PD-1/PD-L1抑制剂治疗中晚期非小细胞肺癌疗效及安全性的Meta分析

目的:运用Meta分析方法系统评价PD-1/PD-L1抑制剂治疗中晚期非小细胞肺癌（NSCLC）的疗效及安全性。方法:检索CNKI、万方、Pubmed和Cochrane图书馆数据库,提取数据并进行核对,利用RevMan5.3软件的Cochrane偏倚风险工具,对随机对照试验进行风险评估,并应用该软件进行Meta分析。结果:共纳入7个随机对照试验,包括3 945例患者。Meta 分析结果显示:PD-1/PD-L1抑制剂在总生存期［HR=0.66,95%CI(0.61,0.72),P＜0.000 01］、无进展生存期［HR=0.72,95%CI(0.59,0.87),P=0.000 7］、总有效率［OR=1.91,95%CI(1.31,2.78),P=0.000 7］方面均高于化疗对照组;任何级别不良反应事件［OR=0.32,95%CI(0.25,0.40),P＜0.000 01］和3、4、5级不良反应事件［OR=0.23,95%CI(0.13,0.43),P＜0.000 01］低于化疗对照组。结论:在中晚期NSCLC的治疗中,PD-1/PD-L1抑制剂的疗效以及安全性均优于化疗药物。     

PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的Meta分析

 目的 系统评价PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的疗效及安全性。方法 通过Web of science等国内外数据库，ASCO会议摘要及杂志筛选文献，进行Meta分析。结果 纳入7项RCT研究，4 101例患者，荟萃分析显示抑制剂联合化疗对比化疗可显著延长患者的PFS（HR=0.59, 95%CI: 0.50~0.70, P<0.00001）、OS（HR=0.65, 95%CI: 0.46~0.92, P=0.02）及ORR（RR=1.72, 95%CI: 1.13~2.62, P=0.01）。亚组分析显示，抑制剂联合化疗可显著延长PFS及OS，且PD-L1表达程度越高，疗效获益越显著。而单药抑制剂对比化疗在延长晚期NSCLC患者的PFS（HR=0.87, 95%CI: 0.57~1.31, P=0.50）、OS（HR=0.82, 95%CI: 0.65~1.03, P=0.09）及提高ORR（RR=1.12, 95%CI: 0.55~2.28, P=0.76）方面两组差异无统计学意义。与化疗相比，单药抑制剂一线治疗PD-L1高表达的晚期NSCLC患者可显著延长OS，但在延长PFS方面未见明显优势。与化疗组相比，抑制剂联合化疗组3~4级不良反应发生率无明显改善（HR=1.09，95%CI: 0.99~1.20, P=0.09），而单药PD-1/PD-L1抑制剂组3~4级不良反应发生率低（RR=0.43, 95%CI: 0.36~0.52, P<0.00001）。 结论 PD-1/PD-L1抑制剂联合化疗一线治疗晚期NSCLC患者疗效优于化疗方案；PD-L1高表达者单药PD-1/PD-L1抑制剂可作为一线治疗的优先选择，且具有良好的安全性。     

PD-1抑制剂治疗晚期黑色素瘤疗效的Meta分析

目的:本文旨在系统评价PD-1抑制剂对比化疗及CTLA-4抑制剂治疗晚期黑色素瘤（advanced melanoma）的有效性和安全性,采用Meta分析方法。方法:计算机检索Cochrane图书馆、Pubmed、Embase、CNKI、CBM、万方数据库、维普数据库,作者独立提取资料,并反复核对,运用Cochrane量表评价纳入文献的方法学质量,同时采用RevMan5.3软件进行Meta分析。结果:本文共纳入8个随机对照试验,包括5 533例病例。Meta分析结果显示:PD-1抑制剂相比较于化疗在无进展生存期［HR=0.54,95%CI（0.48,0.60）,P<0.000 01］、总生存期［HR=0.78,95%CI（0.65,0.93）,P=0.005］、客观缓解率［RR=3.60,95%CI(2.70,4.80),P<0.000 01］高于对照组,任何级别不良反应事件［RR=0.90,95%CI(0.86,0.95),P<0.000 1］,3,4,5级不良反应事件［RR=0.50,95%CI(0.42,0.60),P<0.000 01］低于对照组。PD-1抑制剂相比较于CTLA-4抑制剂在无进展生存期［HR=0.59,95%CI(0.52,0.66),P<0.000 01］、总生存期［HR=0.67,95%CI(0.58,0.76),P<0.000 01］、客观缓解率［RR=2.49,95%CI(2.15,2.88),P<0.000 01］高于对照组,任何级别不良反应事件［RR=0.99,95%CI(0.91,1.07),P=0.80］,3,4,5级不良反应事件［RR=0.63,95%CI(0.42,0.96),P=0.03］低于对照组。结论:PD-1抑制剂方案治疗晚期黑色素瘤患者的疗效高于化疗及CTLA-4抑制剂,且安全性优于后者。     

PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌疗效及安全性的Meta分析

目的：系统评价PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌（non-small lung cancer,NSCLC）的疗效及安全性。方法：检索PubMed、Cochrane Library、EMbase、EBSCO循证医学数据库、中国生物医学文献数据库（Chinese Biomedical Literature Database,CBM）、中国知网（Chinese Journal Full-text Database,CNKI）、中文科技期刊全文数据库（VIP）中收录的PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期NSCLC 的随机对照试验（randomized controlled trials,RCTs）,采用RevMan 5.2 软件进行Meta 分析。结果：纳入6 个临床RCTs 共3 238 例晚期NSCLC。Meta 分析结果显示,PD-1/PD-L1 抑制剂联合化疗与化疗相比可显著延长OS（HR=0.86,95%CI=0.79~0.94,P=0.0006）和PFS（HR=0.81,95%CI=0.78~0.84,P<0.00001）;1~5 级血小板计数减少、呕吐、腹泻、甲状腺功能减低或亢进、皮疹、肺炎、结肠炎、肝炎、味觉障碍,3~5 级肝炎的不良反应发生率较化疗组高,差异具有统计学意义（P<0.01 或P<0.05）。结论：PD-1/PD-L1 抑制剂联合化疗较单独化疗一线治疗晚期NSCLC可显著延长患者OS和PFS,但不良反应发生率较化疗高。     

原发性非小细胞肺癌患者PD-1/PD-L1抑制剂相关急性肾损伤的临床特征分析

目的 探讨原发性非小细胞肺癌(NSCLC)患者发生程序性细胞死亡蛋白1(PD-1)和程序性细胞死亡蛋白配体-1(PD-L1)抑制剂相关急性肾损伤(AKI)的相关因素。方法 本研究采用回顾性病例对照研究,共纳入103例接受PD-1/PD-L1抑制剂治疗的原发性NSCLC患者,将患者分为PD-1/PD-L1抑制剂相关AKI组24例和对照组79例。比较AKI组与对照组患者的基本临床特征,采用多因素Logistic回归分析评估PD-1/PD-L1抑制剂相关AKI发生的风险因素。结果 PD-1/PD-L1抑制剂相关AKI组的患者中合并糖尿病和应用利尿剂、非甾体类抗炎药物(NASIDs)、质子泵抑制剂(PPIs)的比例显著高于对照组,基线肾小球滤过率(e GFR)水平显著低于对照组,PD-1/PD-L1抑制剂使用后出现无菌性白细胞尿、血嗜酸性粒细胞计数增多和肾外免疫相关不良事件(ir AEs)的患者比例显著高于对照组(均P<0.05)。多因素Logistic回归分析结果显示,基线e GFR降低(OR=0.968,95%CI:0.946～0.990,P=0.005)、无菌性白细胞尿(OR=7....     

PD-1/PD-L1抑制剂对比常规疗法治疗癌症的有效性和安全性的Meta分析

目的:系统性评价程序性死亡因子1/程序性死亡因子1配体(PD-1/PD-L1)抑制剂对比常规疗法治疗癌症的有效性和安全性。方法:计算机全面检索PubMed、MEDLINE、EMBASE数据库,收集PD-1/PD-L1抑制剂治疗癌症的文献研究,检索时间为2000年1月1日至2019年6月30日。两位研究人员独立收集和整理资料,评价纳入文献研究的偏倚风险,应用Review Manager 5.3软件对纳入研究进行数据整理。结果:最终纳入11项随机对照试验,共6 295例研究对象,其中PD-1/PD-L1抑制剂试验组3 220例,常规疗法药物对照组3 075例。Meta分析结果显示,PD-1/PD-L1抑制剂试验组的客观反应率（ORR）［RR=1.87,95%CI（1.33,2.64）,P＜0.001］、完全缓解率（CR）［RR=2.45,95%CI（1.27,4.73）,P＜0.001］和部分缓解率（PR）［RR=1.81,95%CI（1.28,2.54）,P＜0.001］优于常规疗法对照组,结果均有统计学差异;在疾病控制率（DCR）［RR=1.03,95%CI（0.89,1.20）,P=0.65］和疾病进展率（PD）［RR=1.16,95%CI（0.95,1.40）,P=0.14］方面,两组比较无统计学差异;而在疾病稳定率（SD）［RR=0.72,95%CI（0.63,0.82）,P＜0.001］方面显示常规疗法对照组优于PD-1/PD-L1抑制剂试验组。药物安全性方面,不良反应发生率（AEs）［RR=0.96,95%CI（0.88,1.04）,P=0.28］两组无统计学差异,但在3-5级不良反应发生率［RR=0.44,95%CI（0.28,0.68）,P＜0.001］方面,PD-1/PD-L1抑制剂试验组明显低于常规疗法对照组。结论:PD-1/PD-L1抑制剂与常规疗法药物相比,可明显提高癌症患者临床治疗的ORR、CR和PR,且出现3-5级不良反应发生率更低,从而证实PD-1/PD-L1抑制剂的有效性和安全性优于常规疗法。     

循环肿瘤细胞预测非小细胞肺癌患者预后价值的Meta分析

目的探讨外周血循环肿瘤细胞(CTCs)在预测非小细胞肺癌(NSCLC)患者预后的价值。方法采用计算机检索Pub Med、Embase、Web of Science、Cochrane Library、万方及中国知网等数据库,检索时间为建库至2017年3月1日。采用Rev Man5.3和STATA14.0软件进行分析,使用一般倒方差法对患者总生存期(OS)与无进展生存期(PFS)的风险比(HR)进行数据处理。结果共纳入22项队列研究,总计1 682例NSCLC患者。Meta分析结果:CTCs与NSCLC组织学类型无相关性[OR=1,95%CI(0.64,1.56),P=1.00];CTCs阳性NSCLC患者具有更短的OS[HR=2.27,95%CI(1.94,2.65),P<0.01]和PFS[HR=1.98,95%CI(1.63,2.41),P<0.01]。根据TNM肿瘤分期进行亚组分析发现,在Ⅰ~ⅢA期和ⅢB/Ⅳ期患者中,CTCs阳性患者的OS均低于CTCs阴性患者(P<0.01)。结论外周血CTCs是NSCLC患者的不良预后因素,且不受TNM分期和组织学类型影响。     

非小细胞肺癌组织中PD-1/PD-L1的表达与EGFR突变的关系及其对预后的影响

目的:探讨非小细胞肺癌(non-small cell lung cancer, NSCLC)中程序性死亡受体1(programmed death receptor-1,PD-1)及程序性死亡受体配体1(programmed death receptor ligand-1,PD-L1)的表达和EGFR突变及其与预后的关系。方法:收集2013年01月至2015年12月由我院病理科经组织学诊断为非小细胞肺癌,并完成EGFR突变检测的150例患者的临床资料,应用免疫组织化学方法检测NSCLC组织中PD-1/PD-L1和CD8蛋白表达情况,分析其与临床病理参数及与EGFR突变的相关性,并对影响患者预后的多个临床病理因素进行分析。结果:非小细胞肺癌组织中PD-1/PD-L1和CD8的阳性表达率分别为34.7%(52/150)、50.4%(57/113)和59.2%(84/142)。其中PD-L1的表达与PD-1的表达(P=0.025,r_s=0.211)有关;PD-1的表达与术后病理分期(P=0.031,r_s=-0.177)及EGFR突变(P=0.001,...     

化疗联合PD-1/PD-L1抑制剂治疗三阴性乳腺癌有效性和安全性的Meta分析

目的:利用循证医学手段,通过Meta分析评估化疗联合PD-1/PD-L1 抑制剂与单纯化疗治疗三阴性乳腺癌的安全性和有效性,从而为临床诊疗提供指导意见。方法:检索Pubmed、Embase、Cochrane图书馆、知网、万方、维普和CBM数据库从建库到2021年08月以来有关化疗联合PD-1/PD-L1 抑制剂治疗三阴性乳腺癌的文献。由两位研究者独立完成筛选文献、提取资料以及评估偏倚风险后,采用RevMan 5.3和STATA 15.1软件进行统计分析。结果:本次研究共纳入8篇文献。汇总结果表明联合治疗组患者的总生存期（overall survival,OS）和无进展生存期（progression-free survival,PFS）明显长于仅接受化疗的患者（HR=0.85,95%CI:0.75~0.96;HR=0.84,95%CI:0.73~0.97）。结果还表明联合治疗组患者的(complete remission rate,CRR)也显著高于仅接受化疗治疗的患者（RR=1.44,95%CI:1.10~1.89）。此外,联合治疗组的不良反应发生率高于单纯化疗组（RR=1.08,95%CI:1.03~1.14）。亚组分析的结果显示接受Atezolizumab联合化疗的患者的 OS 明显长于单独接受化疗的患者（HR=0.85,95%CI:0.75~0.96）,接受Atezolizumab或Pembrolizumab与化疗的联合治疗显著延长了患者的PFS（HR=0.80,95%CI:0.73~0.89;HR=0.79,95%CI:0.67~0.92）,然而接受Durvalumab联合化疗的患者OS和PFS较单纯化疗并无显著差异。结论:化疗联合 PD-1/PD-L1 抑制剂治疗三阴性乳腺癌比单独化疗更有效,但联合治疗有着更高的不良反应发生率。此外,Durvalumab与化疗药的联合使用并不能增加患者的OS和PFS。     

晚期非小细胞肺癌PD-1/PD-L1单抗治疗临床转化现状

随着对肿瘤免疫逃逸机制研究的不断深入,通过阻断程序性死亡因子1（programmed cell death 1,PD-1）及其配体l （PD-1 ligand,PD-L1）构成的 PD-1/PD-L1 通路,证实了 PD-1/PD-L1 抑制剂在晚期非小细胞肺癌（non small cell lung cancer, NSCLC）患者生存的相关性,以及PD-L1作为疗效预测标志物的价值。在NSCLC的局部晚期维持治疗、二线治疗及部分一线治 疗的临床试验中,PD-1/PD-L1抑制剂治疗均获得了较好的治疗效果;PD-1/PD-L1抑制剂联合放化疗、联合细胞因子与其他免疫 抑制剂及联合细胞外调节蛋白激酶(extracel lular regulated protein kinase,ERK)通路靶向治疗也有一定获益。本文就PD-1/PD-L1 抑制剂用于NSCLC治疗现状及其影响因素作一综述。     

PD-(L)1 inhibitors vs. chemotherapy vs. their combination in front-line treatment for NSCLC: An indirect comparison

We comprehensively compared the therapeutic effects and safety of PD-1/L1 antibodies (I), chemotherapy (C) or their combination (I + C) as first-line treatments for advanced NSCLC. Online databases were searched to identify RCTs. Survival outcomes and safety events were pooled by indirect treatment comparison. Main subgroup analyses were conducted according to PD-L1 expression. A total of 11 RCTs involving 6,731 patients were included. Overall, PD-1/L1 inhibitors showed no difference to chemotherapy in PFS (HR 0.90, 0.65–1.24) and OS (HR 0.84, 0.64–1.09), while I + C was superior to chemotherapy both in PFS (HR 0.64, 0.58–0.71) and OS (HR 0.74, 0.62–0.89). I + C also showed advantages over PD-1/L1 in PFS (HR 0.71, 0.51–0.99) but not OS (HR 0.88, 0.64–1.22). In the PD-L1 < 1% subgroup, I + C was beneficial both in OS (HR 0.78, 0.67–0.90) and PFS (HR 0.72, 0.65–0.80) than chemotherapy. In PD-L1 ≥ 50% population, PD-1/L1 had longer OS than chemotherapy (HR 0.71, 0.60–0.84); I + C also had longer OS (HR 0.61, 0.49–0.77) and PFS (HR 0.41,0.34–0.49) than chemotherapy. In indirect analysis (PD-L1 ≥ 50%), I + C was superior to PD-1/L1 in terms of PFS (HR 0.54, 0.35–0.82), but not OS (HR 0.86, 0.65–1.14). Both treatment-related and immune-mediated adverse events occurred most frequently in the combination therapy group. We suggest that a combination regimen is preferable as first-line treatment for NSCLC patients with different PD-L1 expression, in the meanwhile, in cautious of side effects.     

Effect of Primary Systemic Therapy on PD-1, PD-L1, and PD-L2 mRNA Expression in Advanced Breast Cancer

Objective: The association between PD-1, PD-L1, and PD-L2 expression and prognosis has been extensively studied in various cancers but remained controversial in breast cancer. Besides, little is known about the prognostic value of PD-1, PD-L1, and PD-L2 upregulation or downregulation following systemic therapy (chemotherapy and hormonal therapy) in breast cancer. Therefore, we aim to investigate the change of PD-1, PD-L1, and PD-L2 expression in mRNA level after primary systemic therapy in breast cancer patients and its clinical implications. Methods: Expression of PD-1, PD-L1, and PD-L2 mRNA were measured before-after chemotherapy and hormonal therapy with real-time PCR in 80 advanced breast cancer patients. The correlation between alteration of PD-1, PD-L1, and PD-L2 expression and clinicopathological characteristics as well as overall survival was also statistically analyzed. Results: Chemotherapy and hormonal therapy altered PD-1, PD-L1, and PD-L2 expression in breast cancer with most patients have an increase expression. As much as 57.1%, 62.9% and 60% patients have an increase PD-1, PD-L1, and PD-L2 expression after chemotherapy, while 60%, 60%, and 64% patients have an increase PD-1, PD-L1, and PD-L2 expression after hormonal therapy. Alteration of PD-1, PD-L1, and PD-L2 expression was not correlated with all clinicopathological characteristics. Increase in PD-1, PD-L1, and PD-L2 expression was significantly associated with better OS (p=0.031, p=0.019, and p=0.019 for PD-1, PD-L1, and PD-L2, respectively), which remained significant in multivariate analysis including age, stage, primary systemic therapy, histology grade, subtype and primary tumor histology (HR PD-1 0.5 (95% CI 0.28-0.88) p=0.031; HR PD-L1 0.43 (95% CI 0.24-0.8) p=0.019; HR PD-L2 (95% CI 0.24-0.87) p=0.019).  Conclusion: Expression of PD-1, PD-L1, and PD-L2 in breast cancer patients is mostly enhanced after chemotherapy and hormonal therapy, and the enhancement is associated with good OS. This result revealed the potential of measuring PD-1, PD-L1, and PD-L2 mRNA expression in predicting clinical outcome.     

肿瘤突变负荷对PD-1/PD-L1抑制剂治疗非小细胞肺癌临床疗效预测的Meta分析

目的 探讨肿瘤突变负荷(TMB)与PD-1/PD-L1抑制剂治疗非小细胞肺癌(NSCLC)疗效的相关性.方法 系统检索PubMed、Embase和Cochrane Library、CNKI、中国生物医学数据库(Chinese Biomedical Literature Database,CBM)和万方数据库,检索日期截...     

Association of PD-L1 expression status with the efficacy of PD-1/PD-L1 inhibitors and overall survival in solid tumours: A systematic review and meta-analysis

Whether PD-L1-positive patients derive more overall survival benefit from PD-1/PD-L1 inhibitors in the treatment of advanced solid tumours is unclear. We systematically searched the PubMed, Cochrane library and EMBASE databases from January 1, 1966 to March 1, 2019, to identify randomised controlled trials of PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab) that had available hazard ratios (HRs) for death according to PD-L1 status. A random-effects model was used to calculate the pooled overall survival (OS) HR and 95% CI among PD-L1-positive and PD-L1-negative patients. An interaction test was performed to evaluate the heterogeneity between the two estimates. A total of 24 randomised trials, involving 12,966 participants, fulfilled the inclusion criteria. An OS benefit of PD-1/PD-L1 inhibitors was found in both PD-L1-positive patients (HR, 0.65; 95% CI, 0.60–0.70) and PD-L1-negative patients (HR, 0.82; 95% CI, 0.74–0.91) even at the minimum cut-off value of 1%. Significant differences in the efficacy of PD-1/PD-L1 inhibitors between PD-L1-positive and PD-L1-negative patients were noted at different cut-off values. Moreover, there was a positive dose–response relationship between PD-L1 positivity and OS benefit (HR for 1%, 0.58, [0.50, 0.67]; 5%, 0.52 [0.43, 0.64]; 10%, 0.50 [0.40, 0.63]). Subgroup analyses showed that these results were generally consistent, regardless of study design, line of treatment, treatment type, tumour type, PD-L1 staining cell type and median follow-up time. We demonstrated that PD-1/PD-L1 inhibitors significantly improved OS in both PD-L1 positive and PD-L1 negative patients compared to controls, but the magnitude of benefit was clinically PD-L1-dependent.