Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen,Biopsy, and Tissue Microarray

BackgroundThe immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non–small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens.Materials and MethodsIn total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA.ResultsThe proportion of PD–L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens κ value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff.ConclusionThe results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.     

Association Between Sites of Metastasis and Outcomes With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma

BackgroundSites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI.MethodsWe identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd⁺ line.ResultsWe identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd⁺ line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd⁺ line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant.ConclusionBone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.     

PD-1/PD-L1抑制剂联合抗血管生成药物治疗晚期三阴性乳腺癌的研究进展

晚期三阴性乳腺癌较其他亚型乳腺癌的治疗手段少、生存期短、预后差.近年飞速发展的免疫治疗有望延长晚期三阴性乳腺癌的生存时间,但是多项临床研究提示PD-1/PD-L1抑制剂单药治疗晚期三阴性乳腺癌有效率低.新近研究显示抗血管生成药物的治疗不仅可以使血管正常化,抑制肿瘤生长,还可以增强免疫治疗的疗效,与PD-1/PD-L1抑...     

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression,Tumor Mutational Burden,Microsatellite Instability Status,and Response to Immune Check-Point Inhibitors

Introduction

The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown.

Programmed Death Ligand 1; An Immunotarget for Renal Cell Carcinoma

Background: In this era of developing targeted therapies and immunotherapies as a treatment for renal cell carcinoma (RCC), Programmed death ligand 1 (PDL1) as a novel biomarker for RCC is analysed in our study. About 90% of all renal cancers are Renal Cell Carcinoma. Most cases are diagnosed incidentally. 17% of cases are advanced at the time of diagnosis. PDL1 being a trans-membrane cell surface protein is expressed on the tumor cells and is found to have a chief role to inhibit the T cell immune response. It is essential to improve the host immunity by targeting the PD1/PDL1 pathway, thereby destroying the tumor progression. Aim: The aim of this study was to evaluate the expression of PDL1 in tumor cells and adjacent normal tissue among the renal cell carcinoma patients and assess the relation between the PDL1 expression and the tumor characters. Methods: This is a retrospective study. Ethical clearance was obtained from the institution. 150 histopathologically proven RCC cases were chosen. Immunohistochemistry using a PD-L1 rabbit monoclonal antibody was performed on paraffin embedded formalin fixed tissue blocks. Q scoring was done to calculate the expression of PDL1. Statistical analysis: Chi square test was done to assess the comparison between the PDL1 expression in tumor cells and their characteristic features like histology, grade and stage. SPSS (version 20.0) was used for analysis. P value <0.05 was considered significant. It also explains the heterogenous nature of PDL1 as it expressed more in the aggressive pathologic characters like high grade. Results: Positive PD-L1 expression was seen in 44% of tumors. Significant association was observed between high WWHO ISUP grading and positive PDL1 expression (p=0.028). It was expressed in 75% of the sarcomatous type of RCC and 46.8% of clear cell RCCs. Conclusion: Our study suggests that blocking PD1/PDL1 pathway may become an effective mode of treatment in cancer immunotherapy especially for Renal Cell Carcinomas. Our findings confirmed the significant association between expression of PDL1 and the high graded tumors which proves it to be an important prognostic factor.     

免疫检查点抑制剂一线治疗晚期NSCLC的现状与展望

随着程序性凋亡因子1受体(programmed death-1,PD-1)及其配体(PD-L1)抑制剂单药治疗在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的二线和一线治疗中相继取得突破性进展,晚期NSCLC的诊治策略正在逐渐发生演变和优化.免疫联合治疗扩大受益人群、提高疗效,目前已经在一线治疗领域取得初步结果,有多项Ⅲ期随机对照研究正在进行中.本文将对免疫检查点抑制剂在晚期NSCLC一线治疗中的现状和前景进行综述.     

Relationship Between Programmed Death Receptor-Ligand 1 Expression and Response to Checkpoint Inhibitor Immunotherapy in Pulmonary Sarcomatoid Carcinoma: A Pooled Analysis

BackgroundPulmonary sarcomatoid carcinoma (PSC) or pleomorphic carcinoma is a rare subtype of non-small cell lung cancer. Some reports have suggested the efficacy of checkpoint inhibitor immunotherapy for PSC. However, owing to the small number of patients in each report, it remains unclear whether programmed death receptor-ligand 1 (PD-L1) expression is predictive of tumor response or survival.Patients and MethodsThe English literature was systematically searched for articles published from 2015 to 2019 and reported on tumor response or progression-free survival (PFS) after immunotherapy for advanced PSC. In addition, our institutional electronic medical records were searched for eligible cases to be included. Pooled analyses were performed.ResultsAnalyses included 90 patients. Best tumor response was partial or complete response in 54.5%, stable disease 15.9%, and progressive disease in 29.6%. The median PFS was 7.0 months. Among 66 patients with reported PD-L1 expression, the level was <1% in 7 patients (10.6%), 1%-49% in 10 patients (15.2%), and ≥50% in 49 patients (74.2%). A positive relationship between PD-L1 level and tumor response was observed. Among 47 patients with a PD-L1 of ≥50%, 33 patients (70.2%) achieved response, compared with 5 of 10 patients (50%) with a PD-L1 of 1%-49% and 2 of 7 patients (28.6%) with a PD-L1 of <1% (P = .026). PFS was superior among patients with a PD-L1 of ≥1% compared with those with a PD-L1 of <1% (14.4 months vs. 2.7 months respectively; P = .04).ConclusionsAmong patients with advanced PSC, PD-L1 expression is significantly associated with increased tumor responses and improved PFS after checkpoint inhibitor immunotherapy.     

Drug of the year: Programmed Death-1 receptor/Programmed Death-1 Ligand-1 receptor monoclonal antibodies

Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. They indicate important response rates and high quality responses or prolonged duration. Also in renal cancer and in lung cancer remarkable activity has been demonstrated. Thus it is clear that these antibodies have a very broad potential and trials in many tumour types are being initiated. Breaking tolerance at the tumour site is a potent phenomenon and the potential for synergy with other checkpoint inhibitors such as ipilimumab have also been demonstrated in 2013. Long term tumour control now seems achievable and thus the concept of a clinical cure is emerging by modulation of the immune system. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. Because of all these reasons PD-1/PD-L1 antibodies are considered ‘drug of the year’.     

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。     

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Introduction

This study evaluated whether tumor expression of programmed death ligand 1 (PD-L1) could predict the response of EGFR-mutated NSCLC to EGFR tyrosine kinase inhibitor (TKI) therapy.

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。     

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...     

Programmed Death-Ligand 1 Immunohistochemistry Assay Comparison Studies in NSCLC: Characterization of the 73-10 Assay

IntroductionSeveral programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed independently within clinical programs for therapeutic anti–programmed cell death protein 1 (anti–PD-1) or PD-L1 antibodies, necessitating assessment of assay comparability. We characterized the Dako PD-L1 IHC 73-10 assay used in clinical trials of avelumab (anti–PD-L1) or bintrafusp alfa (M7824; bifunctional immunotherapy) and compared it with the Dako PD-L1 IHC 22C3 pharmDx assay, an approved companion diagnostic for pembrolizumab monotherapy in patients with advanced NSCLC.MethodsFormalin-fixed, paraffin-embedded NSCLC tumor samples from a commercial source and from the JAVELIN Solid Tumor phase 1 trial of avelumab (NCT01772004) were stained using the 73-10 and 22C3 IHC assays with a standard protocol.ResultsBoth assays displayed expected PD-L1 staining patterns. In 148 commercial NSCLC samples, the 73-10 assay stained greater than or equal to 1%, greater than or equal to 50%, and greater than or equal to 80% of tumor cells as PD-L1+ in 64.2%, 36.5%, and 23.6% of the samples, respectively, whereas the 22C3 assay stained 20.3% of the samples as greater than or equal to 50% PD-L1+. In 83 NSCLC clinical trial samples, the 73-10 assay stained 79.5% and 31.3% of the samples as greater than or equal to 1% and greater than or equal to 80% PD-L1+, respectively, whereas the 22C3 assay stained 59.0% and 21.7% as greater than or equal to 1% and greater than or equal to 50% PD-L1+, respectively. Efficacy of avelumab was similar in the subgroups classified with the 73-10 and 22C3 assays using greater than or equal to 80% and greater than or equal to 50% PD-L1+ cutoffs, with objective response rates of 26.9% and 33.3%, respectively.ConclusionsThe 73-10 assay demonstrated high sensitivity for PD-L1 staining, and staining was comparable between the greater than or equal to 80% cutoff of the 73-10 assay and greater than or equal to 50% cutoff of the 22C3 assay.     

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced,Programmed Death Ligand 1–Expressing NSCLC

Introduction

In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1–expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.

Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC

IntroductionProgrammed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti–programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression.MethodsWe retrospectively reviewed patients with advanced NSCLC treated with anti–PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti–PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing.ResultsOverall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1_High (tumor proportion score ≥ 50%)/TIL_High (≥85/mm²; n = 73); type II: PD-L1_Low (tumor proportion score < 50%)/TIL_Low (<85/mm²; n = 70); type III: PD-L1_High/TIL_Low (n = 37); and type IV: PD-L1_Low/TIL_High (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti–PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1_High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively.ConclusionsDifferential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti–PD-1/PD-L1 therapy.     

Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma

ObjectiveSecond-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.MethodsTen second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction.ResultsIn the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R² = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R² = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 0.17) with OS12 in the external validation dataset.ConclusionsPFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.     

Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies

BackgroundExtended onset of treatment effect and longer-term survival with anti–programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non–small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources.Materials and MethodsStudies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival.ResultsPD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%).ConclusionThis NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.