| Objective Immune checkpoint inhibitor(ICI)has become the standard treatment for patients with advanced non-small cell lung cancer(NSCLC),but the biomarkers associated with ICI therapy,especially immune-related adverse events,are unknown.Methods In this study,we investigated patients with stage Ⅲ-Ⅳ NSCLC who were treated with ICI in following aspects:(1)409 patients from 12 centers across China from January 1,2015 to February 28,2021 were enrolled in this part to analyze the current occurrence,management pattern and risk factors of irAEs;(2)103 patients attending Peking Union Medical College Hospital from January 1,2015 to December 31,2020 were included to analyze the relationship between their peripheral blood biomarkers(PBBs)and irAEs;Meanwhile,we analyzed the relationship between PBB and the efficacy of immunotherapy in these patients(n=103).Results(1)A total of 409 patients were enrolled in this study,of whom 36.7%(n=150)developed a total of 196 irAEs.Multivariate analysis showed that positive PDL1 expression(odds ratio[OR]1.563;95%confidence interval[CI]1.010-2.420,p=0.039)and a tumor response of PR or SD after treatment with ICI(OR 2.809;95%CI 1.319-5.983,p=0.007)were associated with an increased risk of irAEs.(2)A total of 103 patients were included in the study,of whom 36.9%(n=38)developed irAEs.results showed that high pretreatment absolute peripheral blood lymphocyte value was associated with an increased risk of irAEs in all patients(OR 2.165;95%CI 1.0404.509,p=0.039)and in those treated with ICI only(OR 6.461,95%CI 1.067-39.112;p=0.042).In terms of survival,high pretreatment IL-6 levels were associated with both shorter progression-free survival and shorter overall survival,high prognostic nutritional index at baseline was associated with prolonged overall survival in both patients treated with ICI only and those treated with chemoimmunotherapy(p<0.05).Conclusions This study provides real-world data on irAEs and ICI efficacy in stage Ⅲ-Ⅳ NSCLC patients treated with ICI,identifies clinical and plasma biomarkers associated with ICI treatment outcomes,and provides a basis for clinical screening of the ICI benefit population.Part 1.Analysis of clinical characteristics and risk factors of immune checkpoint inhibitor-related adverse events in patients with advanced non-small cell lung cancer in the real-world settingObjective Immune checkpoint inhibitors(ICI)are the standard treatment strategy for advanced lung cancer,but immune-related adverse events(irAEs)are still poorly understood,especially in the real-world setting.This study aims to analyze the clinical characteristics and the incidence,risk factors and management patterns of irAEs in patients with advanced non-small cell lung cancer(NSCLC)treated with ICI.Methods This is a multicenter observational study that reviewed patients with advanced lung cancer treated with ICI from January 1,2015,to February 28,2021,in 26 hospitals across China.Patients who met the following criteria were included in this study:(1)pathologically confirmed stage Ⅲ-Ⅳ NSCLC;(2)with programmed cell death ligand-1(PD-L1)expression test results;and(3)with confirmed efficacy evaluation results after ICI treatment.Results A total of 409 patients from 12 hospitals across the country were included in this study.The median age was 65 years(range 30-84 years),and the maleto-female ratio was 2.8:1(302/107).Squamous cell carcinoma accounted for 40.0%(n=166).65%(n=266)of patients had a positive PD-L1 tumor cell proportional score(≥1%).The objective response rate for the entire group was 42.3%and the disease control rate was 88.0%.36.7%(n=150)of patients experienced a total of 196 irAEs and 6.4%(n=26)had a total of 30 grade 3-5 irAEs.The most involved organs of irAEs were skin(n=47),thyroid(n=38)and lung(n=33).A total of 45 patients with irAEs were treated with steroids,and one patient eventually died of immune-related hepatic failure.Multivariate analysis showed that PD-L1 positive expression was an independent risk factor for the development of irAEs[odds ratio(OR)1.563;95%confidence interval(CI)1.010-2.420,p=0.039].In addition,patients with an ICI efficacy of PR or SD were significantly associated with an increased risk of irAEs(OR 2.809;95%CI 1.319-5.983,p=0.007).Conclusion Positive PD-L1 expression is related with increased irAEs incidence and irAEs represents good anti-tumor efficacy of ICI.Part 2.Correlations between pretreatment peripheral blood biomarkers and immune checkpoint inhibitor-related adverse events in patients with non-small cell lung cancerObjective This study aimed to determine the predictive value of pretreatment peripheral blood biomarkers(PBB)in developing immune-related adverse events(irAEs)in patients with non-small cell lung cancer(NSCLC).Methods Patients with advanced NSCLC,who had been treated at Peking Union Medical College Hospital and received immune checkpoint inhibitors(ICIs)or chemoimmunotherapy from January 2015 to December 2020,were retrospectively identified.The correlation between PBBs and the incidence of irAEs was assessed using Pearson’s chi-squared and Student’s t-tests as required.Kaplan-Meier plots with log-rank test were used to analyze the correlation between irAEs incidence and survival.The analysis was performed for all patients(n=103),patients treated with ICI only(n=32)and patients treated with chemoimmunotherapy(n=71),respectively.Results A total of 103 patients were enrolled in this study,of whom 38(36.9%)had 57 irAEs,the most common irAEs being rash(n=13),elevated alanine aminotransferase/bilirubin(n=8)and hypothyroidism(n=7).In the whole group of patients,the pretreatment absolute lymphocyte count(ALC)(odds ratio[OR]2.165;95%confidence interval[CI]1.040-4.509,p=0.039],and the number of tumor metastatic sites(>2 vs ≤2,OR 0.196,95%CI 0.051-0.753,p=0.018)were independently associated with the risk of irAEs.In the subgroup of patients treated with ICI alone(n=32),ALC levels were also associated with an increased risk of irAEs(OR 6.461;95%CI 1.067 to 39.112,p=0.042).However,in the subgroup of patients treated with chemoimmunotherapy(n=71),no significant relationship between ALC and irAEs was found.In addition,compared to patients without irAEs,patients who developed irAEs enjoyed longer progression-free survival and overall survival,though there was no statistical difference between the two groups.Conclusion Pretreatment ALC levels and the number of distant metastases of the tumor may be predictive of whether irAEs occur in patients with advanced NSCLC treated with ICI.Part 3.Correlations between peripheral blood biomarkers and efficacy of immune checkpoint inhibitors-based therapy in patients with advanced nonsmall cell lung cancerObjective Immune checkpoint inhibitors(ICI)have become a standard treatment for various cancer types.Peripheral blood biomarker(PBB)to predict the efficacy of ICI therapy in patients with advanced non-small cell lung cancer(NSCLC)is a question worth exploring.The aim of this study was to investigate the relationship between PBB and the efficacy of ICI.Methods Patients with advanced NSCLC treated with ICI or chemoimmunotherapy at Peking Union Medical College Hospital from January 1,2015,to December 31,2020,were retrospectively included.The relationships between PBB and ICI efficacy were analyzed using the Kruskal-Wallis H test and Kaplan-Meier method,respectively,Cox proportional hazards was used to determine independent risk factors.In addition,the relationship between changes in PBB before and during treatment and efficacy was analyzed.Results 103 patients were enrolled in this study.A low prognostic nutritional index(PNI)of ≤45 was associated with poorer overall survival(OS)in all patients(n=103),in patients treated with ICI only(n=32),and in patients treated with chemoimmunotherapy(n=71)(p<0.05).Interleukin-6(IL-6)>13.80 pg/mL in the full group of patients,IL-6>11.30 pg/mL in patients receiving ICI only,and IL-6>11.85 pg/mL in patients treated with chemoimmunotherapy were associated with poorer PFS and OS(p<0.05).In the full group of patients,elevated IL-6 after treatment initiation was associated with poorer OS(p<0.001).Conclusion Whether treated with ICI alone or chemoimmunotherapy,low pretreatment PNI levels and high IL-6 levels were associated with poorer PFS and OS in patients with NSCLC. |
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