A Clinical Study Of Anti-PD-1 Antibody Combined With Pemetrexed As Second-or Further-line Treatment For Advanced Refractory Lung Adenocarcinoma

Background and ObjectiveIn the world,the morbidity and mortality of lung cancer is the highest.Non-small cell lung cancer(NSCLC)accounts for approximately 80%of all lung cancer cases,and the 5-year survival rate is less than 15%.In NSCLC,the majority of pathological types are lung adenocarcinoma.The treatment of advanced lung adenocarcinoma is mainly chemotherapy,radiotherapy and targeted therapy.Despite the advent of targeted therapies and improvements in traditional therapies,disease progression and drug resistance are inevitable.Therefore,it is necessary to explore new treatment methods.In recent years,with the development of immune checkpoint inhibitors(ICIs),advanced cancer has entered the era of immunotherapy.In particular,anti-PD-1/PD-L1 antibody drugs have become an important method for the treatment of lung cancer.However,data have shown that in unselected patients,the effectiveness of-single drug PD-1 antibody is limited,and the objective response rate is less than 20%.Therefore,a reasonable combination of treatment strategy is essential.Some chemotherapy drugs can increase anti-tumor immune monitoring function,enhance T cell activity,and induce tumor cell death.Chemotherapeutic drugs enhance the function of immune cells by reducing the number of regulatory T cells and inducing dendritic cells to mature,thus improving the anti-tumor capacity of human body.Therefore,chemotherapy combined with anti-PD-1 antibody should have synergistic anti-tumor effect.The purpose of this study was to evaluate the clinical efficacy and safety of anti-PD-1 antibody combined with pemetrexed in the treatment of advanced refractory lung adenocarcinoma.MethodsA total of 30 patients with advanced lung adenocarcinoma who were admitted to the Affiliated Cancer Hospital of Zhengzhou University(Henan Cancer Hospital)from November 2017 to January 2020 were selected.All included patients were pathologically or cytologically diagnosed as lung adenocarcinoma,whether or not genes such as EGFR or ALK are mutated and clinical staging for ⅢB or Ⅳ period,with an ECOG score of 0 to 3,and at least first-or further-line treatment failed.All patients were treated with pemetrexed(500mg/m2)combined with anti-PD-1 antibodies every 21 days for at least 4 cycles until disease progression or intolerable adverse reactions occurred.The imaging data within 1 month before enrollment were taken as the baseline,and imaging examination was performed every 2 cycles.The disease was evaluated by standard iRECIST evaluation criteria for solid tumor immune efficacy,and adverse events during treatment were recorded.The evaluation indicators included short-term efficacy(objective response rate ORR,disease control rate DCR)and long-term effi cacy(progression-free survival PFS and overall survival OS).The factors affecting prognosis and the changes of immune function in patients with partial regression were analyzed.ResultsA total of 30 patients were evaluated,and 3 patients lost follow-up.Among them,14 cases achieved PR(46.67%),12 cases SD(40.00%),and 4 cases PD(13.33%).The ORR was 46.67%,DCR was 86.67%,the median PFS was 6.2 months,and the median OS was 11.2 months.No treatment-related deaths in 30 patients,grade 1 bone marrow suppression was observed in 12 patients,and 3 appeared grade 2 bone marrow suppression,10 appeared grade 1 immune associated pneumonia,1 case appeared grade 2 immune associated diarrhea patients and 4 appeared grade 1 rash,no grade 3/4 adverse reactions occur.Gender.ECOG score and NLR(neutrophil-lymphocyte ratio)were independent factors affecting the prognosis of combined therapy.Analysis of peripheral blood immune cells showed that the number of natural killer(NK)cells increased after the combined treatment,the number of B cells and the proportion of PD-1+ in peripheral blood mononuclear cells(PD-I+/PBMC)decreased,both of which were statistically significant(P<0.05).ConclusionsAnti-PD-1 antibody combined with pemetrexed as second-or further-line treatment for advanced refractory lung adenocarcinoma has certain clinical benefits and well tolerance with no obvious adverse reactions;and the patients with gender of female,ECOG score of 0 to 1 and low NLR had better prognosis.After receiving PD-1 antibody combined with pemetrexed,the number of NK cells increased,the number of B cells and PD-1+/PBMC decreased in patients with partial response.