Laura Mezquita1, Isabel Preeshagul2, Edouard Auclin3, Diana Saravia4, Lizza Hendriks5, Hira Rizvi2, Wungki Park4, Ernest Nadal6, Patricia Martin-Romano7, Jose C Ruffinelli6, Santiago Ponce8, Clarisse Audigier-Valette9, Simona Carnio10, Felix Blanc-Durand11, Paolo Bironzo10, Fabrizio Tabbò10, Maria Lucia Reale10, Silvia Novello10, Matthew D Hellmann2, Peter Sawan12, Jeffrey Girshman12, Andrew J Plodkowski12, Gerard Zalcman13, Margarita Majem14, Melinda Charrier15, Marie Naigeon15, Caroline Rossoni16, AnnaPaola Mariniello10, Luis Paz-Ares8, Anne Marie Dingemans16, David Planchard11, Nathalie Cozic17, Lydie Cassard15, Gilberto Lopes4, Nathalie Chaput18, Kathryn Arbour2, Benjamin Besse19. 1. Cancer Medicine Department, Gustave Roussy, Villejuif, France; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi I Sunyer Biomedical Research Institute, Barcelona, Spain. Electronic address: https://twitter.com/LauraMezquitaMD. 2. Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center NY, USA. 3. Medical and Gastrointestinal Oncology Department, Georges Pompidou Hospital, Paris, France. 4. Medical Oncology Department Sylvester Comprehensive Cancer Center, University of Miami. 5. Cancer Medicine Department, Gustave Roussy, Villejuif, France; Pulmonary Diseases GROW- School for Oncology and Biology, Maastricht UMC+, Maastricht, the Netherlands. 6. Medical Oncology Department, Catalan Institute of Oncology, L'Hospitalet, Barcelona Spain. 7. Early Drug Development Department, Gustave Roussy, Villejuif, France. 8. Medical Oncology Department, Hospital 12 Octubre, Madrid, Spain. 9. Centre Hospitalier Sainte Musse, Pneumology Department, Toulon, France. 10. Thoracic Oncology Unit, Department of Oncology, University of Turin, AOU San Luigi, Orbassano (TO) Italy. 11. Cancer Medicine Department, Gustave Roussy, Villejuif, France. 12. Department of Radiology, Memorial Sloan Kettering Cancer Center NY, USA. 13. Thoracic Oncology Department, CIC1425/CLIP2 Paris-Nord, Hôpital Bichat- Claude Bernard, Paris, France. 14. Medical Oncology Department, Hospital San Pau, Barcelona, Spain. 15. Laboratory of Immunomonitoring in Oncology, UMS3655 CNRS US 23 INSERM, Gustave Roussy, Villejuif, France. 16. Department Pulmonology, Erasmus MC, Rotterdam, the Netherlands. 17. Biostatistics Unit, INSERM U1018, Villejuif, France. 18. Laboratory of Immunomonitoring in Oncology, UMS3655 CNRS US 23 INSERM, Gustave Roussy, Villejuif, France; University Paris-Saclay, School of Pharmacy, France. 19. Cancer Medicine Department, Gustave Roussy, Villejuif, France; University Paris-Saclay, School of Medicine, France. Electronic address: Benjamin.besse@gustaveroussy.fr.
Abstract
BACKGROUND: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. PATIENTS AND METHODS: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16lowcells (immature) by flow cytometry. RESULTS: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. CONCLUSION: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.
BACKGROUND:dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. PATIENTS AND METHODS: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16lowcells (immature) by flow cytometry. RESULTS: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. CONCLUSION: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.
Authors: Niklas Klümper; Jonas Saal; Fiamma Berner; Christa Lichtensteiger; Nina Wyss; Annkristin Heine; Franz Georg Bauernfeind; Jörg Ellinger; Peter Brossart; Stefan Diem; Sabine Schmid; Markus Joerger; Martin Frueh; Manuel Ritter; Michael Hölzel; Lukas Flatz; Tobias Bald Journal: J Immunother Cancer Date: 2022-03 Impact factor: 12.469
Authors: Joao V Alessi; Biagio Ricciuti; Stephanie L Alden; Arrien A Bertram; Jessica J Lin; Mustafa Sakhi; Mizuki Nishino; Victor R Vaz; James Lindsay; Madison M Turner; Kathleen Pfaff; Bijaya Sharma; Kristen D Felt; Scott J Rodig; Justin F Gainor; Mark M Awad Journal: J Immunother Cancer Date: 2021-11 Impact factor: 13.751