TY - JOUR
T1 - Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics
AU - Mezquita, Laura
AU - Preeshagul, Isabel
AU - Auclin, Edouard
AU - Saravia, Diana
AU - Hendriks, Lizza
AU - Rizvi, Hira
AU - Park, Wungki
AU - Nadal, Ernest
AU - Martin-Romano, Patricia
AU - Ruffinelli, Jose C.
AU - Ponce, Santiago
AU - Audigier-Valette, Clarisse
AU - Carnio, Simona
AU - Blanc-Durand, Felix
AU - Bironzo, Paolo
AU - Tabbo, Fabrizio
AU - Reale, Maria Lucia
AU - Novello, Silvia
AU - Hellmann, Matthew D.
AU - Sawan, Peter
AU - Girshman, Jeffrey
AU - Plodkowski, Andrew J.
AU - Zalcman, Gerard
AU - Majem, Margarita
AU - Charrier, Melinda
AU - Naigeon, Marie
AU - Rossoni, Caroline
AU - Mariniello, AnnaPaola
AU - Paz-Ares, Luis
AU - Dingemans, Anne Marie
AU - Planchard, David
AU - Cozic, Nathalie
AU - Cassard, Lydie
AU - Lopes, Gilberto
AU - Chaput, Nathalie
AU - Arbour, Kathryn
AU - Besse, Benjamin
N1 - Funding Information:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Laura Mezquita received support from the IASLC Research Fellowship Award (2018), ESMO Translational Research Fellowship (2019) and SEOM retorno de Investigadores (2019).
Funding Information:
Hyperprogressive disease (HPD [31]) (~14% and fast progression/early death (6%) have been described as aggressive progression patterns under ICI, associated with ICI resistance and high mortality rates in NSCLC [32]. Biomarkers to predict these aggressive patterns are currently a major need for patients on ICI therapy. While, in lung cancer, high-dNLR at baseline was not initially associated with HPD [33], Kim et al. recently reported that high-dNLR (>4) was independently associated with HPD (differently defined). We observed, using dNLR score, that 12-week death rate was higher in high-dNLR (B) population (27% vs. 15% overall), and increased up to 32% if continued high-dNLR, supporting the biological hypothesis of neutrophil involvement on ICI resistance [12]. Similarly, other recent work have reported a correlation between dNLR and HPD [34,35]. Although these findings require confirmatory investigations, these studies together with our work, warrant further studies to explore dNLR and its dynamic changes in regards to predicting Fast-PD or HPD.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Laura Mezquita received support from the IASLC Research Fellowship Award (2018), ESMO Translational Research Fellowship (2019) and SEOM retorno de Investigadores (2019).LM: Sponsored Research: Amgen, Bristol-Myers Squibb, Boehringer Ingelheim. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca.LH: none related to the current article, outside of the current article: research funding Roche Genentech, Boehringer Ingelheim, AstraZeneca (all institution), advisory board: Boehringer, BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Boehringer Ingelheim, Amgen (all institution), speaker: MSD, travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Quadia (self), interview sessions funded by Roche Genentech (institution), local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD/Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Cilag.EN: none related to the current article, outside of the current article: research support from Roche and Pfizer; advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen and AstraZeneca.PM: Principal/subinvestigator of Clinical Trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Xencor Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche.MDH receives research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai and Arcus; has a patent filed by his institution related to the use of tumour mutation burden to predict response to immunotherapy (PCT/US2015/062,208), which has received licensing fees from PGDx.LPA: Honoraria (self): Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Ipsen, Merck, Merck Sharp and Dohme, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer; Officer/Board of Directors Genómica.AMD: Consulting, advisory role or lectures: Roche, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar. Research support: Amgen, Abbvie, BMS.GL: Research support Merck serono, BMS, Pfizer, AstraZeneca, Blueprint medicines.KA: Consultant for Astrazeneca and Iovance Biotherapeutics. Her institution has received non-monetary research support from Takeda and Novartis on her behalf.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/7
Y1 - 2021/7
N2 - 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) [dNLRResults: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (similar to 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. (C) 2021 Elsevier Ltd. All rights reserved.
AB - 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) [dNLRResults: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (similar to 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. (C) 2021 Elsevier Ltd. All rights reserved.
KW - dNLR
KW - Neutrophils
KW - Immunotherapy
KW - NSCLC
KW - Biomarker
KW - CELL
KW - NEUTROPHILS
KW - BIOMARKERS
KW - INHIBITORS
KW - NIVOLUMAB
KW - DOCETAXEL
KW - MARKERS
U2 - 10.1016/j.ejca.2021.03.011
DO - 10.1016/j.ejca.2021.03.011
M3 - Article
C2 - 34022698
SN - 0959-8049
VL - 151
SP - 211
EP - 220
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -