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程序性死亡蛋白1/程序性死亡蛋白配体1抑制剂治疗晚期非小细胞肺癌的疗效及疗效和预后预测标志物的真实世界研究

Real-world study on the efficacy and prognostic predictive biomarker of patients with metastatic non-small cell lung cancer treated with programmed death-1/programmed death ligand 1 inhibitors

摘要:

目的:探讨程序性死亡蛋白1(PD-1)/程序性死亡蛋白配体1(PD-L1)抑制剂治疗晚期非小细胞肺癌(NSCLC)的疗效,并探索疗效和预后预测的标志物。方法: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抑制剂单药治疗或PD-1/PD-L1抑制剂联合其他全身药物治疗的晚期转移性NSCLC患者174例,收集患者的人口学、临床病理及生存资料,评估疗效并进行生存分析,主要终点为无进展生存时间(PFS),次要终点包括客观缓解率(ORR)、疾病控制率(DCR)及总生存时间(OS)。结果:174例患者接受PD-1/PD-L1抑制剂治疗后ORR为28.7%,DCR为79.3%。23例(13.2%)出现免疫相关不良反应。脑转移、治疗线数、治疗模式与晚期转移性NSCLC患者免疫治疗的客观疗效有关(均 P<0.05)。中位随访18.8个月,174例患者的中位PFS为10.5个月,中位OS未达到,2年生存率为63.0%。病理类型与晚期转移性NSCLC患者免疫治疗的PFS有关( P=0.028),性别、年龄、脑转移、自身免疫性疾病与OS有关(均 P<0.05)。中性粒细胞与淋巴细胞比值(NLR)预测晚期转移性NSCLC免疫治疗客观疗效的受试者工作特性曲线分析显示,免疫治疗前NLR(NLR C0)、第1周期免疫治疗后NLR(NLR C1)和ΔNLR的曲线下面积分别为0.600、0.706和0.628。多因素logistic回归分析显示,NLR C1为晚期转移性NSCLC免疫治疗客观疗效的独立影响因素( OR=0.161,95% CI为0.062~0.422),与单药免疫治疗相比,联合治疗疗效更优( OR=0.395,95% CI为0.174~0.896),不合并脑转移者免疫治疗疗效较好( OR=0.291,95% CI为0.095~0.887)。多因素Cox回归分析显示,NLR C1为晚期转移性NSCLC免疫治疗后PFS的独立影响因素( HR=0.480,95% CI为0.303~0.759),性别( HR=0.399,95% CI为0.161~0.991, P=0.048)、年龄( HR=0.356,95% CI为0.170~0.745, P=0.006)为晚期转移性NSCLC免疫治疗后OS的独立影响因素。 结论:晚期转移性NSCLC患者接受PD-1/PD-L1抑制剂治疗安全、有效,高龄患者仍可从免疫治疗中获益,合并脑转移者免疫治疗有效率下降。较早应用免疫治疗、免疫联合治疗可提高疗效,且不增加治疗相关不良反应。NLR C1可早期预测晚期转移性NSCLC免疫治疗的疗效和PFS。<75岁的男性患者免疫治疗后可能有望改善OS。

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abstracts:

Objective: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.Methods: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).Results: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 ( P<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 ( P=0.028). Sex, age, brain metastasis and autoimmune diseases were associated with OS ( P<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 ( OR=0.161, 95% CI: 0.062-0.422), and the efficacy of combination therapy was better than that of single agent ( OR=0.395, 95% CI: 0.174-0.896). The immunotherapy efficacy in patients without brain metastasis was better than those with metastasis ( OR=0.291, 95% CI: 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 ( HR=0.480, 95% CI: 0.303-0.759). Sex ( HR=0.399, 95% CI: 0.161-0.991, P=0.048), age ( HR=0.356, 95% CI: 0.170-0.745, P=0.006) were independent influencing factors of OS of metastatic NSCLC patients after immunotherapy. Conclusions: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.

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