The Investigational And Translational Study Of Treatment Strategies In Non-small Cell Lung Cancer

BackgroundAnti-tumor agents for advanced non-small cell lung cancer(NSCLC)include chemotherapy,targeted therapy,and immunotherapy,and anti-angiogenic agents are in conjunction with other agents to promote anti-tumor effect.This study aims to explore the efficacy and safety of diverse combination strategies of anti-angiogenic agents and other anti-tumor agents in advanced NSCLC patients.MethodsAdvanced NSCLC patients who were treated in Cancer Hospital,Chinese Academy of Medical Sciences were included in this retrospective analysis.The patients were divided into three cohorts according to the combination pattern.Cohort 1 included epidermal growth factor receptor(EGFR)-mutant advanced NSCLC patients who had gradual progression after tyrosine kinase inhibitor(TKI)treatment,and then received continuation of TKI combining with bevacizumab.Cohort 2 included EGFR-mutant advanced NSCLC patients who had gradual progression after TKI treatment,and then received continuation of TKI combining with anlotinib.Cohort 3 included advanced NSCLC patients who progressed from at least one line of systemic treatment,and then received combination therapy with a programmed cell death-1(PD-1)inhibitor and anti-angiogenic agent.The response to the combination strategies was evaluated by objective response rate(ORR),defined as the addition of complete response(CR)rate and partial response(PR)rate,and disease control rate(DCR),defined as the rate of CR+PR+stable disease(SD).Post-progression survival(PPS)of Cohort 1 and Cohort 2 was defined as the period between the initiation of the combination therapy and either progression or death from any cause.Progression-free survival(PFS)of Cohort 3 was measured from the time of initiation of the combination therapy to progression or death from any cause;overall survival(OS)was defined as the period from the initiation of the combination strategy to death from any cause,or the last follow-up.ResultsTotally 98 advanced NSCLC patients were enrolled.There were 48 patients in Cohort 1,and the median PPS was 11.4 months(95%CI 7.368-15.492).The ORR was 8.3%(0 CR,3PR;3/36 patients with at least one measurable lesion),and the DCR was 86.1%(0 CR,3PR,28 SD;31/36).There were 20 patients in Cohort 2,and the median PPS was 6.5 months(95%CI 3.799-9.281).The ORR was 5.0%(0 CR,1PR;1/20),and the DCR was 85.0%(0 CR,1PR,16 SD;17/20).Grade 3 adverse events occurred in 20.0%of patients(4/20),including fatigue,short of breath,cerebrovascular event,and diarrhea.There were 30 patients in Cohort 3,the median PFS was 5.0 months(95%CI 3.179-6.821),and the median OS was 14.3 months(95%CI 8.912-19.659).The ORR was 10.3%(0 CR,3PR;3/29 patients with at least one measurable lesion),and the DCR was 86.1%(0 CR,3PR,18 SD;21/29).Patients with programmed cell death-ligand 1(PD-L1)expression of at least 1%of tumor cells had a relatively longer mPFS compared to those with PD-L1-negative(11.6 months vs.3.7 months,HR=0.626,95%CI 0.200-1.964,P>0.05).Treatment was suspended in two patients due to grade 3 immune-related pneumonia and pancreatitis,respectively.ConclusionThe continuation of EGFR-TKI in combination of bevacizumab or anlotinib is a feasible strategy in EGFR-mutant advanced NSCLC who had gradual progression after EGFR-TKI treatment,and the combination of PD-1 inhibitors and anti-angiogenic agents may be beneficial for patients with advanced NSCLC as subsequent treatment,especially for those with positive PD-L1 expression,and the strategy is well tolerated.BackgroundImmunotherapy in combination of platinum-based chemotherapy in the perioperative setting is promising in reducing the recurrence and death rate and promotes the prognosis of resectable non-small cell lung cancer(NSCLC).This study aims to assess the efficacy and safety of perioperative programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)inhibitor combining with chemotherapy in early-stage or locally advanced NSCLC,and to investigate potential predictive biomarkers.MethodsThis study included stage I-IIIB resectable or potentially resectable NSCLC who required neoadjuvant therapy of PD-1/PD-L1 inhibitor combining with standard chemotherapy after assessment by surgeons.We assessed the radiological regression rate,including objective response rate(ORR),defined as the rate of complete response(CR)+partial response(PR),and disease control rate(DCR),defined as the rate of CR+PR+stable disease(SD);the pathological remission rate,including major pathological response(MPR)rate and pathological complete response(pCR)rate.The disease-free survival(DFS),event-free survival(EFS),overall survival(OS),and safety were also assessed.The investigational biomarkers included circulating tumor DNA(ctDNA)monitoring and macrophage detection using multiple immunofluorescence(mIF)assay.ResultsDuring the period of Nov.14th,2018 to Jul.9th,2022,56 NSCLC patients have been included,and over a half of these patients were lung squamous cell carcinoma(LUSC;36/56,64.3%),32.1%of patients were lung adenocarcinoma(LUAD;18/56),and two patients were diagnosed as adenosquamous carcinoma(3.6%).There were 51.8%of stageⅢA disease(29/56),and 32.1%of stage ⅢB(18/56).Totally 42 patients(75.0%)have received resection after neoadjuvant therapy,with an R0 resection rate of 100.0%.Among them,14 patients had pCR(14/42,33.3%),and 23 patients had MPR(23/42,54.8%).The radiological assessment of 42 patients prior to resection showed 2 CR(2/42,4.8%),21 PR(21/42,50.0%),and 19 SD(19/42,45.2%);the ORR was 54.8%(23/42)and the DCR was 100.0%(42/42).The pathological regression rates were significantly higher in 25 LUSC patients than in 15 LUAD patients who had resection.The pCR rate was 48.0%and 13.3%,respectively(P=0.026),and the MPR rate was 80.0%and 20.0%,respectively(P<0.001).Until the cutoff date of Mar.21st,2023,the median period of follow-up was 19.0 months in all enrolled patients(range 8.6-39.4 months),and the data of EFS,DFS,and OS was not matured.Any grade of adverse events that were related to immunochemotherapy occurred in 32.1%of patients(18/56),among whom 6 patients had grade 3 or higher adverse events(10.7%),including rash in 3 patients,myelosuppression in 2 patient,and increased liver transaminase in 1 patient.Among the patients who had a positive result in baseline ctDNA,4 patients had ctDNA clearance after perioperative treatment and achieved a favorable response(MPR/pCR).Among 14 baseline samples tested by mIF,the difference value of M1 and M2 macrophage in MPR group(n=7)was smaller than that in non-MPR group(n=7),with the median density of 25/mm2 and 152/mm2(P=0.749).ConclusionPerioperative PD-1/PD-L1 inhibitor combining with platinum-based chemotherapy is a promising strategy for stage Ⅰ-ⅢB resectable or potentially resectable NSCLC,especially for LUSC patients,with a favorable efficacy and tolerable safety profile.The predictive biomarkers are still worth of investigation.