Clinical Efficacy And Safety Of Sintilimab In Patients With Advanced Non-small-cell Lung Cancer: A Real-world Study

Objective:Non-small-cell lung cancer（NSCLC）is the most common type of lung cancers that are the most malignant tumors with the high morbidity and mortality worldwide.By the time most patients are diagnosed with NSCLC,their disease has progressed to an unresectable locally advanced stage or distant metastases,thus losing the opportunity for surgery.After China officially entered the era of tumor immunotherapy in 2018,the treatment options for unresectable locally advanced and metastatic NSCLC are no longer limited to radiotherapy,chemotherapy and targeted therapy.Furthermore,treatment strategies for immune checkpoint inhibitors（ICIs）in the NCCN guidelines and CSCO guidelines continue to be updated,bringing new light to NSCLC patients.Currently,immune consolidation therapy after concurrent radiotherapy is a Class I recommendation for unresectable stage III patients.For stage IV NSCLC patients with negative driver genes,first-line immunotherapy includes monotherapy and combination two-drug chemotherapy,and the immunotherapy monotherapy is also recommended as a second-line treatment strategy.Sintilimab injection(Daboshu^<sup>?)is the first PD-1 inhibitor originally developed in China.Compared with pembrolizumab or nivolumab,sintilimab has a potentially greater affinity against PD-1.Taking into account the real situation,e.g.,the lack of effective treatment options for NSCLC,the potential benefits of sintilimab in its clinical trials,and the economic conditions of different patients,although Daboshu has not yet been approved for the treatment of NSCLC,many patients choose sintilimab for their treatment of NSCLC.Based on retrospective analysis,this study investigated the clinical efficacy and safety of sintilimab in the treatment of unresectable locally advanced and metastatic NSCLC in the real world,so as to provide a useful reference for clinical medication for NSCLC.Method:Based on case review through the medical record system,telephone follow-up,and follow-up visits,65 patients with unresectable locally advanced and metastatic NSCLC treated with sintilimab at the First Affiliated Hospital of Dalian Medical University and the Second Affiliated Hospital of Dalian Medical University from April 1,2019,to September 31,2020,were followed up until the patients experienced disease progression,died,or reached the follow-up cut-off date（January 31,2021）.The primary study endpoints are progression-free survival（PFS）and safety,and the secondary study endpoints include disease control rate（DCR）,objective response rate（ORR）,durable clinical benefit（DCB）,and overall survival（OS）.SPSS software（Version 26;IBM Corp,Armonk,NY）was used to perform statistical analysis of the collected data.Specifically,the Kaplan-Meier method was applied to plot survival curves,the Log-Rank test was applied to analyze differences between groups,the COX model was applied to perform multifactorial regression analysis,and the chi-square test was applied to analyze the ORR between the epidermal growth factor receptor（EGFR）expression status,where p<0.05 represents statistical significance.Results:1)In terms of the primary study endpoint,the median PFS was 9.57 months（95%CI,8.12 to 11.02 months）.In terms of secondary study endpoints,DCR was47.7%,ORR was 32.3%,DCB was 70.8%（46/65）.Moreover,27（41.5%）patients remained progression-free during follow-up,and the median OS was 14.32 months（95%CI,12.71 to 15.93 months）,10 patients（15.4%）died,and 55 patients（84.6%）are still alive.2)Univariate analysis of PFS showed that age,PD-L1 expression status,and number of drug lines were statistically correlated with PFS（p<0.05）;while gender,ECOG score,pathological type,tumor stage,presence of brain metastasis,the status of EGFR/ALK/ROS1 genes,and drug administration mode were not statistically correlated with PFS（p>0.05）.3)On multifactor analysis for PFS,COX multifactor analysis was performed on factors with p<0.15 in univariate analysis and those clinically considered to be associated with PFS.It was found that patients with PD-L1≥1%,combination chemotherapy and anti-angiogenic therapy had longer PFS（p<0.05）,and the PFS benefit was not significant in patients with third-line and after third-line treatment（p<0.05）.4)In terms of differences in efficacy between EGFR gene status,the results of ORR rate analysis using the chi-square test for patients with positive and negative EGFR were 16.7%（1/6）and 32.3%（10/31）,respectively,with no statistical difference（p>0.05）.5)The adverse event analysis showed that the overall incidence of adverse events was 76.9%（50/65）in 65 patients,most of whom reported symptoms of grade1–2 with an incidence of 76.9%（50/65）,while the incidence of grade 3-4 symptoms was 15.4%（10/65）.Furthermore,for the 18 patients using Sintilimab,the incidence of immune-related adverse events（ir AE）was 72.2%（13/18）and the incidence of grade3-4 symptoms was 27.8%（5/18）;among the 33 patients who underwent combination chemotherapy,the incidence of adverse events was 51.5%（17/33）and the incidence of grade 3-4 symptoms was 12.1%（4/33）;in 11 cases treated with combined anti-angiogenic therapy,the incidence of adverse events was 36.4%（4/11）and the incidence of grade 3-4 symptoms was 9.1%（1/11）;in 3 cases treated with combined chemotherapy+anti-angiogenic therapy,the incidence of adverse events was 66.7%（2/3）,all of which were grade 1-2.It should be noted that 7 patients discontinued due to adverse reactions and 2patients died due to ir AE,while the remaining adverse events were within control limits.The median PFS of patients with adverse events with sintilimab versus those without adverse events was 10.57 months versus 6.00 months,which was not statistically different（p>0.05）.Moreover,three adverse events,rash（14 cases,21.5%）,immune pneumonia（12 cases,18.4%）,and hypothyroidism（6 cases,9.2%）,did not correlate with PFS（p>0.05）.Conclusions:1)The real-world study confirmed the favorable efficacy of sintilimab in patients with unresectable locally advanced and metastatic NSCLC.2)PD-L1 expression status can be potentially helpful in clinical screening the advantageous population that could benefit from sintilimab treatment.3)Treatment with immunologic agents+chemotherapy+anti-angiogenic drug therapy can be an option for patients with good physical status,back-line therapy or rapid tumor growth.4)The real-world study showed that the majority of adverse events occurring with sintilimab in patients with unresectable locally advanced and metastatic NSCLC were grade 1-2,and most of the grade 3-4 adverse events were also within manageable limits.