotherapy, New York, USA. 3. Cardiology Division, Department of Medicine, McGill University, Montreal, Canada. 4. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA. 5. Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, USA. 6. Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA. 7. Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, USA. 8. Department of Imaging, Gustave Roussy, Villejuif, France. 9. Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015; Equipe Labellisée-Ligue Nationale Contre le Cancer, Villejuif, France; Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. 10. Thoracic Oncology Department-CIC1425/CLIP2 Paris-Nord, Hospital Bichat-Claude Bernard, AP-HP, University Paris-Diderot, Paris, France. 11. Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; Immunologie Intégrative des Tumeurs et Génétique Oncologique, GRCC, Villejuif, France. 12. Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; Immunologie Intégrative des Tumeurs et Génétique Oncologique, GRCC, Villejuif, France. 13. Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015; Equipe Labellisée-Ligue Nationale Contre le Cancer, Villejuif, France; Université Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France; Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada. Electronic address: bertrand.routy@umontreal.ca.
Abstract
Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.
Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCCpatients and 48 of 239 (20%) NSCLCpatients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCCpatients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLCpatients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.
Authors: Md Abdul Wadud Khan; Gabriel Ologun; Reetakshi Arora; Jennifer L McQuade; Jennifer A Wargo Journal: Dig Dis Sci Date: 2020-03 Impact factor: 3.199