Investigation On Predictors In The Outcome Of Immune Checkpoint Inhibitors(ICIs) And Hyperprogressive Disease Triggered By ICIs

Objective:This project was designed to evaluate the correlation between baseline neutrophil-to-lymphocyte ratio(NLR)and outcome of immune checkpoint inhibitors(ICIs),and to analyze the clinical characteristics and survivals of hyperprogressive disease(HPD)mediated by ICIs in an attempt to explore the potential predictors.Methods:After thoroughly searching electronic databases(Pub Med,MEDLINE,Google Scholar,Cochrane Library databases,CNKI,Wan Fang and VIP),the studies involving the relationship between NLR and outcome of ICIs and HPD triggered by ICIs were enrolled.Two reviewers screened the enrolled studies according to the inclusion and exclusion criteria and assessed the quality of each study based on the Newcastle Ottawa Quality Assessment Scale(NOS)independently.Then the data were extracted and the pooled data were analyzed with Review manager 5.3software.And a random effect model or fixed effect model was adopted according to the result of Chi-square and I-square tests.Furthermore,we observed the stability of results by eliminating each study and tested the heterogeneity by conducting stratified analyses.Publication bias was analyzed using funnel plot.Results:1.Study on predictive value of NLR in the outcome of ICIsFourteen studies(16 cohorts)incorporating 1751 participants were involved.The overall analyses suggested that elevated pretreatment NLR was associated with poor OS(HR=2.61,95% CI 1.77-3.86,P<0.00001)and PFS(HR=1.74,95% CI1.34-2.27,P<0.0001)after ICI therapy.Stratified analyses on tumor types,ICI agents,the cut-off value of NLR and study regions exhibited the similar outcomes(OS: melanoma: HR=2.51,P=0.0001;NSCLC: HR=2.52,P=0.002;Ipilimumab:HR=2.55,P=0.0008;Nivolumab: HR=2.58,P<0.00001;the cut-off value of NLR =5;HR=3.26,P<0.00001;the cut-off value of NLR≠5: HR=1.75,P=0.01;non-Asian countries: HR=2.29,P<0.0001;Asian countries: HR=7.18,P<0.00001;PFS: melanoma: HR=2.07,P<0.00001;NSCLC: HR=1.39,P=0.008;Ipilimumab: HR=2.12,P<0.00001;Nivolumab: HR=1.54,P=0.001;the cut-off value of NLR=5: HR=1.99,P<0.00001;the cut-off value of NLR≠5: HR=1.42,P=0.03;non-Asian countries: HR=1.86,P=0.002;Asian countries:HR=1.69,P<0.00001).2.The predictive factors of HPD triggered by ICIs and survival analysisTwelve studies incorporating 1766 individuals(323 cases of HPD)were eligible.The overall analyses revealed that HPD held a significant relation with number of previous metastatic sites >2(OR=1.86,95% CI 1.33-2.59,P = 0.0003),with liver metastasis(OR = 3.35,95% CI 2.09-5.35,P < 0.00001),with Royal Marsden Hospital(RMH)score ≥2(OR = 2.80,95% CI 1.85-4.23,P < 0.00001),with higher Eastern Cooperative Oncology Group Performance Status(ECOG PS)score(OR= 1.60,95% CI 1.13-2.27,P = 0.008)and with serum lactate dehydrogenase(LDH)> upper limits of normal(ULN)(OR= 2.32,95% CI1.51-3.58,P = 0.0001).No statistical correlation existed between the incidence of HPD and sex,age,smoking status,programmed death-ligand 1(PD-L1)expression,current or previous therapeutic methods and NLR(all P-value>0.05).Furthermore,the incidence of HPD displayed no statistical significance in the histology(squamous vs non-squamous),epidermal growth factor receptor(EGFR)mutation,anaplastic lymphoma kinase(ALK)arrangement and kirsten rat sarcoma viral oncogene(KRAS)mutation in non-small cell lung cancer(NSCLC)(all P-value>0.05).Then,no statistical difference of HPD was explored in human epidermal growth factor receptor-2(HER-2)expression of advanced gastric cancer(AGC)(P-value>0.05).Analyses exhibited that HPD was vitally correlated with shorter OS(HR= 2.92,95% CI 1.79-4.76,P < 0.0001)and PFS(HR = 3.62,95% CI 2.79-4.68,P < 0.00001).The same phenomena existed in the stratified studies based on study regions and tumor types(OS: Asian countries: HR=3.74,P<0.00001;non-Asian countries: HR=1.77,P=0.009;NSCLC: HR=2.29,P=0.001;AGC: HR=6.70,P<0.00001;PFS: Asian countries: HR=4.22,P<0.00001;AGC: HR=4.15,P<0.00001).Conclusions:(1)Elevated baseline NLR was related to poor OS and PFS in ICI therapy.(2)HPD was statistically correlated with numbers of metastatic sites > 2,liver metastasis,RMH score ≥ 2,higher ECOG PS score and LDH > ULN before ICI treatment.(3)HPD was correlated with shorter OS and PFS in patients treated with ICIs.