Zhu W J, Zhu H H, Liu Y T, Lin L, Xing P Y, Hao X Z, Cong M H, Wang H Y, Wang Y, Li J L, Feng Y, Hu X S
Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Zhonghua Zhong Liu Za Zhi. 2022 May 23;44(5):416-424. doi: 10.3760/cma.j.cn112152-20210709-00504.
To describe the actual efficacy of programmed death-1 (PD-1)/ programmed-death ligand 1 (PD-L1) inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) and explore potential prognostic predictive biomarkers. Patients with metastatic NSCLC who were treated with PD-1/PD-L1 inhibitors at Cancer Hospital, Chinese Academy of Medical Sciences from January 2016 to December 2019, either as monotherapy or in combination with other agents, were consecutively enrolled into this study. We retrospectively collected the data of demographics, clinical information and pathologic assessment to evaluate the therapeutic efficacy and conduct the survival analysis. Major endpoint of our study is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). The ORR of 174 patients who underwent PD-1/PD-L1 inhibitor was 28.7%, and the DCR was 79.3%. Immune-related adverse events (irAEs) occurred in 23 patients (13.2%). Brain metastasis, line of treatment, and treatment patterns were associated with the ORR of metastatic NSCLC patients who underwent immunotherapy (<0.05). After a median follow-up duration of 18.8 months, the median PFS was 10.5 months (ranged from 1.5 to 40.8 months) while the median OS was not reached. The 2-year survival rate was estimated to be 63.0%. The pathologic type was related with the PFS of metastatic NSCLC patients who underwent immunotherapy (=0.028). Sex, age, brain metastasis and autoimmune diseases were associated with OS (<0.05). Analysis of the receptor characteristic curve (ROC) of neutrophil/lymphocyte ratio (NLR) predicting ORR of immunotherapy in metastatic NSCLC showed that the areas under the curve of NLR before immunotherapy (NLR(C0)), NLR after one cycle of immunotherapy (NLR(C1)) and ΔNLR were 0.600, 0.706 and 0.628, respectively. Multivariate logistic regression analysis showed that NLR(C1) was an independent factor of the ORR of metastatic NSCLC patients who underwent immunotherapy (=0.161, 95% 0.062-0.422), and the efficacy of combination therapy was better than that of single agent (=0.395, 95% 0.174-0.896). The immunotherapy efficacy in patients without brain metastasis was better than those with metastasis (=0.291, 95% 0.095-0.887). Multivariate Cox regression analysis showed that NLR(C1) was an independent influencing factor of PFS of metastatic NSCLC patients after immunotherapy (=0.480, 95% 0.303-0.759). Sex (=0.399, 95% 0.161-0.991, =0.048), age (=0.356, 95% 0.170-0.745, =0.006) were independent influencing factors of OS of metastatic NSCLC patients after immunotherapy. PD-1/PD-L1 inhibitors are proved to be efficacious and have tolerable toxicities for patients with metastatic NSCLC. Patients at advanced age could still benefit from immunotherapy. Brain metastasis is related to compromised response. Earlier application of immunotherapy in combination with other modalities enhances the efficacy without elevating risk of irAEs. NLR(C1) is an early predictor of clinical outcome. The OS of patients younger than 75 years may be improved when treated with immunotherapy.
描述程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）抑制剂在转移性非小细胞肺癌（NSCLC）患者中的实际疗效，并探索潜在的预后预测生物标志物。2016年1月至2019年12月在中国医学科学院肿瘤医院接受PD-1/PD-L1抑制剂治疗的转移性NSCLC患者，无论是单药治疗还是与其他药物联合治疗，均连续纳入本研究。我们回顾性收集了人口统计学、临床信息和病理评估数据，以评估治疗效果并进行生存分析。本研究的主要终点是无进展生存期（PFS）。次要终点包括客观缓解率（ORR）、疾病控制率（DCR）和总生存期（OS）。174例接受PD-1/PD-L1抑制剂治疗的患者的ORR为28.7%，DCR为79.3%。23例患者（13.2%）发生了免疫相关不良事件（irAEs）。脑转移、治疗线数和治疗模式与接受免疫治疗的转移性NSCLC患者的ORR相关（<0.05）。中位随访时间为18.8个月后，中位PFS为10.5个月（范围为1.5至40.8个月），而中位OS未达到。估计2年生存率为63.0%。病理类型与接受免疫治疗的转移性NSCLC患者的PFS相关（=0.028）。性别、年龄、脑转移和自身免疫性疾病与OS相关（<0.05）。中性粒细胞/淋巴细胞比值（NLR）预测转移性NSCLC免疫治疗ORR的受体特征曲线（ROC）分析显示，免疫治疗前NLR（NLR(C0)）、免疫治疗一个周期后NLR（NLR(C1)）和ΔNLR的曲线下面积分别为0.600、0.706和0.628。多因素逻辑回归分析显示，NLR(C1)是接受免疫治疗的转移性NSCLC患者ORR的独立因素（=0.161，95% 0.062-0.422），联合治疗的疗效优于单药治疗（=0.395，95% 0.174-0.896）。无脑转移患者的免疫治疗疗效优于有脑转移患者（=0.291，95% 0.095-0.887）。多因素Cox回归分析显示，NLR(C1)是免疫治疗后转移性NSCLC患者PFS的独立影响因素（=0.480，95% 0.303-0.759）。性别（=0.399，95% 0.161-0.991，=0.048）、年龄（=0.356，95% 0.170-0.745，=0.006）是免疫治疗后转移性NSCLC患者OS的独立影响因素。PD-1/PD-L1抑制剂被证明对转移性NSCLC患者有效且毒性可耐受。老年患者仍可从免疫治疗中获益。脑转移与反应受损有关。免疫治疗与其他方式更早联合应用可提高疗效而不增加irAEs风险。NLR(C1)是临床结局的早期预测指标。免疫治疗可改善75岁以下患者的OS。
