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投稿时间：2025-05-04 网络发布日期：2026-03-04
投稿时间：2025-05-04 网络发布日期：2026-03-04
中文摘要: 目的 明确非小细胞肺癌（NSCLC）患者接受程序性死亡受体1（PD-1）及其配体（PD-L1）抑制剂治疗后发生获得性耐药的关键影响因素，并构建多因素预测模型，为临床个体化免疫治疗提供参考。方法 回顾性纳入2020年1月至2023年12月于河北北方学院附属第一医院接受PD-1/PD-L1免疫检查点抑制剂治疗的晚期NSCLC患者共214例。依据免疫相关实体瘤反应评估标准（iRECIST），初始疾病控制后再次出现进展者定义为获得性耐药。根据是否出现获得性耐药分为耐药组（n=113）与持续获益组（n=101），并按7∶3比例分为训练集（n=150）与验证集（n=64）。收集临床资料、肿瘤特征、治疗策略及免疫相关不良事件（irAEs）等变量，采用logistic回归筛选独立危险因素，构建列线图模型，并以受试者工作特征（ROC）曲线、C指数及Bootstrap法进行列线图模型的内部验证和外部验证。结果 多因素logistic 回归分析显示，ECOG 评分≥2分（OR=2.564，P=0.006）、肝转移（OR=2.312，P=0.014）、PD-L1表达<1%（OR=1.988，P=0.041）、肿瘤突变负荷（TMB）<7.5 muts/Mb（OR=2.439，P=0.011）、未发生irAEs（OR=2.076，P=0.027）为获得性耐药的独立危险因素。列线图模型在训练集曲线下面积（AUC）为0.842，C指数为0.834，Hosmer-Lemeshow检验P=0.571，Bootstrap验证C指数为0.826；验证集AUC为0.813，C指数为0.808。结论 基于五因素构建的列线图模型，表现出良好判别力与稳定性，可辅助临床早期识别易发生对PD-1/PD-L1抑制剂获得性耐药的NSCLC高风险患者，优化个体化免疫治疗策略。
中文关键词: 非小细胞肺癌 免疫治疗 程序性死亡受体1/程序性死亡配体1抑制剂 获得性耐药 肿瘤突变负荷
Abstract:Objective To identify key risk factors associated with acquired resistance to programmed death protein 1（PD-1）and its ligand（PD-L1）inhibitors in patients with non-small cell lung cancer（NSCLC），and to construct a multivariable predictive nomogram to support individualized immunotherapy management. Methods A retrospective study was conducted on 214 patients with advanced NSCLC who received PD-1/PD-L1 immune checkpoint inhibitors at The First Affiliated Hospital of Hebei North University from January 2020 to December 2023. Acquired resistance was defined as disease progression after initial disease control，based on immune Response Evaluation Criteria in Solid Tumors（iRECIST）. According to whether acquired resistance occurred，214 patients were categorized into a resistance group（n=113）and a sustained benefit group（n=101），and randomly assigned to a training set（n=150）and a validation set（n=64）in a 7 to 3 ratio. Clinical characteristics，tumor profiles，treatment regimens，and immune-related adverse events（irAEs）were collected. Logistic regression analyses were used to identify independent risk factors and construct a nomogram model，and the internal and external validation of the nomogram model was performed using receiver operating characteristic（ROC）curve，concordance index（C-index），and the Bootstrap. Results Multivariate logistic regression analysis identified that an ECOG score ≥2（OR=2.564，P=0.006），liver metastasis（OR=2.312，P=0.014），PD-L1 expression<1%（OR=1.988，P=0.041），tumor mutation burden（TMB）<7.5 muts/Mb（OR=2.439，P=0.011），and absence of irAEs（OR=2.076，P=0.027）were independent risk factors for acquired resistance. The nomogram model showed an AUC of 0.842 and a C-index of 0.834 in the training set，with a Hosmer-Lemeshow test P value of 0.571，and a Bootstrap-validated C-index of 0.826；in the validation set，the AUC was 0.813 and the C-index was 0.808. Conclusion The nomogram model constructed based on the five factors demonstrates good discrimination and stability，and can assist in the early clinical identification of NSCLC patients at high risk of developing acquired resistance to PD-1/PD-L1 inhibitors，thereby optimizing individualized immunotherapy strategies.
keywords: Non-small cell lung cancer Immunotherapy Programmed death protein 1/ programmed death ligand- 1 inhibitor Acquired resistance Tumor mutation burden
文章编号： 中图分类号：R734.2 文献标志码：A
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附件
| 作者 | 单位 |
| 赵丽娜 | 1. 河北北方学院附属第一医院呼吸科, 河北 张家口 075000 |
| 王朝阳 | 2. 河北北方学院附属第一医院心内科, 河北 张家口 075000 |
| 王布 | 1. 河北北方学院附属第一医院呼吸科, 河北 张家口 075000 |
| Author Name | Affiliation |
| ZHAO Lina*，WANG Zhaoyang，WANG Bu | *Department of Respiratory Medicine,The First Affiliated Hospital of Hebei North University,Zhangjiakou,Hebei 075000,China |
引用文本：
赵丽娜,王朝阳,王布.非小细胞肺癌患者PD-1/PD-L1抑制剂治疗后获得性耐药的影响因素及预测模型[J].中国临床研究,2026,39(2):221-225.
赵丽娜,王朝阳,王布.非小细胞肺癌患者PD-1/PD-L1抑制剂治疗后获得性耐药的影响因素及预测模型[J].中国临床研究,2026,39(2):221-225.