Prognostic and Predictive Role of Neutrophil to lymphocyte Ratio in Second Line Immunotherapy of Non-small Cell Lung Cancer

Abstract

Background: Programmed death-ligand 1 (PD-L1) expression at immunohistochemistry is the only approved, but still unsatisfactory, biomarker for immunotherapy in Non-Small Cell Lung Cancer (NSCLC). Neutrophil to Lymphocyte ratio (NLR) is a surrogate of systemic inflammation and could correlate with outcome to immunotherapy. This retrospective study (NCT03816657) explored the role of NLR in predicting benefit to nivolumab and susceptibility to hyperprogression (HPD). Methods: PD-L1, baseline and on-therapy NLR values were available in 173NSCLC patients receiving nivolumab. PD-L1 positivity was defined as expression on ≥1% of tumor cells; NLR was dichotomized in high (≥5) or low (<5). Patients were divided in 4 cohorts: 1 (PD-L1+/low NLR), 2 (PD-L1-/high NLR), 3 (PD-L1+/high NLR), 4 (PD-L1-/low NLR). A landmark analysis explored the impact of cohorts and NLR change on objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and its influence on HPD. Results: PD-L1 was positive in 48% and negative in 52% of cases. Pre-treatment NLR was ≥5in 42% and <5 in 58%of patients; on-treatment NLR was ≥5in approximately 50% of patients. PD-L1 positivity was not associated with outcome. Both high pre- and on-therapy NLR was a negative predictor of ORR (p=0.004), PFS (p<0.0001) and OS (p<0.0001). High NLR cohorts (2 and 4) showed poorer outcome than low NLR cohorts. Relative NLR excursion ≥25% at 4 weeks from nivolumab start was associated with reduced PFS and OS, while its decrease or stability was associated with improved outcomes. Although NLR value and its dynamic did not influence HPD occurrence (p=0.062), 53% of hyperprogressors belonged to high NLR cohorts. Conclusion: The current retrospective analysis supports the role of high NLR as a independent negative predictive factor. Its increment during immunotherapy may identify patients with low likelihood of response to immunotherapy.