晚期肺腺癌表皮生长因子受体突变阳性靶向耐药后免疫治疗预后列线图的建立及验证

Establishment and verification of nomogram prognostic model of immunotherapy after epidermal growth factor receptor mutant advanced lung adenocarcinoma resistance to targeted drugs

目的探讨影响表皮生长因子受体(EGFR)突变的晚期肺腺癌患者靶向耐药后行免疫检查点抑制剂(ICI)治疗疗效及预后因素,建立肺腺癌靶向耐药后ICI治疗预后列线图。方法回顾性分析2018-01-01-2021-12-31哈尔滨医科大学附属肿瘤医院收治的EGFR突变患者靶向治疗耐药后行ICI治疗的72例肺腺癌患者的临床资料,采用单因素及多因素Cox分析影响患者生存的独立预后因素,建立基于总生存期的列线图预后模型,并通过一致性指数(C-index)、时间依赖性受试者工作特征曲线、重抽样检验内部验证、决策曲线分析、风险得分图及风险分组生存分析来评估模型的有效性。结果多因素分析显示,免疫治疗前中性粒细胞与淋巴细胞比值(P=0.004)、红细胞体积分布宽度(P=0.006)、淋巴细胞与单核细胞比值(P=0.019)及免疫治疗后出现不良反应(P=0.035)是影响预后的独立因素。总生存期C-index为0.799(95%CI:0.734~0.864)。淋巴细胞与单核细胞比值>3.38、红细胞体积分布宽度≤13.65%、中性粒细胞与淋巴细胞比值≤2.85及免疫治疗后出现不良反应与患者预后有正向关联性,均P<0.05。高风险组中位总生存期及中位无进展生存期分别为7.45(95%CI:5.1~9.9)和2.25个月(95%CI:1.8~4.4)。结论免疫治疗前基线中性粒细胞与淋巴细胞比值、红细胞体积分布宽度、淋巴细胞与单核细胞比值及免疫治疗后有无免疫不良反应可以作为靶向耐药后接受免疫治疗的肺腺癌患者独立预后因素。依此建立的列线图预后模型内部验证的准确性较高。

Objective To explore the prognostic factors that affect the therapeutic effect of immune checkpoint inhibitor(ICI) in patients with epidermal growth factor receptor(EGFR)-mutant advanced lung adenocarcinoma who were resistant to targeted drugs, and to establish a nomogram of ICI.Methods We retrospectively analyzed the clinical data of 72 patients with advanced lung adenocarcinoma with EGFR-mutant who was resistance to EGFR-TKI treatment in the Cancer Hospital of Harbin Medical University from 1 January 2018 to 31 December 2021.Univariate and multivariate Cox analysis was carried out to analyze the independent prognostic factors affecting survival.The prediction nomogram model was established based on overall survival(OS).The effectiveness of the model was evaluated by the consistency index, time-dependent receiver operating characteristic(td-ROC) curves, Bootstrap internal verification, decision curve analysis risk score curve, and risk group analysis.Results Multiple Cox regression analysis showed the baseline of neutrophil-to-lymphocyte ratio(NLR,P=0.004),red blood cell distribution width(RDW,P=0.006),lymphocyte-to-monocyte ratio(LMR,P=0.019) and immune-related adverse event(irAE,P=0.035) were independent prognostic factors affecting the prognosis of patients.The nomogram model based on Cox multiple regression made the prediction model more convenient for evaluating patients in clinical work.The C-index of OS was 0.799(95%CI:0.734-0.864).LMR>3.38,RDW≤13.65%,NLR≤2.85,or irAEs were favorably associated with significantly better OS(P<0.05).The median OS and median progression free survival(PFS) in the high-risk group were 7.45 months(95%CI:5.1-9.9) and 2.25 months(95%CI:1.8-4.4).Conclusions The baseline NLR,RDW,LMR before immunotherapy and whether there is the irAEs after immunotherapy can be used as independent prognostic factors in patients with lung adenocarcinoma who receive immunotherapy after targeted drug resistance.The established nomogram prognostic model has high accuracy in internal verification.