BACKGROUND: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported.
METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc.
RESULTS: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy.
CONCLUSIONS: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed.
BACKGROUND: ClinicalTrials.gov, NCT03189719.

UNASSIGNED: Immune checkpoint inhibitor therapy has demonstrated impressive clinical benefits in multiple tumor types. TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1, has shown safety and efficacy in preclinical studies.
UNASSIGNED: This first-in-human study aimed to evaluate the safety/tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of TQB2450 in patients with advanced malignant tumors.
UNASSIGNED: In this phase I study, eligible patients with advanced malignant tumors received intravenous TQB2450 once every 3 weeks. This study consisted of a 3 + 3 dose-escalation phase (1-30 mg/kg) and a specific dose-expansion phase (1200 mg). The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety. The secondary endpoints were PK, immunogenicity, and investigator-assessed response rate.
UNASSIGNED: Between April 2018 and February 2020, 40 patients were enrolled (22 in the dose-escalation phase and 18 in the dose-expansion phase). No DLT was reported and the MTD was not reached. Grade ⩾3 or worse treatment-related treatment-emergent adverse events (AEs) occurred in 11 (27.50%) patients, with the most frequent being aspartate aminotransferase increased (5.00%), leukopenia (5.00%), and anemia (5.00%). Treatment-related serious AEs were reported in six patients, the most common of which was decompensated liver function (5.00%). No treatment-related death was reported. The maximum serum concentration of TQB2450 increased in a dose-proportional manner. Treatment-induced anti-drug antibodies were detected in 31.58% (12/38) of patients. The investigator assessed the objective response rate as 5.00% and the disease control rate was 52.50%, including 2 partial responses and 19 stable diseases. The median progression-free survival was 2.69 (95% confidence interval, 2.07-6.14) months.
UNASSIGNED: TQB2450 has a manageable safety profile with favorable PK and immunogenicity and has shown early evidence of clinical activity in advanced malignant tumors.
UNASSIGNED: NCT03460457.

OBJECTIVE: Nanobodies have become promising carriers due to excellent in vivo properties. Radiopharmaceutical therapy targeting programmed cell death ligand 1 (PD-L1) is an effective therapeutic strategy. Our study aimed to explore therapeutic efficacy of 131I labeled PD-L1 nanobody (Nb109) in non-small cell lung cancers (NSCLCs) in vitro and in vivo.
METHODS: 131I-Nb109 was synthesized by chloramine-T method. We implemented stability analysis, SDS-PAGE and lipid-water partition coefficient test to assess its quality. Cell uptake assay and SPECT/CT scan were applied to evaluate its ability to target NSCLCs (H460 and A549). CCK8 assay and in vivo efficacy assay were conducted to estimate its therapeutic effect in H460 tumors. Damage-associated molecular patterns (DAMPs) release in H460 cells incubated with 131I-Nb109 was investigated by western blot and ATP test kit.
RESULTS: 131I-Nb109 was hydrophilic with high labeling rate (69.51-98.06%), radiochemical purity (99.17% ± 0.76%) and stability. Cell uptake experiments showed that H460 cells (PD-L1 positive) compared with A549 cells (PD-L1 negative) had higher 131I-Nb109 uptake. SPECT/CT imaging revealed the accumulation of 131I-Nb109 in H460 tumor within 48 h. 131I-Nb109 inhibited H460 tumor growth without toxic side effects in contrast with control group. It also induced H460 cells to release DAMPs (adenosine triphosphate, high mobility group box 1, and heat shock protein 70).
CONCLUSIONS: 131I-Nb109 had high stability, excellent ability to target and treatment PD-L1 positive tumors, and can improve tumor immunogenicity. The results of our study were expected to inspire the development of more novel radiopharmaceuticals to treat NSCLCs.

BACKGROUND: The expression of programmed cell death ligand 1 (PD-L1) as a biomarker for immunotherapy in non-small cell lung cancer (NSCLC) is routinely detected in clinical pathology department. However, the spatial heterogeneity of PD-L1 expression in intrapulmonary tumors and extrapulmonary metastases is still a challenge for the clinical testing. This study aims to explore the differences of PD-L1 expression in test samples obtaining from different sites of NSCLC. This study may contribute to the detection strategy of PD-L1 in patients with advanced lung cancer.
METHODS: One hundred and thirty-one cases of consecutively detected PD-L1 (22c3 assay, Dako) staining in metastatic NSCLC and 972 cases of non-paired intrapulmonary NSCLC were collected. The discrepancies of tumor proportion score (TPS) of PD-L1 expression in intrapulmonary samples and extrapulmonary metastatic samples of different sites were compared.
RESULTS: The positive expression rate of PD-L1 in extrapulmonary metastatic NSCLC (TPS ≥ 1%) was 61.83%, and the TPS was significantly higher than that in intrapulmonary tumors (P=0.03). The PD-L1 scores of the specimens obtained from different sites were significantly different (P=0.007). The positive rates of PD-L1 in liver and adrenal metastases were 85.71% and 77.78% respectively, and their TPS were significantly higher than that of the intrapulmonary samples (P<0.05). The positive rates of PD-L1 in lymph node, bone, brain, soft tissue, and pleural metastases was 40.00%-66.67%, with no significant differences compared to intrapulmonary tumors. The analysis of histological subtype and sample type showed that the PD-L1 score of extrapulmonary samples of adenocarcinoma subtype or surgical specimen was significantly higher than that of intrapulmonary tumors. The analysis of clinicopathological parameters showed that the PD-L1 positive expression or high expression were significantly correlated with male patients, smoking history, and epidermal growth factor receptor (EGFR) wild type.
CONCLUSIONS: The expression of PD-L1 in metastatic NSCLC is generally higher than that in intrapulmonary tumor, and the positive rate of PD-L1 expression was discrepant in different sites of specimen. The differences of PD-L1 score between extrapulmonary metastatic samples and intrapulmonary samples may be associated with different metastatic sites, histological subtype, and specimen type.
【中文题目：非小细胞肺癌不同部位组织样本PD-L1
表达水平比较研究】 【中文摘要：背景与目的 程序性死亡配体1（programmed cell death ligand 1, PD-L1）作为非小细胞肺癌（non-small cell lung cancer, NSCLC）免疫治疗患者分层标志物已进入临床病理常规检测。然而PD-L1表达在肺内和肺外不同转移部位的空间异质性是困扰临床检测的难题。本研究旨在探讨NSCLC不同部位组织样本的PD-L1表达评分的差异，从而有助于晚期肺癌患者的PD-L1检测策略的制定。方法 回顾性收集PD-L1（22c3抗体，Dako）临床病理连续检测的131例肺外转移性NSCLC以及同期非配对肺内肿瘤972例进行对照分析，对比肺外与肺内肿瘤组织样本检测的PD-L1肿瘤阳性比例评分（tumor proportion score, TPS）差异。结果 肺外转移性NSCLC的PD-L1阳性表达率（TPS≥1%）为61.83%，TPS评分显著高于同期肺内肿瘤（P=0.03）。不同部位组织样本的PD-L1表达评分具有显著差异（P=0.007）。肝脏和肾上腺转移瘤的PD-L1阳性率高，分别为85.71%和77.78%，其TPS评分均显著高于肺内肿瘤（P<0.05）。淋巴结、骨、脑、软组织和胸膜转移瘤的PD-L1表达率为40.00%-66.67%，TPS评分与肺内肿瘤无显著差异。组织学和样本类型分析显示，腺癌类型和手术切除的肺外样本PD-L1表达评分显著高于同类型肺内肿瘤。临床病理参数分析显示，PD-L1阳性表达和高表达均与患者男性、吸烟史以及表皮生长因子受体（epidermal growth factor receptor, EGFR）野生型显著相关。结论 肺外转移性NSCLC样本的PD-L1表达评分高于肺内肿瘤，且不同部位组织样本的PD-L1表达阳性率存在差异。肺外转移性肿瘤与肺内肿瘤的PD-L1检测差异可能与不同转移部位、组织学和样本类型相关。
】 【中文关键词：肺肿瘤；程序性死亡配体1；异质性；肿瘤阳性比例评分】.

暂无摘要。

Immunotherapy has become a cornerstone of the modern cancer treatment. It might be crucial to predict its expression non-invasively by imaging. The present study used diffusion-weighted imaging (DWI) quantified by whole lesion apparent diffusion coefficient (ADC) values to elucidate possible associations with programmed cell death ligand 1(PD-L1) expression in head and neck squamous cell cancer (HNSCC).
Overall, 29 patients with primary HNSCC of different localizations were involved in the study. DWI was obtained by using a sequence with b - values of 0 and 800 s/mm2 on a 3 T MRI. ADC values were evaluated with a whole lesion measurement and a histogram approach. PD-L1 expression was estimated on bioptic samples before any form of treatment using 3 scores, tumor positive score (TPS), immune cell score (ICS), and combined positive score (CPS).
An inverse correlation between skewness derived from ADC values and ICS was identified (r = -0.38, p = 0.04). ADCmax tended to correlate with ICS (r = -0.35, p = 0.06). Other ADC parameters did not show any association with the calculated scores.
There is a weak association between skewness derived from ADC values and PD-L1 expression in HNSCC, which might not be strong enough to predict PD-L1 expression in clinical routine. Presumably, ADC values are more influenced by complex histopathology compartments, comprising cellular and extracellular aspects of tumors than only of a single subset of tumor associated cells.

OBJECTIVE: The purpose of the study was to determine DTI properties of brain metastases in subjects with non-small cell lung carcinoma (NSCLC), to evaluate whether there was a correlation between DTI findings and programmed cell death ligand-1 (PD-L1).
METHODS: The study population (n:22) was assigned to PD-L1 negative (Group 1: PD-L1 expression<%50) (n=11) or positive (Group 2: PD-L1 expression ≥%50) (n=11). We compared ADC and FA values measured from the enhanced solid metastases and peritumoral edema area with PD-L1 protein status.
RESULTS: The mean ADC values were lower in group 2 compared to group 1. The peritumoral ADC values were higher in group 2 compared to group 1. Mean peritumoral edema FA values are lower in group 2 compared to group 1. The peritumoral edema nADC values were higher in group 2 compared to group 1. As PD-L1 expression frequency increased, ADC values in the peritumoral edema area increased and FA values decreased.
CONCLUSIONS: We thought that the existence of PD-L1 protein doesn\'t affect ADC and FA values of brain metastasis (BM) originating from NSCLC. DTI characteristics of the peritumoral edema area could be a guide in determining PD-L1 protein status of brain metastases of NSCLC. The relationship between PD-L1 expression status and DTI features in BM from NSCLC could help us to have an idea in response to immunotherapy.

The impact of concurrent autoimmune thyroid disease on the tumour microenvironment and disease progression in papillary thyroid cancer (PTC) is not well understood. Studies evaluating the programmed cell death ligand 1 (PD-L1) tumour expression in PTC have shown variable results, and the effect of lymphocytic thyroiditis (LT) on tumour PD-L1 expression has not been adequately assessed. The main aim of this study was to determine expression of PD-L1 in PTC with and without LT. We examined 81 PTC cases; 28.5% of all reviewed PTC had presence of LT. In PTC specimens without LT, tumour PD-L1 expression was significantly lower compared to PD-L1 expression in PTC with LT, 6.9% vs 39.1%, respectively. Expression of PD-L1 did not differ with PTC stage, even when sub-categorised according to the presence and absence of LT. Utility of PD- L1 expression as a prognostic marker in thyroid cancer needs to be interpreted with caution.

Background Pembrolizumab has robust antitumor activity in advanced melanoma and has been approved for the treatment of melanoma in many countries. Adjuvant pembrolizumab was associated with longer recurrence-free survival (RFS) in patients with resected stage III melanoma. We herein report on the RFS outcomes of Chinese patients with resected stage III melanoma receiving adjuvant pembrolizumab in comparison to those receiving interferon α-2b (IFN-α-2b). Methods We retrospectively investigated the medical records of subjects with resected stage III melanoma with no in-transit metastases diagnosed who were treated at the Cancer Hospital of the University of Chinese Academy of Sciences and collected historical clinical data of patients receiving adjuvant IFN-α-2b therapy in our hospital. The RFS rates were evaluated using Kaplan-Meier curves, and the differences between the groups were tested using the log-rank test. Results A total of 29 patients receiving adjuvant pembrolizumab therapy and 27 patients receiving adjuvant IFN-α-2b therapy were enrolled. The median RFS was not reached (95% CI not estimable [NE]) in the pembrolizumab group and was 25 months in the IFN-α-2b group, and there was no significant difference in RFS between the pembrolizumab and IFN-α-2b groups (HR = 1.20, log-rank p = 0.75). There was no significant difference in RFS for acral melanoma between the pembrolizumab group and IFN-α-2b group (HR = 1.22, log-rank p = 0.79). For patients with IIIC or IIID melanoma, the RFS in the pembrolizumab group was also similar to that of the IFN-α-2b group (HR = 0.80, log-rank p = 0.47). The RFS for patients receiving pembrolizumab with programmed cell death ligand 1 (PD-L1)-positive tumors might tend to be longer than that for patients with PD-L1-negative tumors, but there was no significant difference between the groups (HR = 3.37, log-rank p = 0.17). High tumor mutational burden (TMB) did not reveal a trend to predict a longer RFS than low TMB in patients receiving pembrolizumab (HR = 1.63, log-rank p = 0.63). Grade 3-4 adverse events occurred in 6 (22.22%) of 27 patients in the IFN-α-2b group. Discontinuations attributed to adverse events (AEs) occurred in 2 patients treated with IFN-α-2b. Immune-related adverse events were observed in 5 (17.24%) patients in the pembrolizumab group. In the pembrolizumab group, grade 3-4 adverse events occurred in 2 (6.90%) patients, 1 of which required the discontinuation of a study drug and corticosteroid treatment. None of the patients discontinued treatment due to treatment-related or immune-mediated AEs. Conclusions Adjuvant pembrolizumab appeared to be as effective as IFN-α-2b in prolonging RFS in Chinese patients with resected stage III melanoma. Adjuvant pembrolizumab was associated with a lower rate of treatment-related AEs than IFN-α-2b. A prospective study is needed to confirm the clinical benefit of adjuvant pembrolizumab and determine dependable biomarkers.

We evaluated the impact of patient characteristics, sample types, and prior non-immunotherapy treatment on tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression using samples from patients with advanced NSCLC.
Patients (N = 1590) screened for the ATLANTIC study submitted a recently acquired (≤3 months) or archival (>3 months to >3 years old) tumor sample for PD-L1 assessment using the VENTANA PD-L1 (SP263) Assay with a cutoff of ≥25% of TCs expressing PD-L1 (TC ≥25%). Samples were acquired either before or after the two or more treatment regimens required for study entry and sample age varied among patients. A subset of patients (n = 123) provided both recent and archival samples.
A total of 517 of 1590 (32.5%) patients had TC greater than or equal to 25%: prevalence was greater in smokers versus nonsmokers (p = 0.0005) and those with EGFR- versus EGFR+ tumors (p = 0.0002); these effects were independent. Prevalence of TC greater than or equal to 25% was increased in recent metastatic versus primary (p = 0.005) and recent versus archival (p = 0.039) samples. Chemotherapy or radiotherapy, but not tyrosine kinase inhibition, before sampling was associated with significantly increased PD-L1 prevalence. PD-L1 status (TC ≥25% cutoff) remained unchanged in 74.0% of patients with recent and archival samples; where PD-L1 status changed, it was more likely to increase than decrease over time or with intervening treatment.
Several factors potentially impact PD-L1 TC greater than or equal to 25% prevalence in advanced NSCLC; however, no characteristic can be considered a surrogate for PD-L1 expression. Fresh biopsy may provide more accurate assessment of current tumoral PD-L1 expression where a low/negative result is seen in an archival sample, especially if the patient has received intervening therapy.