The Role Of Inflammatory Markers In Predicting The Efficacy And Safety Of Anti-PD-1 Therapy In Advanced Non-small Cell Lung Cancer

Objective:Programmed cell death protein-1(PD-1)inhibitors have changed the treatment mode of advanced non-small cell lung cancer(NSCLC)by reshaping the tumor-killing function of T cells,and significantly improved the response rate and durability of NSCLC.Nonetheless,given the outcome of anti-PD-1 therapy in some patients,the complexity of systemic immune system-tumour interactions,the changing tumor immune microenvironment and the potential risk of immune-related side events(ir AEs),this study dynamically monitored the serum inflammatory markers to predict the efficacy of immune checkpoint inhibitors and the risk of ir AEs in patients with advanced NSCLC,to screen the best patient population for anti-PD-1 therapy to guide clinical decision-making.Methods:1.Data acquisitionThe clinical information of 254 lung cancer patients who received anti-PD-1 treatment in the Department of Respiratory and Critical Care Medicisne,Changhai Hospital from January 1,2018 to December 31,2020 were collected.According to the inclusion and exclusion criteria,general information,clinicopathological characteristics,inflammatory indicators,immunotherapy information,follow-up and ir AEs occurrence of 222 NSCLC patients were collected,including: general information such as name,age,gender,smoking history and underlying diseases;clinicopathological characteristics such as tumor pathological type,clinical stage,gene mutation status and programmed cell death ligand-1(PD-L1)expression level;inflammatory indicators such as complete blood count,interleukin,lactate dehydrogenase and C-reactive protein;Anti-PD-1 treatment time,regimen,evaluation results,progression-free survival(PFS)and overall survival(OS);ir AEs occurrence time,type,grade and follow-up situation;The follow-up period was up to July31,2021.2.Evaluation criteria for therapeutic efficacy and side effectsThe tumor response was assessed according to the Response Evaluation Criteria for Solid Tumors(RECIST version 1.1),classified as progressive disease(PD),stable disease(SD),partial response(PR)and complete response(CR),and the prognosis was recorded;the Common Terminology Criteria for Adverse Events(CTCAE 4.0)was used to grade toxicity,and follow-up was recorded.3.Statistical analysisThe ROC curve was used to calculate the optimal cut-off value and the inflammatory indexes were divided into two groups of high and low levels.Log-rank test and KaplanMeier method were used to analyze the relationship between clinicopathological characteristics of patients and the levels of inflammatory markers and prognosis of patients,and univariate and multivariate Cox regression analysis were used to estimate hazard ratios for PFS and OS.Fisher’s exact test was used to analyze the correlation between the two groups of the baseline levels of inflammatory markers and ir AEs.The Wilcoxon rank test was used to compare the differences of inflammatory markers before treatment(baseline)with at the time of the first PR,at the time of PD,and at the occurrence of ir AEs.All statistical analyses of data were performed using R version 4.0.3,and P < 0.05 was defined as a statistically significant difference.Results:1.General information and clinicopathological characteristics of patients with advanced NSCLC treated with anti-PD-1 therapyThe median age of patients in this study was 64(39-87)years old,173(77.9%)were male,former or current smokers were 141(63.5%).110(49.6%)had lung adenocarcinoma,98 cases(44.1%)with lung squamous cell carcinoma and 14 cases(6.3%)with other types of non-small cell lung cancer.More than three-quarters of patients were in stage Ⅳ,of which54 patients(24.3%)had more than 2 distant metastases.26(11.7%)patients with positive driver genes received anti-PD-1 therapy.21 cases(9.5%)had high PD-L1 expression,and88 cases(39.6%)were not tested for PD-L1.There were 100(45.05%)patients received anti-PD-1 therapy as first-line,and 149 patients(67.1%)received anti-PD-1 combined with chemotherapy,radiotherapy or anti-angiogenic drugs.2.Predictive role of inflammatory markers on PFS and OS in patients with advanced NSCLCUnivariate analysis showed that other pathological types,metastatic sites ≥2,anti-PD-1 monotherapy,second-line and post-line treatment,and multiple markers NLR,PLR,MLR,LDH,CRP and IL-6 in NSCLC with high baseline levels were significantly associated with shortened PFS and OS(P < 0.05 or P < 0.01);baseline IL-8 and TNF-a were only significantly associated with PFS(P < 0.05).The results of multivariate analysis showed that other pathological types and baseline elevated NLR,PLR,MLR,LDH were independent risk factors for PFS(P < 0.05 or P < 0.01);baseline elevated PLR,MLR and LDH were independent risk factors for OS factor(P<0.01).In the subgroup analysis,high baseline levels of NLR,PLR,MLR,LDH,CRP,IL-6and IL-10 in the immune monotherapy group predicted a poor prognosis(P<0.05 or P<0.01);High baseline levels of NLR,PLR,MLR,LDH,CRP,IL-6,IL-8 and TNF-a The immunocombination therapy group suggested a poor prognosis(P<0.05 or P<0.01).Elevated baseline levels of NLR,PLR,MLR,CRP,IL-6,IL-8,IL-10 and TNF-a in the firstline treatment group were associated with poorer prognosis(P<0.05 or P<0.01);elevated baseline levels of NLR,PLR,MLR,LDH,CRP and IL-6 in the second-line and post-line treatment groups were associated with poorer prognosis(P<0.01).3.Predictive role of inflammatory markers on efficacy PR and PDCompared with the baseline level,the levels of NLR,LDH,CRP and IL-6 were significantly decreased when the patients first obtained PR(P<0.05 or P<0.01),and the levels of LDH,CRP,IL-6 and TNF-α were significantly increased when the patients obtained PD(P<0.05 or P<0.01).4.ir AEs in anti-PD-1 therapy in advanced NSCLCAs of July 31,2021,all grades of ir AEs were observed in 70 patients(31.53%),the most common being immune-related dermatitis 9.46%(21/222),immune-related pneumonia9.01%(20/222),immune-related gastroenteritis 3.60%(8/222),and immune-related hypothyroidism 3.15%(7/222).Thirteen patients(5.86%)had grade Ⅲ and higher ir AEs,including grade Ⅲ immune-related exfoliative dermatitis in 6 cases,grade Ⅲ immunerelated pneumonia in 5 cases and grade Ⅲ immune-related colitis in 2 cases.Thirty-three patients(14.86%)were discontinued due to ir AEs,and 2 patients died due to ir AEs,both of which were immune-related pneumonia.5.Relationship between inflammatory markers and ir AEs in patients with advanced NSCLCThe results of this study showed that baseline levels of NLR,PLR,MLR,LDH,CRP,IL-6,IL-8,IL-10,and TNF-α were not significantly correlated with the development of ir AEs.When ir AEs occurred,the levels of LDH,CRP,IL-6,IL-10,and TNF-α increased significantly compared with baseline levels(P < 0.05 or P < 0.01),and the levels of NLR,PLR,MLR,and IL-8 were not significantly different from baseline levels.Conclusions:In this study,the changes of serum inflammatory markers were dynamically monitored to explore their relationship with the efficacy of anti-PD-1 therapy and the occurrence of ir AEs in patients with advanced NSCLC,in order to screen the optimal patient population for anti-PD-1 therapy and identify and dynamically monitor the occurrence and development of ir AEs.In clinical practice,when starting or withdrawing anti-PD-1 therapy in patients with advanced NSCLC,clinicians should balance the risk of toxicity with the clinical benefit by taking into account the dynamic changes in serum inflammatory markers,and make individualized management decisions for patients with advanced NSCLC.