Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort

BackgroundAnticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).Patients and MethodsTumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.ResultsPD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1–expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1–stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1–positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).ConclusionAlthough high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.     

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.     

Analysis of radiotherapy-induced alteration of CD8+ T cells and PD-L1 expression in patients with uterine cervical squamous cell carcinoma

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8⁺ T-cell infiltration and programmed death-ligand 1 (PD-L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8⁺ T-cell infiltration and PD-L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre-RT) and after 10 Gy radiotherapy (post-10 Gy). The PD-L1⁺ rate was significantly increased from 5% (4/75) pre-RT to 52% (39/75) post-10 Gy (P<0.01). Despite this increase in the PD-L1⁺ rate post-10 Gy, there was no significant association between both pre-RT and post-10 Gy and overall survival (OS), locoregional control (LC) and progression-free survival (PFS). On the other hand, the CD8⁺ T-cell infiltration density was significantly decreased for all patients (median, 23.1% pre-RT vs. 16.9% post-10 Gy; P=0.038); however, this tended to increase in patients treated with radiotherapy alone (median, 17.7% pre-RT vs. 24.0% post-10 Gy; P=0.400). Notably, patients with high CD8⁺ T-cell infiltration either pre-RT or post-10 Gy exhibited positive associations with OS, LC and PFS. Thus, the present analysis suggested that CD8⁺ T-cell infiltration may be a prognostic biomarker for patients with cervical cancer receiving radiotherapy. Furthermore, immune checkpoint inhibitors may be effective in patients who have received radiotherapy, since radiotherapy upregulated PD-L1 expression in cervical cancer specimens.     

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1–treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.     

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy

BackgroundExpression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT).MethodsWe retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis.ResultsUnivariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups.ConclusionsAmong stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.     

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。     

基于PD-1/PD-L1抑制剂联合疗法对比舒尼替尼治疗晚期肾细胞癌安全性和有效性的Meta分析

目的：系统评价基于PD-1/PD-L1抑制剂的免疫联合治疗（以下称“免疫联合治疗”）对比舒尼替尼治疗晚期肾细胞癌（RCC）的安全性和有效性。方法：检索PubMed、Embase、Cochrane Library及中国知网（CNKI）数据库，收集国内外公开发表的免疫联合治疗对比舒尼替尼应用于晚期RCC的随机对照试验（RCT），检索时间均为自建库时间至2022年10月。由两名研究者独立评价纳入研究的质量、提取资料并交叉核对，采用StataMP16.0软件进行Meta分析。结果：共纳入6项RCT,Meta分析结果显示，（1）有效性：与舒尼替尼相比，免疫联合治疗显著提高了晚期RCC患者的总生存期[OS,HR=0.74,95%CI(0.67,0.80),P<0.01]和无进展生存期[PFS,HR=0.66,95%CI(0.51,0.81),P<0.01](;2)安全性：两治疗组均有较高的不良反应（AE）发生率，差异无统计学意义。但免疫联合治疗组发生皮肤及内分泌系统AE显著高于舒尼替尼治疗组，而血液系统相关AE则明显低于舒尼替尼治疗组（；3）以1%为临界点，免疫联合治疗组的RCC患者，...     

PD-1/PD-L1抑制剂在晚期非小细胞肺癌中的治疗进展

程序性死亡受体1(programmed death 1,PD-1)抑制剂Pembrolizumab进入一线正式标志着免疫检查点抑制剂在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗体系中占据了重要地位.临床试验结果证实PD-1/程序性死亡配体1(programmed death ligand 1,PD-L1)抑制剂在晚期NSCLC的一线、二线和多药耐药后治疗的疗效均要优于传统的化疗.一线使用Pembrolizumab联合化疗的客观有效率(objective response rate,ORR)最高可达80%;单药Pembrolizumab的无疾病进展时间(progression-free survival,PFS)接近1年(10.3个月),死亡风险比含铂双药化疗下降40%.单药Pembrolizumab、Nivolumab和Atezolizumab用于二线的疗效同样突出,总生存时间(overall survival,OS)可至1年左右.PD-L1的表达是PD-1/PD-L1抑制剂疗效的预测因子,在晚期NSCLC中阳性(≥1%)的比例约为60%左右,组织类型间差异不大,但是目前并无检测的金标准.     

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，检索日期截至2020年3月25日。RevMan5.3和STATA15.0进行分析。结果 纳入12项研究，共计1209例患者。结果提示TMB显著提高PD-1/PD-L1抑制剂治疗过的NSCLC疾病无进展生存期（PFS）（HR=0.54, 95%CI: 0.42~0.70, P<0.001），但TMB却降低客观缓解率（ORR）（OR=4.41, 95%CI: 2.54~7.63, P<0.001）。亚组分析结果显示，TMB对PD-1/PD-L1抑制剂联合抗CTLA-4抑制剂或化疗治疗的非小细胞肺癌的预测价值显著。Begg’s检验和Egger’s检验未观察到显著的发表偏倚。结论 高TMB可预测PD-1/PD-L1抑制剂治疗非小细胞肺癌PFS的提高，但对OS、ORR及长期生存的预测价值需进一步研究。     

TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究

  目的  评估TKI耐药后晚期EGFR突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）在真实世界中化疗、化疗联合抗血管和免疫治疗的临床疗效以及最佳免疫治疗联合方案和探讨优势人群临床病理特征。  方法  回顾性分析2014年1月至2022年10月于广东省人民医院肿瘤医院收治229例TKI耐药后晚期EGFR突变型NSCLC患者的临床病理资料。本研究将纳入的患者分为非ICI治疗组（化疗和化疗联合抗血管）122例,ICI治疗组（含免疫治疗）107例,分析患者临床特征与治疗疗效之间的关系。  结果  纳入患者非ICI治疗组和ICI治疗组的中位无进展生存期（progression-free survival,PFS）分别为5.2个月和5.2个月（P=0.129）,中位生存期（overall survival,OS）分别为18.2个月和14.1个月（P=0.026）。进一步分析107例ICI治疗组,使用化疗联合免疫治疗、化疗联合抗血管联合免疫治疗和免疫单药或抗血管联合免疫治疗的中位PFS分别为5.6、6.7和2.3个月（P=0.074）,中位OS分别为15.5、18.6和8个月（P=0.165）。PD-L1表达≥50%患者的中位PFS和中位OS较PD-L1表达<50%患者明显延长（中位PFS:5.6个月vs. 5.0个月,P=0.040;中位OS:19.2个月vs. 12.6个月,P=0.046）。  结论  晚期EGFR突变型NSCLC患者TKI耐药后四药联合免疫治疗似乎呈现出更好的生存获益趋势,PD-L1表达是预测该人群免疫治疗获益的生物标志物。      

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。     

In the immuno-oncology era,is anti-PD-1 or anti-PD-L1 immunotherapy modifying the sensitivity to conventional cancer therapies?

IntroductionThe advent of anti-programmed death receptor-1/ligand-1 antibodies (anti-PD(L)1) is profoundly changing the therapeutic strategy of oncology. As anti-PD(L)1 modulate tumour microenvironment, it might impact sensitivity to conventional cancer therapy (CCT). Therefore, we explored whether sensitivity to CCT was different before and after anti-PD(L)1 therapy.MethodsPatients who started anti-PD(L)1 treatment at Gustave Roussy Cancer Centre between February 2012 and December 2015, and who received at least one line of CCT immediately before and immediately after anti-PD(L)1, were eligible. We analysed progression-free survival (PFS) and overall response rate (ORR) of the CCT line immediately before (PFSpre/ORRpre) and after (PFSpost/ORRpost) anti-PD(L)1. PFS and ORR were compared using Wilcoxon signed rank and McNemar tests in a paired data subset for patients having received identical class of CCT pre and post anti-PD(L)1 therapy.ResultsAmong 118 eligible patients, 65% received anti-PD1 and 35% anti-PD-L1 agents. Median PFSpre versus PFSpost was 4.7 versus 3.5 months (p = 0.011), respectively; it was 5.7 versus 6.8 months (NS) for patients who derived clinical benefit from immunotherapy and 3.9 versus 3.0 months (p = 0.012) for patients who were primary resistant to anti-PD(L)1 therapy. Subgroup analysis did not reveal any significant difference in PFS or ORR before versus after anti-PD(L)1 therapy according to CCT class or to its ability to induce immunogenic cell death.ConclusionPatients who derive benefit from immune therapies tend to have better PFS on conventional therapies after having received the anti-PD(L)1 agent. Further studies on larger data sets are warranted to confirm these findings.     

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

IntroductionData of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)–positive NSCLC (cohort E) are reported (NCT02443324).MethodsIn this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell–inflamed, Gajewski, and effector T cells) and CD274 gene expression.ResultsCohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%–49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.ConclusionsFirst-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.     

Clinical significance of circulating exosomal PD-L1 and soluble PD-L1 in extranodal NK/T-cell lymphoma,nasal-type

Exosomal PD-L1 (exoPD-L1) is reported to be associated with immunosuppression in various cancers. However, its clinical value in extranodal NK/T cell lymphoma (ENKTL) has not been defined yet. We retrospectively evaluated the prognostic value of pretreatment circulating soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in ENKTL patients treated with VIPD-containing chemotherapy. A total of 107 ENKTL patients, including 101 early stage and 6 advanced stage patients were enrolled in our study. ExoPD-L1 and sPD-L1 in the blood were measured by single molecule array (Simoa) and enzyme-linked immunosorbent assay (ELISA), respectively. Compared with the healthy individuals (n=16), the patients with ENKTL (n=107) exhibited significantly elevated exoPD-L1 and sPD-L1 levels in the blood. High pretreatment plasma exoPD-L1 concentration was associated with higher SUVmax level and recurrence rate. Similarly, high sPD-L1 group was also associated with some adverse clinical parameters, including advanced stage, elevated LDH levels, B symptoms, high IPI score and PINK score. The 5-year progression-free survival (PFS) rate and overall survival (OS) rates were 65.2% and 85.7% for the whole cohort, respectively. Patients with a low pretreatment exoPD-L1 level (simoa signal < 1.2) had 5-year OS and PFS rates of 88.1% and 86.1%, respectively, compared with 56.0%. (P=0.012) and 35.7% (P=0.007) in patients with high exoPD-L1 level (simoa signal > 1.2). The 5-year OS and PFS rates for patients with low sPD-L1 group (< 219 pg/mL) was significantly higher than high sPD-L1 group (≥ 219 pg/mL) (OS, 91.3% vs. 55.5%, P < 0.001; PFS, 68.9% vs. 34.6%, P=0.003). However, no correlation was found between circulating exoPD-L1 and sPD-L1 levels. This is the first study to measure plasma exoPD-L1 level on the Quanterix Simoa platform. Our results proved that circulating exoPD-L1 and sPD-L1 levels were significantly elevated in ENKTL and might be potential biomarkers for predicting the survival outcomes of ENKTL patients.     

Programmed cell death ligand-1 (PD-L1) expression combined with CD8 tumor infiltrating lymphocytes density in non-small cell lung cancer patients

Cancer immunotherapy targeting programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway has shown promising results in treatment of non-small cell lung cancer (NSCLC) patients. T cells play a major role in tumor-associated immune response. This study aimed to investigate PD-L1 expression alone and combined with CD8 tumor infiltrating lymphocytes (TILs) density in relation to clinicopathologic parameters and survival in NSCLC patients. Immunohistochemical analysis was used to evaluate PD-L1 expression and CD8 TILs density in 55 NSCLC patients. PD-L1 immunopositivity was detected in 36 (65.5%) of NSCLC cases. PD-L1 expression was significantly related to high tumor grade (p value?=?0.038) and low CD8 TILs density (p value?=?0.004), whereas no significant relations were detected between PD-L1 expression and tumor stage (p value?=?0.121), overall survival (OS) (p value?=?0.428) and progression-free survival (PFS) (p value?=?0.439). Among PD-L1/CD8 TILs density groups, PD-L1⁺/CD8^Low group was significantly associated with high tumor grade compared to PD-L1^?/CD8^high group (pairwise p?=?0.016). PD-L1⁺/CD8^Low group was significantly related to advanced tumor stage compared to PD-L1⁺/CD8^high and PD-L1^?/CD8^Low groups (pairwise p?=?0.001 and 0.013 respectively). PD-L1^?/CD8^high group exhibited the best OS and PFS whereas PD-L1⁺/CD8^low group had the poorest OS and PFS (p value?=?0.032 and 0.001 respectively). Assessment of PD-L1 combined with CD8 TILs density, instead of PD-L1 alone, suggested important prognostic relevance in NSCLC patients.     

KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated,PD-L1-positive,advanced NSCLC

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m² every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.     

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-L1表达对晚期肺腺癌患者培美曲塞化疗效果的影响及其机制

背景与目的：肺癌组织程序性死亡配体-1（programmed death ligand-1,PD-L1）表达水平不仅是程序性死亡［蛋白］-1（programmed death-1,PD-1）/PD-L1抑制剂最主要的疗效预测生物标志物,还可能影响表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）的疗效。然而,肺癌组织PD-L1表达水平能否影响肺腺癌患者化疗效果,目前相关文献报道较少。探讨肺腺癌组织PD-L1表达对培美曲塞为基础的化疗效果的影响及其潜在机制。方法：2015年10月—2018年12月于中国人民解放军西部战区总医院肿瘤诊治中心确诊为肺腺癌且符合研究入组条件的患者共185例。应用免疫组织化学法分别检测肺腺癌组织中PD-L1和培美曲塞疗效预测分子胸苷酸合酶（thymidylate synthase,TS）的表达。采用Kaplan-Meier法绘制患者的生存曲线,采用log-rank检验和COX回归模型分析影响患者无疾病进展生存（progression-free survival,PFS）的临床病理学因素,采用log-rank检验分别分析PD-L1和TS表达对患者PFS和总生存（overall survival,OS）的影响,采用Spearman秩相关性检验分析肺腺癌组织中PD-L1表达与TS表达的相关性。应用蛋白质印迹法（Western blot）及实时荧光定量聚合酶链反应（real-time fluorescent quantitative polymerase chain reaction,RTFQ-PCR）分别检测6种肺腺癌细胞系中PD-L1、TS的蛋白水平和mRNA表达。采用Pearson相关性检验分析PD-L1和TS在蛋白表达水平及mRNA表达水平的相关性。结果：在51例一线接受培美曲塞为基础化疗的晚期肺腺癌患者中,PD-L1表达阳性患者的客观有效率（objective response rate,ORR）和疾病控制率（disease control rate,DCR）与PD-L1表达阴性患者相比差异无统计学意义（ORR：20.0% vs 35.5%,χ ² =1.404,P=0.236;DCR：60.0%vs 80.6%,χ ² =2.602,P=0.107）。PD-L1表达阴性患者的中位无疾病进展生存（median progression-free survival,mPFS）显著优于PD-L1表达阳性患者（mPFS：5.6个月vs 4.1个月,log-rank=5.406,P=0.020）,两组患者中位总生存（median overall survival,mOS）差异无统计学意义（mOS：15.9个月 vs 12.7个月,log-rank=0.525,P=0.469）。单因素分析发现PD-L1和TS表达阳性是影响患者PFS的危险因素（P=0.023和P=0.003）,多因素分析发现TS表达阳性是影响患者PFS的独立危险因素（P=0.034）。在51例一线接受培美曲塞为基础化疗的晚期肺腺癌患者中,患者肺腺癌组织PD-L1表达与TS表达呈显著正相关性（r _s =0.691,P<0.001）;进一步扩大样本检测发现：在不同肿瘤分期和一线治疗模式的185例肺腺癌患者中,癌组织PD-L1表达与TS表达仍然呈显著正相关（r _s =0.588,P<0.001）。在包括A549在内的6种肺腺癌细胞系中PD-L1与TS在蛋白水平和mRNA表达均呈显著正相关（蛋白水平：r _s =0.899,P<0.05;mRNA表达：r _s =0.861,P<0.05）。结论：在一线接受培美曲塞为基础化疗的晚期肺腺癌患者中,PD-L1表达阳性患者的mPFS较PD-L1表达阴性患者显著缩短,提示PD-L1表达可能作为晚期肺腺癌患者培美曲塞为基础化疗的潜在疗效预测生物标志物。PD-L1和TS的表达不论在肺腺癌组织水平还是细胞系水平均存在显著相关性,可能是PD-L1表达影响培美曲塞化疗效果的潜在原因之一。     

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer

BackgroundProgrammed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC.Patients and MethodsEligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed.ResultsSeventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS.ConclusionAtezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.