Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictor of Survival and Response to Therapy in Patients Treated with Immune Checkpoint Inhibitors

Background: Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients benefit, there is a strong need for predictive biomarkers. The aim of this study was to analyze the predictive capacity of neutrophil-to-lymphocyte ratio (NLR) in cancer patients treated with ICI, and to analyze the predictive value of combining NLR with tumor mutational burden (TMB). Methods: Retrospective cohort study of patients treated during 2015-2018. A total of 1714 patients with 16 different cancer types, who had complete blood count within 30 days prior to first ICI infusion, and whose tumors underwent next-generation sequencing were included. Overall survival, progression-free survival, response to ICI, and clinical benefit (response or stable disease ≥6 months) were the primary endpoints. Findings: Patients with NLR in the top 20th percentile within cancer type had significantly poorer overall survival (HR = 2·17; 95% CI, 1·89-2·50; P<0·001), progression-free survival (HR = 1·60; 95% CI, 1·41-1·81; P<0·001), response rate (18% vs 29%; P<0·001), and clinical benefit rate (21% vs 35%; P<0·001). Consistent results were obtained stratifying by cancer type. In multivariable analyses, NLR and TMB demonstrated independent association with clinical benefit. A combined variable of NLR and TMB was strongly associated with outcome. The probability of clinical benefit from ICI was 4 times higher in the NLR-low/TMB-high group compared to the NLR-high/TMB-low group (OR = 3·88; 95% CI, 2·72-5·54; P<0·001). Interpretation: In cancer patients, higher NLR was associated with poorer survival and lower likelihood of response to ICI. NLR is a suitable candidate for a cost-effective and widely accessible predictive biomarker, and can be combined with TMB for additional predictive capacity. Funding Statement: Fundacion Alfonso Martin Escudero (to CV), NIH K08 DE024774 and R01 DE027738 (to LGTM), and the NIH/NCI Cancer Center Support Grant P30 CA008748. Declaration of Interests:DH receives funding from AstraZeneca. MAP reports consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, and Aduro, honoraria from BMS and Merck, and research support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. ANS reports advisory board position with BMS, Immunocore, and Castle Biosciences, and institutional research support from BMS, Immunocore, and Xcovery. VPB is a recipient of an immuno-oncology translational research grant from Bristol-Myers Squibb and is an inventor on a patent application related to work on neoantigen modelling. AMC reports advisory board position with Springworks Therapeutics. JJS has received travel support from Intuitive Surgical Inc. for fellow education and has served as a clinical advisor to Guardant Health, Inc. SGP has a patent PCT/US2016/026717 Methods of Cancer Detection Using PARPIFL pending, holds equity in Summit Biomedical Imaging, has a patent US 10,016,238B2 Apparatus, system and method for providing laser steering and focusing for incision, excision and ablation of tissue in minimally-invasive surgery, and holds equity in ColdSteel Laser Inc. NR reports research support from Pfizer and BMS, and consulting fees from REPARE Therapeutics, Mirati Therapeutics and Illumina. AZ reports honoraria from Illumina. TAC acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai, and An2H, holds equity in An2H, and is a co-founder of Gritstone Oncology and holds equity. LGTM reports laboratory research funding from Illumina, Inc. and AstraZeneca. Ethics Approval Statement: The study was approved by the Memorial Sloan Kettering Cancer Center institutional review board (IRB).