Clinical Observation Of Immune Checkpoint Inhibitor In The Treatment Of Advanced Non-Small Cell Lung Cancer

Background and objectiveImmunotherapy opens a new era of tumor therapy.Programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1)inhibitors play an extremely important role in the treatment of advanced non-small cell lung cancer(NSCLC).A number of clinical studies have confirmed that immune checkpoint inhibitors(ICIs)have significantly longer overall survival(OS)than traditional chemotherapy,and the adverse events are acceptable.However,the objective response rate(ORR)in monotherapy is very limited.Clinical studies have shown that the combination of ICIs can bring more significant clinical benefits.Whereas,these clinical studies are randomized controlled trials(RCT),with strict inclusion criteria,exclusion criteria and treatment regimens,and only about 10%of NSCLC patients can be included.There are very few studies on the benefits of“non-quality patients”that require complex treatment decisions in clinical practice,and RCT cannot provide sufficient evidence for guidance.Different from the traditional RCT,real world research(RWR)performs statistical and systematic analysis on the data generated in real clinical practice,and the results have more clinical reference significance.Previous studies have found that response evaluation criteria in solid tumors(RECIST 1.1)used in traditional RCT may determine the effectiveness of tumor treatment in patients as disease progression,and modified RECIST 1.1 for immune based therapeutics(iRECIST)can effectively avoid misjudgment and can more accurately evaluate tumor response.In addition,some studies have shown that body mass index(BMI),and antibiotics can affect clinical benefits.Exploring the correlation between clinical characteristics and efficacy could provide evidence for the selection of clinical treatment regimens.This study aims to obtain real-world data about ICIs for advanced NSCLC based on iRECIST,and compare the results with traditional RCT studies,and analyze the correlation between common clinicopathological features and prognosis.To provide references for the effectiveness and safety of different treatment lines and combinations of immunotherapy and prognostic factors in the real world.MethodsBased on real-world research methods,patients with advanced NSCLC who were treated with ICIs from Aug 10,2016 to July 10,2019 were enrolled.Baseline clinicopathological characteristics were collected,including age,gender,performance status(PS),BMI,pathological type,smoking status,receiving antibiotics during immunotherapy,TNM stage.The clinical efficacy of first-line monotherapy,first-line combination,second-line monotherapy,and second-line combination was evaluated according to iRECIST criteria,including best overall response(bOR),progression-free survival(PFS),duration of response(Do R).bOR,PFS,Do R,and OS were used as endpoints to conduct stratified analysis of clinicopathological characteristics.And immune-related adverse events(ir AEs)were assessed.Results1.A total of 61 patients with stage IV NSCLC were included,of whom mainly were males(54 cases,88.5%),and the median age was 58 years(34～81 years).PS scores were mostly 0～1(59 cases,96.7%).Median BMI was 23.1 kg/m~2(15.6 kg/m~2～32.3 kg/m~2).Those 61 cases included 31 cases(50.8%)of adenocarcinoma and 30 cases(49.2%)of squamous carcinoma,of whom there were 40 cases(65.6%)with smoking history,and 21cases(34.4%)who had received antibiotics during immunotherapy.2.The bOR rate of first-line monotherapy and first-line combination was 27.3%and47.1%(P=0.314),respectively.The bOR rate of second-line monotherapy and second-line combination was 30.0%and 41.7%(P=0.675),respectively.The bOR rate of first-line overall and second-line overall was 35.9%and 36.4%(P=0.971),respectively.The bOR rate(14.3%vs 47.5%,P=0.010)significantly decreased in patients who received antibiotics.And patients with high BMI had a tendency to obtain bOR(52.4%vs 27.5%,P=0.055).There was no statistical difference in stratified analysis of gender and pathological type.3.The median PFS(mPFS)of first-line monotherapy and first-line combination was12.3 months and 16.7 months(P=0.600),respectively.The mPFS of second-line monotherapy and second-line combination was 6.0 months and 6.8 months(P=0.917),respectively.The mPFS of the first-line overall and second-line overall was 16.7 months and 6.3 months(P=0.010),respectively.Patients who received antibiotics had a significant shorter PFS(7.0 months vs 17.8 months,P=0.001).There was no statistical difference in stratified analysis of gender,BMI,and pathological type.4.The median Do R(mDo R)of first-line monotherapy and first-line combination did not reach(P=0.967).The mDo R of second-line monotherapy and second-line combination was 7.8 months and NR(P=0.843),respectively.The mDo R of the first-line overall and second-line overall was NR and 7.8 months(P=0.029),respectively.Patients who received antibiotics had a significant shorter Do R(5.9 months vs NR,P<0.001).There was no statistical difference in stratified analysis of gender,BMI,and pathological type.5.The median OS(mOS)of first-line monotherapy and first-line combination was23.0 months and NR(P=0.542),respectively.The mOS of second-line monotherapy and second-line combination was 9.0 months and NR(P=0.172),respectively.The mOS of the first-line overall and second-line overall was 23.0 months and 22.0 months(P=0.080),respectively.Patients who received antibiotics had a significant shorter OS(12.2 months vs23.0 months,P=0.004).There was no statistical difference in stratified analysis of gender,BMI,and pathological type.6.The overall incidence of ir AEs was 49.2%and the incidence of severe ir AEs was5.0%.The most common ir AEs were skin toxicity,endocrine toxicity,gastrointestinal toxicity,etc.Three patients with grade 3 ir AEs improved after stopping immunotherapy and receiving hormonal treatment.No grade 4 ir AEs occurred.7.Two patients had PS score of 2,the PFS was 1.9 months and 3.2 months,respectively.Three patients were older than 75 years,2 of them were evaluated as iPR.The Do R was 13.0 months and 16.3 months,and no progress has been occurred so far.Grade1～2 ir AEs occurred in only 2 cases.8.Based on the iRECIST criteria,2 patients were evaluated as pseudoprogression.One of them was evaluated as iPR after follow-up treatment,with the Do R of 5.9 months and the PFS of 16.7 months,still alive.Another one was evaluated as iSD after follow-up treatment,with the OS of 23.0 months.9.Thirty-nine patients were evaluated as iCPD.Twelve patients(30.8%)had the primary lesions progression.Ten patients(25.6%)had the metastatic lesions progression.Seventeen patients(43.6%)had the primary and metastases progression.Six patients had slow or local progression,immunotherapy was still maintained,and anti-angiogenic therapy or local radiotherapy was added.The range of OS was 14.1～34.5 months,of which 2patients died,and the OS was 13.7 and 15.3 months,respectively.Conclusions1.This real-world research evaluated the efficacy based on the iRECIST criteria,the clinical benefit of first-line monotherapy,first-line combination,and second-line monotherapy in immunotherapy of NSCLC patients was better than the RCT studies.2.Second-line combination could bring significant improvement in efficacy.3.Receiving antibiotics during immunotherapy could negatively affect the efficacy.4.In the real world research,the ir AEs of"non-quality patients"were controllable.5.Based on the iRECIST criteria,patients with pseudoprogression,slow-progression,or local progression experienced sustainable clinical benefit from immunotherapy.