Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy.

Sirish Dharmapuri,Celina Ang,Myron Schwartz,Max Sung,Umut Özbek,Andrea D Branch,Jung‐Yi Lin

doi:10.1002/cam4.3135

Sirish Dharmapuri, Celina Ang + Show 5 more

Open Access

https://doi.org/10.1002/cam4.3135

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Journal: Cancer medicine	Publication Date: May 18, 2020
Citations: 79	License type: CC BY 4.0

Affiliation: Icahn School of Medicine at Mount Sinai

Abstract

BackgroundCurrently, there are no recognized or validated biomarkers to identify hepatocellular carcinoma patients (HCC) likely to benefit from anti–PD‐1 therapy. We evaluated the relationship between neutrophil‐lymphocyte ratio (NLR) and platelet‐lymphocyte ratio (PLR) and survival outcomes, pretreatment and after three doses (posttreatment) of nivolumab in HCC patients.MethodsMedical records of HCC patients treated with nivolumab between June 2016 and July 2018 were reviewed. Kaplan‐Meier analysis and the log‐rank test were used to calculate and compare overall survival between NLR < 5 Vs ≥ 5 and among PLR tertiles.ResultsA total of 103 patients were identified. Median age was 66 (29‐89) years. Median treatment duration was 26 (2‐149) weeks. Sixty‐four (62%) patients had Child‐Pugh class A (CP‐A) liver function. Barcelona Clinic Liver Cancer stage was B in 20 (19%) and C in 83 (81%) patients. CP‐A patients who achieved a partial or complete response had significantly lower posttreatment NLR and PLR (P < .001 for both) compared to patients who had stable disease or progression of disease. No relationship was observed between response and pretreatment NLR and PLR. NLR < 5 was associated with improved OS compared to NLR ≥ 5 both pretreatment (23 Vs10 months, P = .004) and posttreatment (35 Vs 9 months, P < .0001). Survival also differed significantly among PLR tertiles both pre‐ (P = .05) and posttreatment (P = .013). In a multivariable model, posttreatment NLR (HR = 1.10, P < .001) and PLR (HR = 1.002, P < .001) were strongly associated with survival. In a composite model of posttreatment NLR and PLR, a combination of high NLR and PLR was associated with an eightfold increased risk of death (HR = 8.3, P < .001).ConclusionsThis study suggests a strong predictive role of these inflammatory cell ratios in the posttreatment setting in HCC patients treated with anti anti–PD‐1 therapy and should be evaluated in a larger cohort.

Highlights

An evolving understanding of the molecular pathogenesis of hepatocellular carcinoma (HCC) and its complex interactions with the tumor microenvironment has led to the introduction of immunotherapy in the hepatocellular carcinoma patients (HCC) treatment landscape
The downside, is the unsustainable cost burden associated with anti–Progression of disease (PD)-1 therapy, as well as the life-threatening array of immune-mediated toxicities observed in about 2%-4% of patients,[5] validating the need for development of predictive biomarkers to identify patients that are likely to benefit from anti–PD-1 therapy
Tertiles were used when describing survival based on prior literature,[13,14] but this was limited to binary groups in the neutrophil-lymphocyte ratio (NLR)/platelet-lymphocyte ratio (PLR) model described below to optimize the number of groups created and to power each group adequately

Summary

| INTRODUCTION

An evolving understanding of the molecular pathogenesis of hepatocellular carcinoma (HCC) and its complex interactions with the tumor microenvironment has led to the introduction of immunotherapy in the HCC treatment landscape. Nivolumab and pembrolizumab are IgG4 monoclonal antibodies to PD-1 that are FDA approved for second line therapy after sorafenib These drugs have demonstrated durable responses and prolonged survival in a subset of patients, and have a better safety profile over sorafenib.[1,2,3,4] The downside, is the unsustainable cost burden associated with anti–PD-1 therapy, as well as the life-threatening array of immune-mediated toxicities observed in about 2%-4% of patients,[5] validating the need for development of predictive biomarkers to identify patients that are likely to benefit from anti–PD-1 therapy. Responses to anti–PD-1 therapy have been observed irrespective of baseline PD-L1 expression 1,3,6,7 suggesting its limited sensitivity as a predictive biomarker in HCC. We studied the predictive value of NLR and PLR on survival outcomes in advanced hepatocellular carcinoma (aHCC) patients treated with nivolumab at the Mount Sinai Hospital

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