【作者】 秦静；

【导师】 王秀问； 刘延国；

【作者基本信息】 山东大学 ， 肿瘤学（专业学位）， 2022， 硕士

【摘要】 目的晚期驱动基因阴性非鳞非小细胞肺癌(non-small cell lung cancer,NSCLC)可选择的一线治疗策略包括化疗、抗血管生成治疗及免疫检查点治疗等。这些治疗方案之间疗效和安全性的差异目前缺乏对比,我们通过网状Meta分析进行了分析和比较,以期为临床治疗策略制定提供依据。方法检索 PubMed、Cochrane Library、Embase 数据库及 ClinicalTrials.gov 网站自从建库到2021年10月15日的晚期驱动基因阴性非鳞NSCLC一线治疗研究,纳入包括化疗、免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)、抗血管生成药物及其联合治疗的 Ⅱ/Ⅲ 期随机对照试验(randomized controlled trial,RCT);使用 StataMP 16.0 及 R 4.1.0软件进行网状Meta分析。结果纳入16个RCT,共8080例非鳞NSCLC患者,涉及16种治疗方案,分别为:化疗(chemotherapy,Che)、纳武利尤单抗(nivolumab,Niv)、西米普利单抗(cemiplimab,Cem)、帕博利珠单抗(pembrolizumab,Pem)、阿替利珠单抗(atezolizumab,Ate)、阿替利珠单抗联合化疗(atezolizumab+chemotherapy,AteChe)、帕博利珠单抗联合化疗(pembrolizumab+chemotherapy,PemChe)、信迪利单抗联合化疗(sintilimab+chemotherapy,SinChe)、卡瑞利珠单抗联合化疗(camrelizumab+chemotherapy,CamChe)、替雷利珠单抗联合化疗(tislelizumab+chemotherapy,TisChe)、贝伐珠单抗联合化疗(bevacizumab+chemotherapy,BevChe)、阿替利珠单抗联合贝伐珠单抗及化疗(atezolizumab+bevacizumab+chemotherapy,AteBevChe)、纳武利尤单抗联合贝伐珠单抗及化疗(nivolumab+bevacizumab+chemotherapy,NivBevChe)、纳武利尤单抗联合伊匹单抗(nivolumab+ipilimumab,NivIpi)、帕博利珠单抗联合伊匹单抗(pembrolizumab+ipilimumab,PemIpi)、纳武利尤单抗联合伊匹单抗及化疗(nivolumab+ipilimumab+chemothrepy,NivIpiChe)。在非鳞 NSCLC 总体人群中,对于 OS,PemChe较 Che 及 Niv 显著延长 OS。对于 PFS,AteBevChe、SinChe、PemChe 及 AteChe 较 Che显著延长 PFS,NivBevChe、AteBevChe 较 BevChe 显著延长 PFS,NivBevChe、AteBevChe、SinChe、PemChe、AteChe 均较 Niv 显著延长 PFS。对于客观缓解率(objective response rate,ORR),PemChe、SinChe、CamChe、TisChe、AteChe 均较 Che 显著提高 ORR,PemChe 较 CamChe、TisChe、AteChe、Che 显著提高 ORR。在 PD-L1<1%亚组,各治疗方案OS和PFS未见显著统计学差异,概率排序居第1位的分别是PemChe和NivBevChe。在 ORR 方面,PemChe、AteChe 的 ORR 显著高于 Che。在 1%≤PD-L1≤49%亚组,各治疗方案OS、PFS及ORR未见显著统计学差异。OS概率排序居第一位的是PemChe,PFS及ORR概率排序居第一位的是SinChe。在PD-L1≥ 50%亚组,各治疗方案OS及PFS未见显著统计学差异。在ORR方面,PemChe、TisChe及SinChe的ORR显著高于Che;PemChe较AteChe显著提高ORR。在所有级别不良反应率方面,CamChe的不良反应率高于Che及SinChe,在≥ 3级不良反应率方面,各治疗方案无显著统计学差异。结论在晚期驱动基因阴性非鳞NSCLC患者,PemChe方案在各PD-L1表达亚组中疗效及安全性均较好。虽然不同一线治疗方案在各PD-L1表达亚组的OS及PFS未见显著差异,但免疫联合化疗方案在PD-L1<1%及PD-L1≥50%亚组的有效率较化疗显著提高;且在PD-L1≥50%亚组,PemChe相对于AteChe有效率显著提高。对于晚期驱动基因阴性非鳞NSCLC患者,化疗、抗血管生成联合化疗、免疫单药、免疫联合化疗、免疫联合抗血管生成及化疗以及双免联合治疗(PD-Ⅰ抑制剂联合CTLA-4抑制剂)等方案需要根据患者的个体情况进行选择。更多还原

【Abstract】 Objective:The first-line treatment strategies for advanced driver-gene wild-type non-squamous non-small cell lung cancer(NSCLC)include chemotherapy,antiangiogenic therapy and immunotherapy.Currently,there is a lack of comparison of the efficacy and safety between these treatment regimens.Therefore,a network meta-analysis was performed to evaluate this issue.Methods:PubMed,Cochrane Library,Embase database and ClinicalTrials.gov website were searched for first-line treatment trials of advanced driver-gene wild-type non-squamous NSCLC from inception to 15 October 2021.Phase Ⅱ/Ⅲ randomized controlled trials(RCTs)comparing first-line treatments including chemotherapy,immune checkpoint inhibitors(ICIs),antiangiogenic therapy and their combinations were included.StataMP 16.0 and R 4.1.0 were used for data analysis.Results:A total of 16 RCTs were eventually included,involving 8080 non-squamous NSCLC patients and 16 treatment regimens.The regimens are chemotherapy(Che),nivolumab(Niv),cemiplimab(Cem),pembrolizumab(Pem),atezolizumab(Ate),atezolizumab+chemotherapy(AteChe),pembrolizumab+chemotherapy(PemChe),sintilimab+chemotherapy(SinChe),camrelizumab+chemotherapy(CamChe),tislelizumab+chemotherapy(TisChe),bevacizumab+chemotherapy(BevChe),atezolizumab+bevacizumab+chemotherapy(AteBevChe),nivolumab+bevacizumab+chemotherapy(NivBevChe),nivolumab+ipilimumab(NivIpi),pembrolizumab+ipilimumab(PemIpi)and nivolumab+ipilimumab+chemothrepy(NivIpiChe).In the general population of non-squamous NSCLC,the overall survival(OS)of PemChe was significantly longer than that of Che and Niv.For progression-free survival(PFS),AteBevChe,SinChe,PemChe and AteChe were significantly longer than Che;NivBevChe and AteBevChe were significantly longer than BevChe;NivBevChe,AteBevChe,SinChe,PemChe and AteChe were significantly longer than Niv.In the subgroup of programmed death-ligand 1(PD-L1)<1%,there was no significant difference in OS and PFS among the treatment regimens.PemChe and NivBevChe ranked first in probability,respectively.As for objective response rate(ORR),PemChe,SinChe,CamChe,TisChe and AteChe were significantly higher than Che;PemChe was significantly higher than CamChe,TisChe,AteChe and Che.In terms of ORR,PemChe and AteChe were significantly higher than Che.In the 1%≤ PD-L1 ≤ 49%subgroup,there was no significant difference in OS,PFS and ORR among the treatment regimens.PemChe ranked first in probability of OS.SinChe ranked first in probability of PFS and ORR.In the subgroup of PD-L1≥50%,there was no significant difference in OS and PFS among the treatment regimens.The ORR of PemChe,TisChe and SinChe were significantly higher than that of Che.The ORR of PemChe was significantly higher than that of AteChe.In terms of all grade adverse events(AEs),CamChe was higher than Che and SinChe.There was no significant difference in≥3 grade AEs.Conclusions:In patients with advanced driver-gene wild-type non-squamous NSCLC,PemChe was effective and safe in all PD-L1 expression subgroups.Although there was no significant difference in OS and PFS among different PD-L1 expression subgroups,the response rates of immunotherapy+chemotherapy in PD-L1<1%and PD-L1≥50%subgroups were significantly higher than that of chemotherapy.In PD-L1≥50%subgroup,the response rate of PemChe was significantly higher than that of AteChe.For patients with advanced driver-gene wild-type non-squamous NSCLC,chemotherapy,antiangiogenic therapy+chemotherapy,immune monotherapy,immunotherapy+chemotherapy,immunotherapy+antiangiogenic therapy+chemotherapy and double immunotherapy need to be selected according to the individual conditions.更多还原