Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics

Laura Mezquita; Isabel Preeshagul; Edouard Auclin; Diana Saravia; Lizza Hendriks; Hira Rizvi; Wungki Park; Ernest Nadal; Patricia Martin-Romano; Jose C. Ruffinelli; Santiago Ponce; Clarisse Audigier-Valette; Simona Carnio; Felix Blanc-Durand; Paolo Bironzo; Fabrizio Tabbo; Maria Lucia Reale; Silvia Novello; Matthew D. Hellmann; Peter Sawan; Jeffrey Girshman; Andrew J. Plodkowski; Gerard Zalcman; Margarita Majem; Melinda Charrier; Marie Naigeon; Caroline Rossoni; AnnaPaola Mariniello; Luis Paz-Ares; Anne Marie Dingemans; David Planchard; Nathalie Cozic; Lydie Cassard; Gilberto Lopes; Nathalie Chaput; Kathryn Arbour; Benjamin Besse

doi:10.1016/j.ejca.2021.03.011

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics

Laura Mezquita, Isabel Preeshagul, Edouard Auclin, Diana Saravia, Lizza Hendriks, Hira Rizvi, Wungki Park, Ernest Nadal, Patricia Martin-Romano, Jose C. Ruffinelli, Santiago Ponce, Clarisse Audigier-Valette, Simona Carnio, Felix Blanc-Durand, Paolo Bironzo, Fabrizio Tabbo, Maria Lucia Reale, Silvia Novello, Matthew D. Hellmann, Peter SawanJeffrey Girshman, Andrew J. Plodkowski, Gerard Zalcman, Margarita Majem, Melinda Charrier, Marie Naigeon, Caroline Rossoni, AnnaPaola Mariniello, Luis Paz-Ares, Anne Marie Dingemans, David Planchard, Nathalie Cozic, Lydie Cassard, Gilberto Lopes, Nathalie Chaput, Kathryn Arbour, Benjamin Besse^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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

Results: 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.

Original language	English
Pages (from-to)	211-220
Number of pages	10
Journal	European Journal of Cancer
Volume	151
DOIs	https://doi.org/10.1016/j.ejca.2021.03.011
Publication status	Published - Jul 2021

Keywords

dNLR
Neutrophils
Immunotherapy
NSCLC
Biomarker
CELL
NEUTROPHILS
BIOMARKERS
INHIBITORS
NIVOLUMAB
DOCETAXEL
MARKERS

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10.1016/j.ejca.2021.03.011

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Mezquita, L., Preeshagul, I., Auclin, E., Saravia, D., Hendriks, L., Rizvi, H., Park, W., Nadal, E., Martin-Romano, P., Ruffinelli, J. C., Ponce, S., Audigier-Valette, C., Carnio, S., Blanc-Durand, F., Bironzo, P., Tabbo, F., Reale, M. L., Novello, S., Hellmann, M. D., ... Besse, B. (2021). Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics. European Journal of Cancer, 151, 211-220. https://doi.org/10.1016/j.ejca.2021.03.011

@article{cccdafa9322e4c22bbe4523cd77d7777,

title = "Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics",

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) [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.",

keywords = "dNLR, Neutrophils, Immunotherapy, NSCLC, Biomarker, CELL, NEUTROPHILS, BIOMARKERS, INHIBITORS, NIVOLUMAB, DOCETAXEL, MARKERS",

author = "Laura Mezquita and Isabel Preeshagul and Edouard Auclin and Diana Saravia and Lizza Hendriks and Hira Rizvi and Wungki Park and Ernest Nadal and Patricia Martin-Romano and Ruffinelli, {Jose C.} and Santiago Ponce and Clarisse Audigier-Valette and Simona Carnio and Felix Blanc-Durand and Paolo Bironzo and Fabrizio Tabbo and Reale, {Maria Lucia} and Silvia Novello and Hellmann, {Matthew D.} and Peter Sawan and Jeffrey Girshman and Plodkowski, {Andrew J.} and Gerard Zalcman and Margarita Majem and Melinda Charrier and Marie Naigeon and Caroline Rossoni and AnnaPaola Mariniello and Luis Paz-Ares and Dingemans, {Anne Marie} and David Planchard and Nathalie Cozic and Lydie Cassard and Gilberto Lopes and Nathalie Chaput and Kathryn Arbour and Benjamin Besse",

note = "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 Gen{\'o}mica.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: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = jul,

doi = "10.1016/j.ejca.2021.03.011",

language = "English",

volume = "151",

pages = "211--220",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "ELSEVIER SCI LTD",

}

Mezquita, L, Preeshagul, I, Auclin, E, Saravia, D, Hendriks, L, Rizvi, H, Park, W, Nadal, E, Martin-Romano, P, Ruffinelli, JC, Ponce, S, Audigier-Valette, C, Carnio, S, Blanc-Durand, F, Bironzo, P, Tabbo, F, Reale, ML, Novello, S, Hellmann, MD, Sawan, P, Girshman, J, Plodkowski, AJ, Zalcman, G, Majem, M, Charrier, M, Naigeon, M, Rossoni, C, Mariniello, A, Paz-Ares, L, Dingemans, AM, Planchard, D, Cozic, N, Cassard, L, Lopes, G, Chaput, N, Arbour, K & Besse, B 2021, 'Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics', European Journal of Cancer, vol. 151, pp. 211-220. https://doi.org/10.1016/j.ejca.2021.03.011

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 -