Programmed Cell Death Ligand 1 Inhibitors Research Articles

Comparative study of the PD-L1 expression and CD8+ tumor-infiltrating lymphocyte between surgically resected and matched re-biopsy specimens in recurrent non-small cell lung cancer.

Introduction: Numerous studies conducted until date have reported that the chemotherapy regimen could affect the programmed cell death ligand 1 (PD-L1) expression status in patients with non-small cell lung cancer (NSCLC).Materials and methods: A total of 36 NSCLC patients for whom both the surgically resected specimens of the primary tumors and re-biopsy specimens of the recurrent tumors were available were enrolled in this study. The PD-L1 expression status and tumor-infiltrating CD8-positive T lymphocytes (CD8+TILs) count were measured in paired samples by immunohistochemistry. The concordance rate in the tumor immune microenvironment (TIME) classification based on the PD-L1 expression status and CD8+TILs count was analyzed.Results: While the PD-L1 expression levels were similar between the surgical and re-biopsy specimens in 77.8% of cases, in 16.7% of cases, the expression levels were higher in the re-biopsy specimens. When the analysis was confined to patients who had received platinum-based chemotherapy, the percentage increased to 42.9%. The TIME classification changed in the re-biopsy specimens as compared to the surgical specimens in one-third of the patients, especially in those who had received chemotherapy previously. The TIME classification in the re-biopsy specimens more closely resembled that in the metastatic lymph nodes as compared to that in the primary tumor.Conclusion: In patients with recurrent NSCLC, especially those who have received chemotherapy previously, a recent re-biopsy sample is required to determine whether PD-1/PD-L1 inhibitors should be used for treatment or not.

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice. To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types. PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018. Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included. Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis. Incidences of treatment-related adverse events and differences between different drugs and cancer types. This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54). Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity-From Case Report to Mouse Model Validation.

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8+ T cells and NKG2D+ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary.

PD-1/PD-L1 Inhibitors for Non-Small Cell Lung Cancer: Incorporating Care Step Pathways for Effective Side-Effect Management.

Programmed cell death protein 1 receptor and programmed cell death ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) that provide a survival benefit for select patients with advanced non–small cell lung cancer (NSCLC). Nivolumab, pembrolizumab, and atezolizumab are second-line therapies for advanced NSCLC after chemotherapy failure. Pembrolizumab and atezolizumab are also approved as first-line treatment for advanced NSCLC, and durvalumab is a PD-L1 inhibitor indicated as consolidation therapy in individuals with locally advanced NSCLC. The novel mechanism of action of these agents provides clear efficacy benefits to many NSCLC patients without good alternatives, but it may also result in unique immune-related adverse events that many health-care providers are unfamiliar with or uncertain about how to diagnosis and manage. Highlighting the resources of the Immuno-Oncology Essentials Initiative, particularly the Care Step Pathways (CSPs), this article addresses the role of the advanced practice provider in administration, side-effect identification and management, and education of patients with advanced NSCLC receiving ICI therapy. The diagnosis and management of pneumonitis, hypophysitis, diabetes mellitus, and arthralgias/myalgias are examined in detail, addressing special considerations in the NSCLC population.

A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC).

TPS500 Background: Standard of care (SoC) for high-risk NMIBC patients is transurethral resection of the bladder tumor followed by BCG. Although several randomized clinical studies have demonstrated the efficacy of BCG in NMIBC, recurrence rates are as high as 50% in the first 3 yrs of follow up and can be even higher for aggressive histologic subtypes. Immunotherapy agents active in the programmed cell death (PD) pathway responsible for suppressing anti-tumor immunity present an emerging treatment opportunity. In trials treating patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy, response rates doubling those with traditional chemotherapy have been reported for immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with a manageable safety and tolerability profile. PD-L1 inhibition with durvalumab in combination with other immunotherapies, including SoC BCG, may improve response rate and duration of tumor response. Methods: POTOMAC is an open-label, multicenter, global Phase 3 trial enrolling approximately 1,300 patients ≥18 yrs with histologically confirmed high-risk NMIBC who have undergone complete resection of papillary tumors (patients with residual carcinoma in situ [CIS] are eligible) and are BCG-naïve. Of those, approximately 975 patients will be randomized (1:1:1) to durvalumab (1500 mg every 4 wks for 13 cycles) + BCG induction (6x every 1 wk instillation) and 2 yrs of maintenance (3 doses x every 1 wk at 3, 6, 12, 18, and 24 months), durvalumab + BCG (induction only) or BCG (induction and 2 yrs of maintenance). Randomization will be stratified by high-risk papillary disease (Y/N) and CIS (Y/N). The primary endpoint is disease-free survival. Secondary endpoints include proportion of patients alive and disease free at 24 months, overall survival at 5 yrs, pharmacokinetics, immunogenicity, safety and tolerability, and HRQoL. Clinical trial information: NCT03528694.

Immunotherapy in Bladder Cancer.

Bladder cancer is the fifth most common cancer in the United States. Cisplatin-based chemotherapy is the current standard of care in stage IV bladder cancer. It has increased overall survival but rarely results in complete remission, with an overall survival of 14-15 months. The most significant breakthrough in cancer therapy over the last decade was the development of immunotherapy. KEYNOTE-045, IMvigor211, CheckMate275, Javelin Solid Tumor, MEDI4736, and KEYNOTE-0528 clinical trials. There are ongoing clinical trials using combination of immunotherapy and chemotherapy as first line of therapy in the setting of metastatic urothelial cancer and also to determine the duration of treatment. Immunotherapy is approved as a second-line treatment for metastatic urothelial cancer. Their use as a first-line agent is only limited to patients who are ineligible for cisplatin-based treatments. Five drugs are approved by Food and Drug Administration for metastatic urothelial cancer including 3 Programmed cell-death protein 1 (PD-1) inhibitors and 2 programmed cell-death ligand 1 (PD-L1) inhibitors in patients who have progressed during or after platinum-based therapy. Pembrolizumab, nivolumab, and atezolizumab are PD-1 inhibitors. Durvalumab and avelumab are PD-L1 inhibitors. However, only 2 drugs were approved based on phase III clinical trials-pembrolizumab and atezolizumab, of which only KEYNOTE study performed with pembrolizumab showed overall survival difference. Atezolizumab and pembrolizumab are the Food and Drug Administration-approved checkpoint inhibitors in cisplatin-ineligible patients. This review article summarizes the significance of immunotherapy in treatment of bladder cancer, its side effects, and limitations.

CCTG CO.26 trial: A phase II randomized study of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with advanced refractory colorectal carcinoma (rCRC).

481 Background: D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Targeting both PD-L1 and CTLA-4 may have additive/synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study evaluated whether combining PD-L1 and CTLA-4 inhibition would lead to improved pt survival vs BSC alone in rCRC. Methods: Pts with rCRC were randomized 2:1 to D+T vs BSC . Pts were eligible if they failed all standard regimens; containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor if Ras wild type). Prior treatment (Tx) with anti-VEGF agents or TAS-102 was permitted but not mandatory. Tx consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and all appropriate supportive measures. Primary endpoint was overall survival (OS) and a two-sided p-value < 0.10 was considered statistically significant. Results: Between August 2016 and June 2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced. 85% of pts received ≥ 90% of planned doses of D and T. No pts with known defective mismatch repair (dMMR) tumors were enrolled. With a median (med) follow-up of 15.2 months (mo), the med OS was 6.6 mo for D+T and 4.1 mo for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54–0.97). Med progression free survival was 1.8 mo and 1.9 mo respectively (HR 1.01, 90% CI 0.76–1.34; p=0.97). Disease control rate was 22.7% for D+T and 6.6% for BSC (p = 0.006). Grade 3/4 abdominal pain, fatigue, lymphocytosis and eosinophilia were significantly higher in D+T. At 16 weeks, there was significantly less deterioration on EORTC QLQ-C30 physical function for D+T. Confirmation of MMR status is ongoing. Conclusions: D+T significantly prolonged OS in pts with rCRC and preserved quality of life. Adverse events were more frequent with D+T. This is the first study showing that combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with advanced refractory CRC not selected for dMMR. Clinical trial information: NCT02870920.

Efficacy and safety of programmed cell death-1/programmed cell death ligand-1 inhibitors in advanced urothelial malignancy: A systematic review and meta-analysis.

Introduction:Programmed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings.Methods:Extensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis.Results:Ten nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1–21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3–14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9–27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5–2.9 vs. 2.0–2.7 months and 7.9–18.2 vs. 15.9 months) and second-line chemotherapy (3.3–4.0 months and 7.4–8 months). Odds of achieving ORR was 0.10 (95% CI 0.03–0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19–0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible.Conclusions:PD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

The clinical utility of tumor mutational burden in non-small cell lung cancer.

Despite advances made during the last two decades, lung cancer remains the leading cause of cancer-related death worldwide. Recently, immune checkpoint inhibitors (ICIs) became available for the treatment of advanced non-small cell lung cancer (NSCLC) patients. Although ICIs showed a survival advantage in comparison with chemotherapy in the second and first-line setting, overall response rate is only around 20% and a large proportion of patients will undergo disease progression within the first weeks of treatment. For this reason, there is a need for biomarkers to predict the efficacy of ICIs in NSCLC and to identify patients who will benefit from ICIs. The first biomarker developed was programmed cell death ligand 1 (PD-L1) expression. However, the predictive role of PD-L1 expression varied from one clinical trial to another, due to the multiple assays used, with different antibodies, different platforms, and different thresholds. Moreover, PD-L1 expression is highly heterogeneous. For these reasons, PD-L1 expression alone is not a good biomarker to predict the efficacy of ICIs and there is a need for the identification of other biomarkers. Tumor mutational burden (TMB) is defined as the number of mutations per DNA megabases. It was first assessed as a biomarker for ICI based on the observation of successful immune checkpoint inhibition in solid tumors with high TMB such as NSCLC, melanoma or bladder cancer. Pre-clinical data suggested that the association between TMB and ICIs efficacy could be explained by the creation of neoantigens induced by mutations acquisition, increasing tumor immunogenicity and response to ICIs. Preliminary observations of TMB role as a predictive biomarker for the efficacy of ICIs in patients with advanced NSCLC led to the assessment of TMB clinical utility in phase III clinical trials. This review reports the clinical features and prognostic role of TMB in NSCLC. This review also focuses on TMB predictive role for the treatment of NSCLC patients with single-agent programmed cell death 1 (PD-1) and PD-L1 inhibitors such as pembrolizumab, nivolumab and atezolizumab or ICIs combination.

Atezolizumab for the treatment of triple-negative breast cancer

ABSTRACTIntroduction: Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options. However, TNBC is known to be more immunogenic compared to other breast cancer subtypes, with tumor-infiltrating lymphocytes playing an important prognostic and predictive role. Furthermore, TNBC has a higher level of programmed cell death-ligand 1 (PD-L1) expression. Therapeutic blockade of PD-L1 using atezolizumab is thus expected to activate and enhance tumor-specific T-cell responses, resulting in improved anti-tumor activity.Areas covered: This review summarizes the development and the impact of the PD-L1 inhibitor atezolizumab in advanced TNBC; it examines the mechanism of action, pharmacokinetics and the available preclinical and clinical data.Expert opinion: Atezolizumab, a novel immune checkpoint inhibitors targeting PD-L1, is an effective and well-tolerated treatment option for metastatic TNBC. In general, TNBC has a high unmet medical need, hence the clinical development of atezolizumab should continue, particularly for TNBC. Indeed, atezolizumab has the potential to substantially augment the therapeutic armamentarium for TNBC. This should lead to improved immunotherapeutic strategies and the enhancement of the outcome for this group of breast cancer patients.

Prospect of liquid biopsy application for precise medication of PD-1/PD-L1 inhibitor

In recent years, liquid biopsy has been widely used in cancer early screening, companion diagnosis, drug efficacy prediction and monitoring, etc. Liquid biopsy has the advantages of real time, noninvasive, sequential sampling etc., and is one of the most promising cancer diagnosis methods. Liquid biopsy includes circulating tumor cells (CTC), cell-free circulating tumor DNA (ctDNA), and exosomes to obtain tumor lesion information. For early screening and diagnosis of tumors, targeted drug prediction, dynamic monitoring of efficacy, drug resistance analysis and prognosis evaluation, it is a representative diagnostic technology in the contemporary precise medical system. At the same time, the revolutionary immunotherapy puts forward higher requirements for the precise diagnosis, especially for the precise medication of programmed death 1/programmed death ligand 1(PD-1/PD-L1) inhibitors. In normal organisms, PD-L1 (programmed cell death-Ligand 1) is a protein expressed on the cell surface, also known as B7-H1 protein. It binds to PD-1 protein (programmed death receptor-1) on effector T cells, conducts immunosuppressive signals, and inhibits the activity of immune effector T cells. The expression of PD-L1 on the surface of tumor cells is the material basis for tumor escape from immune cell attack and a marker for poor prognosis. PD-1/PD-L1 immunotherapy is being used for other larger tumors. Currently, hundreds of clinical trials of monotherapy and combination therapy are being carried out intensively, to exploit the clinical potential and value of a largest number of such IO drugs. PD-L1 companion diagnostics is a screening for responders to drugs by identifying the expression of the drug target PD-L1 protein. The Merck East team identified patients with non-small cell lung cancer who responded to drugs by using tissue-expressed PD-L1>50% criteria, segmented patient populations, and identified potentially beneficial patients. This precise medical strategy was obtained in clinical trials and commercial promotion. Tumor mutation burden (TMB) is the number of somatic mutations in the whole genome after accounting for germline DNA variants. Studies have found that if there are many genes mutated in tumor tissues, the possibility of activating the bodys immune system is high, and the probability of benefiting from immunotherapy is greater. Therefore, TMB high mutations are also an important biomarker for predicting the effectiveness of PD-1 antibodies. Many existing immunotherapies inhibit the PD-1/PD-L1 pathway, and if immune T cells can be blinded by cancer cells, they can remain active and attack cancer cells. Researchers expect to be able to find indications in the patients blood through a simple blood test to tell the doctor if the immunotherapy is effective. How to improve the efficacy of PD-1/PD-L1 inhibitors, accurate prediction and dynamic monitoring of therapeutic effects has become the most concerned issue in the clinical community. In this paper, we compare several liquid biopsy technologies including CTC, ctDNA and exosomes for the prediction and surveillance of PD-1/PD-L1 inhibitor drugs in immunotherapy.

Clinical and molecular characteristics associated with the efficacy of PD-1/PD-L1 inhibitors for solid tumors: a meta-analysis.

We conducted a meta-analysis to estimate the impact of different clinical and molecular characteristics on the efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PubMed and Web of Science were searched for related trials. Eleven eligible studies, comprising 5,663 patients, were included in this meta-analysis. We found that the PD-1/PD-L1 inhibitor was associated with a 31% reduction in the risk of death (hazard ratio [HR]=0.69; 95% CI 0.64–0.74; P<0.00001) for patients with melanoma, non-small-cell lung cancer (NSCLC), urothelial carcinoma, head and neck carcinoma, and renal cell carcinoma. In subgroup analyses, all the patients with PD-L1-positive tumors had overall survival (OS) benefits from PD-1/PD-L1 inhibitors regardless of PD-L1 expression level, and a dose–effect relationship between the expression of PD-L1 and OS benefit from PD-1/PD-L1 inhibitors was observed. There was an OS improvement for patients with a smoking history (P<0.00001), but no OS benefit was observed for nonsmokers (P=0.28). In addition, first-line therapy had better OS than second-line or later treatment (P=0.02). No significant improvement of OS was observed (P=0.70) in patients aged ≥75 years. The relative treatment efficacy was similar according to sex (male vs female, P=0.60), performance status (0 vs ≥1, P=0.68), tumor histology (squamous NSCLC vs non-squamous NSCLC vs melanoma vs urothelial carcinoma vs head and neck carcinoma vs renal cell carcinoma, P=0.64), and treatment type (PD-1 inhibitor vs PD-L1 inhibitor, P=0.36). In conclusion, PD-L1-positive tumors, smoking history, and first-line treatment were potential factors for the efficacy of PD-1/PD-L1 inhibitors. Patients with higher PD-L1 expression might achieve greater OS benefits. In addition, sex, performance status, tumor histology, and treatment type could not predict the efficacy of this therapy. In contrast, patients aged >75 years and nonsmokers might not get OS benefits from this treatment. These results may improve treatment strategies and patient selection for PD-1/PD-L1 inhibitors.

P3.04-07 Correlation Between PD-L1 Expression and Expression of CDK4 and SPOP in Non-Small Cell Lung Cancer

Immunotherapy that targets programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has emerged as a novel treatment modality for cancers. Clinical trials have reported durable responses and long-term remissions using PD-1/PD-L1 inhibitors, and the expression level of PD-L1 at the tumor cells was correlated with a response to PD-1/ PD-L1 inhibitors. However these inhibitors are only effective in a subset of lung cancer patients, and the underlying molecular mechanisms are not well understood. Recently, it has been reported that PD-L1 expression can be regulated at both transcriptional and post-translational levels, such as cyclinD-CDK4 and the cullin 3-SPOP (phosphorylation of speckle-type POZ protein) E3 ligase. In this study, we focus on the regulation of PD-L1 expression in lung cancer, and we investigated the association between the expression of PD-L1 and biomarkers in regard to clinical outcomes. We invested CDK4, CDK6 and SPOP expression of lung cancer, and CD4 and CD8 expression of tumor-infiltrating lymphocytes (TILs) by immunohistochemistry of 36 non-small cell lung cancers, those had undertaken an operation or chemotherapy from March 2007 to January 2018 and analyzed PD-L1 expression (negative:0%, low expression:1-49%, high expression:≥50%). The staining intensity of CDK4, CDK6 and SPOP was scored as 0 (negative), 1 (weak), 2 (medium), and 3 (strong). Extent of staining was scored as 0 (0-10%), 1 (11-25%), 2 (26-50%), 3 (51-75%), and 4 (76-100%) according to the percentages of the positive staining areas in relation to the whole cancer area. For CD4+ and CD8+ cells, a maximum numbers of stained cell were counted semi-quantitatively in high-powered fields for the scoring as 1-4. The observed protein expression levels and TILs counts were analyzed for correlation to PD-L1 expression, clinicopathological parameters and the responses of PD-1 inhibitors. PD-L1 expression was observed in 15 (48%) patients of lung cancer, 8 (26%) of low expression and 7 (23%) of high expression. Positive expression rates of SPOP were 56.3% of negative expression of DP-L1, 50.0% of low expression and 28.6% of high expression. That of CDK4 and CDK6 was 43.8%, 25.0%, 16.6%, and 43.8%, 62.5%, 51.7%, respectively. The positive rate of SPOP (p=0.67), CDK4 (p=0.16) and CDK6 (p=0.37) in PD-L1 positive group was lower than that of PD-L1 negative group, but significant. CD8+ cell count was positive relation to PD-L1 expression. Our data supported previous findings that inhibition of CDK4 and CDK6 increases PD-L1 protein levels and SPOP-deficiency correlated with increased PD-L1 protein abundance.

Predictive Markers for Treating Efficacy of PD-1/PD-L1 Inhibitors in Patients with Lung Cancer: A Review of the 18th World Conference on Lung Cancer

程序化死亡受体-1（programmed cell death-1, PD-1）/程序化死亡受体的配体（programmed cell death-ligand 1, PD-L1）免疫检查点抑制剂治疗非小细胞肺癌（non-small cell lung cancer, NSCLC）是近年来最引人注目的进展之一，但目前尚无明确的疗效预测标志物，研究者期望找到明确的标志物来筛选免疫治疗有效的患者，最大程度地让患者获益。第18届世界肺癌大会有关PD-1/PD-L1免疫治疗疗效预测的标志物的研究成为热点。本综述整理分析本次大会上关于肺癌免疫治疗标志物的内容，归纳为以下6个方面：PD-L1表达、肿瘤突变负荷及基因突变修复能力、肿瘤驱动基因突变、免疫效应标志物、血细胞计数、综合分析模型，以帮助临床医生选择合适的生物标志物来筛选能够获益的患者和对治疗疗效进行有效评估。

Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis

ObjectiveTo evaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive...

Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown. To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Abstract IA24: Setting the stage for immunotherapy in breast cancer: where are we and where are we going in the clinic?

Abstract IA24: Setting the stage for immunotherapy in breast cancer: where are we and where are we going in the clinic?

SLAG-3 in non-small-cell lung cancer patients' serum.

BackgroundAnti-programmed cell death-1/programmed cell death ligand-1 monoclonal antibodies have been widely used in non-small-cell lung cancer (NSCLC), but not every patient can get benefits from them. Whether other molecular markers can predict the results of programmed cell death-1/programmed cell death ligand-1 inhibitors need to be explored. Lymphocyte-activation gene-3 (LAG-3) is another important immune checkpoint, which can inhibit tumor immunity. Soluble LAG-3 (sLAG-3) plays different functions from LAG-3. In this study, we detected the serum sLAG-3 level in NSCLC patients.MethodssLAG-3 was detected in 247 hospitalized patients by enzyme-linked immunosorbent assay. Every sample was repeated three times.ResultsTwo-hundred forty-seven hospitalized patients were enrolled in this study. Of them, 71 had benign diseases and 176 were NSCLC patients. sLAG-3 in NSCLC serum was correlated with NSCLC stage. The sLAG-3 levels were significantly higher in stage I–II NSCLC than in stage III–IV (p<0.001).ConclusionThe advanced NSCLC had the lower sLAG-3 expression. This might be related to the poor cancer immune response. Increasing sLAG-3 level might be a promising treatment in advanced NSCLC patients.

Abstract 2366: The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer

Abstract Immune checkpoint inhibitors, specifically those which target T cell surface receptor Programmed Cell Death-1 (PD-1) and its ligand, Programmed cell death ligand-1 (PD-L1), have demonstrated clinical benefit in patients with non-small cell lung cancer (NSCLC). Currently, tumor expression of PD-L1 serves as the FDA-approved companion diagnostic for response to anti-PD-1/PD-L1 therapy. However, a fraction of patients who express PD-L1 exhibit a response to treatment, and in some cases, patient tumors that do not express PD-L1 demonstrate response to therapy, making this a poor predictive biomarker. Further, the mechanism by which PD-L1 expression is controlled remains under-studied. In this study, we seek to determine the impact of the protein tyrosine phosphatase, SHP-2, on PD-L1 expression through Jak/STAT- mediated signaling in NSCLC cell lines. SHP-2 can harbor activating mutations which prevent auto-inhibition of the catalytic phosphatase domain, and that may be pro-tumorigenic in some tumors. To understand the impact of SHP-2 activity on PD-L1 expression, we first assessed activation of STAT3 in NSCLC tumor cells after treatment with IFNγ and other mitogens. We then transfected NSCLC cells with wildtype and hyperactive SHP-2 mutants or ablated SHP-2 with siRNA specific for SHP-2 and measured both STAT3 and PD-L1 expression. Cell lines A549 and H661 exhibit low endogenous expression of both SHP-2 and PD-L1, and thus were chosen for transfection with hyperactive SHP-2 mutants (E76K and G503V), which also altered PD-L1 expression by western blot analysis. Quantitative real-time PCR (qPCR) and western blot analysis revealed that siRNA ablation of SHP-2 led to increased PD-L1 expression in the H460 cell line. Cells transfected with the SHP-2 activating mutants will also be assessed alteration of cell proliferation. Finally, using data obtained from The Cancer Genome Atlas project, STAT3 and PD-L1 expression levels are being evaluated in NSCLC tumor samples in which SHP-2 is mutated (E76K or G503V). With these data, we expect to gain a more complete understanding of the role of SHP-2 within the tumor microenvironment and the extent to which it controls PD-L1 expression, leading to new drug targets or combinations of drugs and better predictive biomarkers of response to PD-1 and PD-L1 inhibitors. Citation Format: Keller Toral, Brent Harris, Jarrod Creameans, Penni Black. The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2366.

Potential predictive value of JAK2 expression for Pan-cancer response to PD-1 blockade immunotherapy

Background: Recent clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) signaling in malignant tumors. However, reliable biomarkers for predicting who would benefit from anti-PD-1/PD-L1 inhibitors have not been fully elucidated.