PD-L1 Inhibitors In Patients Research Articles

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The efficacy and safety of PD-1/PD-L1 inhibitors in patients with recurrent or metastatic nasopharyngeal carcinoma: A systematic review and meta-analysis.

There is currently no effective salvage therapeutic modality that improves the survival outcomes of patients with recurrent or metastatic nasopharyngeal carcinoma. However, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors may provide clinical benefit for these advanced patients. The databases, including PubMed, Web of Science, EMBASE and Cochrane Library, were systematically searched up to Nov 5, 2019. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, and drug-related adverse events were extracted and pooled meta-analyzed. From 71 search records, eight studies were included in the systematic review, of which three were eligible for final meta-analysis. In recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy, the pooled ORR was 27% (95% confidence interval [CI] 19-36%), DCR was 63% (95% CI 50-75%), 6months PFS rate was 49% (95% CI 40-58%), 1-year PFS rate was 25% (95% CI 19-32%), 1-year OS rate was 61% (95% CI 49-72%). The pooled incidences of any grade and grade≥3 drug-related adverse events were 94% and 20% respectively. We present the aggregate response rates, survival rates and incidences of drug-related adverse events for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-1/PD-L1 blockage treatment, which could provide useful information for future design of clinical studies. There is a need for more randomized controlled studies with head-to-head comparison of PD-1/PD-L1 inhibitors and traditional chemotherapeutic strategies to enable better recommendations for optimal advanced nasopharyngeal carcinoma treatment.

Evaluation of the Length of Treatment With PD-1/PD-L1 Inhibitors in Patients With Advanced Solid Tumors

Evaluation of the Length of Treatment With PD-1/PD-L1 Inhibitors in Patients With Advanced Solid Tumors

JCSE01.22 Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored. Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored. A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells. In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor. PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.

P1.04-42 Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer

P1.04-42 Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer

P2.04-21 Serum CRP Decrease Has Predictive Value for Long-Term Disease Control by PD-1/ PD-L1 Inhibitors in Patients with NSCLC

Several studies showed the predictive or prognostic value of systemic inflammatory markers such as C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In OAK study, serum CRP decrease at 6 weeks from baseline was associated with the favorable clinical efficacy of atezolizumab, a PD-L1 inhibitor. However, the result is not validated in the clinical practice setting including patients treated with anti PD-1 antibodies. The aim of this study is to investigate the significance of serum CRP change from baseline as a biomarker in NSCLC patients treated with PD-1/PD-L1 inhibitors. The current study is a retrospective cohort study. NSCLC patients treated with anti-PD-1/PD-L1 inhibitors in 2nd or later line setting were reviewed at Nagoya University Hospital and Tosei General Hospital. Patients were divided into two groups by serum CRP change (Group 1; patients with serum CRP decrease at 6 weeks by ≥33% compared to the baseline, and Group 2; the others except Group 1). From January 2016 to September 2018, 124 advanced or recurrent NSCLC patients were enrolled. 34 (27.4%) patients were divided into Group 1 and 90 (72.6%) were into group 2, respectively. Group 1 showed statistically significant higher objective response rate compared with Group 2 (38.2% vs 7.0%, p<0.01), and longer progression-free survival (PFS) (1-year PFS rate: 34.2% vs. 11.7%, HR of group 1 to group 2: 0.63 (95%CI: 0.39-0.98), p=0.04). Multivariate analysis also identified the CRP decrease as an independent favorable factor of PFS (adjusted HR of group 1 to group 2: 0.45 (95%CI: 0.26-0.77), p<0.01). In contrast, PFS and OS were similar between the patients treated with PD-1 and PD-L1 inhibitors. Serum CRP decrease at 6 weeks from baseline would have predictive value for long-term disease control by PD-1/PD-L1 inhibitors for NSCLC in the clinical practice setting.

1984PD - Functional cell profiling (FCP) of ∼100,000 CTCs from multiple cancer types identifies morphologically distinguishable CTC subtypes within and between cancer types

BackgroundDifferent cancers subtypes can often be effectively treated with similar Rx classes, i.e., with PARPi in the case of BRCA mutations or with anti-PD1/PDL1 inhibitors for patients with mismatch repair deficiencies. Using the Epic Sciences Functional Cell Profiling (FCP) platform utilizing high resolution digital pathology and machine learning, we analyzed ∼100,000 single CTCs from multiple indications to index metastatic cancers, with the longer-term hypothesis that sub-classification of CTCs may help define therapeutic decisions across cancer types. Methods92,300 CTCs underwent FCP analysis (single cell digital pathology features of cellular and sub-cellular morphometrics) were collected from cancer patients comprising Prostate (1641 pts, 70,747 CTCs), Breast (268 pts, 8,718 CTCs), NSCLC (110 pts, 1884 CTCs), SCLC (141 pts, 8,872 CTCs) and Bladder (65 pts, 2079 CTCs). An equal number of CTCs from each indication was sampled to create a balanced cohort for training. K-means clustering was applied on the training set and an optimized number of clusters were determined using the elbow approach. After defining the clusters on the training set, the cluster centers were extracted from k-means, and used to train a k-Nearest Neighbor (k-NN) classifier to predict the cluster assignment for the remaining CTCs designated as the test set. ResultsThe optimized number of clusters was 9. Breast cancer CTCs were more enriched with higher CK expressing CTCs (c1), while SCLC and some of mCRPC shared similar small cell like features (c5). Cluster subtypes and characteristics are listed.Table1984PDTableClusterCharacteristicsBladderBreastNSCLCSCLCProstatec1Highest CK8%24%1%5%9%c2Highest N/C ratio13%15%7%35%21%c3Large, Elongated1%3%12%1%3%c4Low N/C, Low CK33%24%25%8%12%c5Small, Higher N/C ratio, More Round11%12%11%37%33%c6Low CK, Elongated8%4%8%2%4%c7Highest Nucleoli Count0%0%17%1%4%c8Large Nuclear Area, Highest Nuclear Entropy21%14%10%11%10%c9Most Elongated Cytoplasm4%3%9%2%4% ConclusionsHeterogeneous CTC phenotypic subtypes were observed across multiple indications. Each indication harbored subtype heterogeneity and shared clusters with other cancers. Patient cluster subtype analysis for prognosis and therapy benefit as well as linkage of CTC subtype genotypes to patient survival by cancer type is ongoing. Legal entity responsible for the studyThe authors. FundingEpic Sciences. DisclosureA. Jendrisak: Full / Part-time employment: Epic Sciences. R. Sutton: Full / Part-time employment: Epic Sciences. S. Orr: Full / Part-time employment: Epic Sciences. D. Lu: Full / Part-time employment: Epic Sciences. J. Schonhoft: Full / Part-time employment: Epic Sciences. Y. Wang: Full / Part-time employment: Epic Sciences.

P1.01-62 Association of Baseline Pulmonary Fibrosis with the Outcome of PD-1 Inhibitor in Patients with Advanced Non-Small Cell Lung Cancer

PD-1/PD-L1 inhibitors have become standard care for previously treated advanced non-small cell lung cancer (NSCLC). However, not all patients are suitable for the immunotherapy. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced NSCLC and pre-existing pulmonary fibrosis (PF). Patients who had a NSCLC diagnosis, received anti-PD-1/PD-L1 monotherapy and had baseline chest HRCT screen at Shanghai Pulmonary Hospital, Tongji University were retrospectively collected from January 2016 to February 2019. The pre-existence of PF was identified by reviewing baseline chest imaging. Baseline clinicopathologic characteristics, treatment outcomes and immune-related pneumonitis were collected. 116 patients were included with 61 age < 65. Among them, 97 (83.6%) were male, 76 (65.5%) were smoker, 51 (44%) were squamous, 61 (52.6%) received anti-PD-1 monotherapy (Pembolizumab n=62, Nivolumab n=28) as 2nd line setting, 28 (24.1%) had PF prior to PD-1 inhibitors. Baseline characteristics such as age, gender, ECOG PS, smoking history, pathology are similar between patients with or without PF. Patients with PF had a comparable response (ORR: 25% vs 15.9%, p=0.277, figure A), disease control (DCR: 60.7% vs 48.9%, p=0.274, figure B) and PFS (median 2.5 vs 2.8 months, p=0.950). The incidence of immune-related pneumonitis in the entire cohort was 9.2%, which was numerally higher in PF group (17.9% vs 6.8%, p=0.172, figure C). No death from immune-related pneumonitis occurred. NSCLC patients with pre-existing PF showed comparable response to PD-1 inhibitors but a higher incidence to immune-related pneumonitis.

The effects and safety of PD-1/PD-L1 inhibitors on head and neck cancer: A systematic review and meta-analysis.

BackgroundInhibitors of programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) have been increasingly used in head and neck cancer therapy and reported to improve the outcomes with an acceptable safety profile. This systematic review and meta‐analysis was conducted to assess the benefit and risk of PD‐1/PD‐L1 inhibitors in patients with head and neck cancer.MethodThe PubMed, Cochrane Library, EMBASE and Web of Science databases were systematically searched to find potentially eligible studies up to May 30, 2019. Primary outcomes were overall survival (OS), progression‐free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events.ResultsOverall, this analysis consisted of nine eligible studies, with two randomized controlled trials and seven single arm trials. In the treatment of recurrent or metastatic head and neck cancer, PD‐1 inhibitors showed significantly lower relative risk of death than standard‐of‐care therapy (odds ratio [OR] = 0.60, 95% confidence interval [CI]: 0.44‐0.82, I 2 = 0%, P = .001). Programmed cell death‐1 inhibitors also decreased the risk of disease progression, however, there was no statistically significant difference of PFS between the treatments (OR = 0.69, 95% CI: 0.48‐1.01, I 2 = 0%, P = .05). Subgroup analysis showed that human papillomavirus (HPV) positive patients had higher response rates than HPV negative patients in PD‐1/PD‐L1 inhibitors‐treated population (ORR: 18.8% vs 12.2%; DCR: 42.8% vs 34.4%). The most common any‐grade and grade ≥3 treatment‐related adverse events were fatigue (14.7%, 95% CI: 12.3%‐17.1%) and aspartate aminotransferase increased (1.6%, 95% CI: 0.3%‐2.9%), respectively.ConclusionProgrammed cell death‐1 inhibitors prolonged OS in comparison with standard‐of‐care therapy in recurrent or metastatic head and neck cancer patients. Human papillomavirus positive patients were superior to HPV negative patients in the treatment of PD‐1/PD‐L1 inhibitors. More phase III randomized controlled trials are warranted to confirm our findings.

Efficacy of PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer: A meta-analysis of randomized clinical trials.

BackgroundThis meta‐analysis systematically evaluated the efficacy of PD‐1 and PD‐L1 inhibitors for the treatment of advanced non‐small cell lung cancer (NSCLC) and investigated the efficacy of first‐line therapy and PD‐1 versus PD‐L1 inhibitors.MethodsPubMed, The Cochrane Library, and Embase were searched up to November 2018 for randomized controlled trials (RCTs) for eligible studies. The outcome of interest was overall survival (OS). The methodology was based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and Cochrane Collaboration guidelines. Data were pooled by using the random effects model and expressed as hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Heterogeneity was assessed and quantified (I 2).ResultsSeven RCTs were included in this study. PD‐1/PD‐L1 inhibitors achieved superior OS compared to chemotherapy (HR 0.72, 95% CI 0.63–0.82; P < 0.0001). OS was superior in previously treated patients compared to untreated patients (HR 0.69, 95% CI 0.63–0.76; HR 0.82, 95% CI 0.47–1.44, respectively). No significant differences in OS were observed between PD‐1 and PD‐L1 inhibitors (HR 0.71, 95% CI 0.59–0.86; HR 0.73, 95% CI 0.63–0.84, respectively).ConclusionsPD‐1/PD‐L1 inhibitors significantly prolonged the OS of previously treated patients. No significant differences in OS were observed between PD‐1 and PD‐L1 inhibitors.

Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma.

We evaluated the predictive role of EGFR mutation on the efficacy of PD-1/PD-L1 inhibitor therapy in patients with advanced pulmonary adenocarcinoma while considering clinical factors such as PD-L1 expression, gender, and smoking status. Patients were required to have available data for EGFR mutation, PD-L1 expression, and efficacy of PD-1/PD-L1 inhibitors. Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factors: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001); never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03); and females vs. males (21.0% vs. 33.6%, p = 0.08). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53). Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.

A meta-analysis of the efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors as treatments for metastatic bladder cancer.

BackgroundThis article is a meta-analysis aiming to systematically assess the efficacy and safety profiles of PD-1/PD-L1 inhibitors in patients with advanced or metastatic bladder cancer.MethodsWe extracted and examined data from phase I, II, and III clinical trials from the Medline, Embase, and the Cochrane Library, which included patients with metastatic bladder cancer who were treated with PD-1/PD-L1 inhibitors. We performed a meta-analysis to investigate several indexes of efficacy and safety, including the objective response rate (ORR), 1-year overall survival (OS) rate, 1-year progression-free survival (PFS) rate, and adverse event (AE) rate of immune checkpoint inhibitors. The material data were calculated and pooled using The R Project for Statistical Computing and Review Manager 5.3.ResultsAfter excluding ineligible records, 14 clinical trials were included in our analysis. The pooled frequencies of all-grade AEs and grade ≥3 AEs were 0.63 (95% CI 0.61–0.65, P=0.34) and 0.14 (95% CI 0.11–0.17, P=0.0072), respectively. The summary ORR was 0.21 (95% CI 0.18–0.24 P=0.07), and the 1-year OS and 1-year PFS rates were 0.48 (95% CI 0.42–0.54 P=0.0013) and 0.21 (95% CI 0.16–0.26 P=0.04), respectively. The OR of ORR between the PD-L1-positive and -negative groups was 3.09 (95% CI 2.01–4.75, P=0.08).ConclusionThe PD-1/PD-L1 therapy showed appropriate efficacy and acceptable incidence of treatment-related AEs. In addition, the level of discrimination of PD-L1 expression might be related to the effect of the PD-1/PD-L1 inhibitors, and patients displaying positive expression might experience a better curative effect than patients displaying negative expression.

Clinical value of neutrophil-to-lymphocyte ratio in patients with non-small-cell lung cancer treated with PD-1/PD-L1 inhibitors

IntroductionThere is unmet need to explore the predictive biomarkers of PD-1/PD-L1 inhibitors in patients with non-small-cell lung cancer (NSCLC). Here, we aimed to investigate the predictive and prognostic value of blood neutrophil-to-lymphocyte ratio (NLR) in NSCLC patients treated with PD-1/PD-L1 inhibitors. MethodsWe performed a comprehensive online search to explore the association between blood NLR and overall survival (OS) or progression-free survival (PFS) in NSCLC patients received PD-1/PD-L1 inhibitors. Published data including hazard ratios (HRs) and 95% confidence interval (CI) were eligible. Pooled estimates of treatment outcomes were calculated using Stata/MP 14.1. Results1700 patients from sixteen studies were included. The pooled results suggested that high blood NLR was correlated with significantly shorter OS (HR = 2.07, P < 0.001) and PFS (HR = 1.59, P < 0.001). The predictive and prognostic significance of blood NLR were observed consistently across most subgroups including publication year, study design, research region, PD-L1 expression detection, sample size, NLR cutoff, median follow-up time and study quality score. Additionally, there was a significant correlation between elevated NLR cutoff values and OS benefit (r = 0.585, P = 0.036) but not for PFS benefit (r = 0.198, P = 0.496). Notably, HRs of PFS showed significant correlation with HRs of OS (r = 0.686, P = 0.041). ConclusionElevated blood NLR was associated with shorter PFS and OS in NSCLC patients treated with PD-1/PD-L1 inhibitors, suggesting its potential predictive and prognostic value in this clinical scenario.

The Relative Risk and Incidence of Immune Checkpoint Inhibitors Related Pneumonitis in Patients With Advanced Cancer: A Meta-Analysis.

Background: Recently, immune checkpoint inhibitors (ICIs) have been proved one of the most promising anti-cancer therapy, series clinical trials have confirmed their efficacy. But they are also associated with distinctive set of toxic effects, which are recognized as immune-related adverse events. Among those immune-related adverse events, pneumonitis is rare, but it is often clinically serious and potentially life-threatening. Although many clinical trial results of PD-1/PD-L1 inhibitors had been reported incidence of pneumonitis, the knowledge based on the individual cohort data from each clinical trial is limited. So we conducted a meta-analysis of trials of PD-1/PD-L1 inhibitors in patients with advanced cancer and compared relative risk and incidence among different tumor types and therapeutic regimens. Such an analysis may provide important knowledge of this rare but clinically significant and potentially serious immune-related adverse event.Methods: Electronic databases were used to search eligible literatures, include randomized controlled trials (RCTs) comparing immune checkpoint inhibitors vs. standard therapies. All-grade (1–4) or high-grade (3–4) pneumonitis events were extracted. The summary relative risk, summary incidence, and 95% confidence intervals were calculated.Results: The incidence of all-grade and high-grade pneumonitis in non-small cell lung cancer (NSCLC) was significantly higher compared with other tumor types, such as Melanoma, urothelial carcinoma (UC), head and neck squamous cell carcinoma (HNSCC) (3.1% vs. 2.0%; p = 0.02, 1.4% vs. 0.6%; p = 0.03). The risk of all-grade pneumonitis was obtained from all patients in both experimental arm and control arm. Treatment with immune checkpoint inhibitors targeting PD-1/PD-L1 did significantly increase the risk of all-grade and high-grade pneumonitis compared with controls (fixed effects, RR: 4.70; 95% CI: 2.81–7.85; p < 0.00001, RR: 3.33; 95% CI: 1.68–6.59; p = 0.0006).Conclusion: The incidence of immune checkpoint inhibitors related pneumonitis was higher in NSCLC than other tumor types. Patients treated with immune checkpoint inhibitor in experiment arms are more likely to experience any grade pneumonitis than control arms. These findings suggest that clinician need to draw more attention on this rare but serious adverse event.

Thrombocytopenia Is a Biomarker for Response in Patients Treated with Anti PD-1/Pdl-1 Therapy

Background: Immunotherapy directed against the PD-1/PDL-1 (programmed cell death protein [ligand] 1) pathway has shown activity across a range of malignancies. Immune-related adverse events have been shown to be associated with the efficacy of PD-1/PDL-1 inhibitors in patients with melanoma and non-small cell lung cancer. Thrombocytopenia has been reported in up to 33% of patients receiving anti PD-1/PDL-1 therapy. Our hypothesis is that immune-mediated thrombocytopenia may be a biomarker for response to anti PD-1/PDL-1 therapy.Methods: We collected data on 250 patients aged 18 years and older who were treated with anti PD-1/PDL-1 therapy at the University of Oklahoma Health Sciences Center between January 2014 and January 2016. Initial platelet count at baseline as well as nadir platelet count during treatment were examined. Patient's clinicopathologic characteristics were analyzed using simple descriptive statistics [median (range) for continuous covariates and n (%) for categorical variables]. Kaplan Meier Analysis was performed to assess how thrombocytopenia was associated with overall survival (OS) and progression free survival (PFS). Patients were grouped according to their nadir platelet count: normal platelets (≥150k), grade 1 (75k-150k), and combined grades 2, 3, 4 (<75k). Cox proportional hazard regression models were used to assess the association of thrombocytopenia with OS and PFS adjusted for various covariates. The objective of the study is to assess whether the degree of thrombocytopenia correlates with the PFS and OS in patients receiving anti PD-1/PDL-1 therapy.Results: A total of 250 patients were reviewed in this study. After excluding 27 patients with baseline platelet count <100k and 14 patients with missing platelet count data, 209 patients were included in the analysis. Fifty-five percent were females. Median age at diagnosis was 62 (23-91) years. The most common cancer diagnoses were lung cancer (21.1%), melanoma (17%), and ovarian cancer (9%). Nivolumab was the most commonly used agent (40.9%), followed by Pembrolizumab (38.4%). Median number of treatments received was 5. Median platelet count at baseline was 227 (102-535). Median nadir platelet count was 180 (4-552). Thrombocytopenia of any grade was observed in 70 (33%) patients .The number of patients with grade 1, 2, and 3/4 were 56 (26.8%), 1 (0.5%) and 13 (6.2%), respectively. Median follow-up time was 226 days. Univariate analysis showed that patients with grade I thrombocytopenia had higher PFS and OS when compared to patients who did not develop thrombocytopenia [HR 0.48 (95% CI, 0.29-0.81), P = 0.0053 and HR 0.49 (95% CI, 0.27-0.9), P = 0.0209, respectively]. When adjusted for age, cancer type, performance status, and line of treatment, grade 1 thrombocytopenia remained positively associated with survival outcome [HR 0.50 (95% CI, 0.29-0.87), P = 0.0146 for PFS and HR 0.40 (95% CI, 0.21-0.77), P = 0.0061 for OS]. Only 14 patients had grade 2-4 thrombocytopenia, and there was no statistically significant difference in survival compared to patients with no thrombocytopenia [adjusted HR 0.52 (95% CI, 0.2-1.38), P = 0.189 for OS].Conclusion: Our study shows that in patients treated with anti PD-1/PDL-1 therapy, grade 1 thrombocytopenia appears to be positively correlated with survival outcomes. This survival advantage was not seen with higher grades of thrombocytopenia. PD-L1 was recently shown to be expressed on human platelets; thus, thrombocytopenia is likely immune-mediated. Thrombocytopenia may be a biomarker for efficacy of immune checkpoint therapy. The predictive significance of thrombocytopenia in patients receiving PD-1/PDL-1 therapy warrants further investigations. DisclosuresNo relevant conflicts of interest to declare.

Pilot evaluation of PD-1 inhibition in metastatic cancer patients with liver transplantations (LT): The Mayo Clinic experience.

328 Background: Patients with a history of solid organ transplants have been excluded from PD-1/PD-L1 inhibitor clinical trials due to concern for graft rejection. Only 2 case reports of PD-1 inhibitor use in patients with liver transplantation (LT) have been reported thus far. Here, we report our experience with using checkpoint inhibitors in metastatic cancer patients with LT. Methods: A single center pilot evaluation was conducted to evaluate the safety and efficacy of PD-1/PD-L1 inhibitors in patients with LT. PD-L1 staining on both the tumor and allograft were assessed if there was available tissue. The primary endpoint was evaluation of the risk for allograft rejection. Secondary endpoints included RECIST v1.1 and Immune-Related Response criteria (iRC) response rates, progression free survival (PFS) and overall survival (OS). Translational objectives included the relationship of PD-L1/PD-1 staining of tumor/allograft with response and rejection. Results: Six metastatic cancer patients with a history of LT received PD-1 inhibitor therapy (hepatocellular n=5, melanoma n=1). 3 patients were on mTOR inhibitor as immunosuppressive regimen and 3 on calcineurin inhibitor. Overall, allograft rejection was observed in 1/6 patients (on mTOR inhibitor). One patient achieved a CR (melanoma), 3 patients had PD and 2 patients discontinued therapy prior to restaging assessments. A single response (by both RECIST v1.1 and iRC) and rejection were reported in patients who received mTOR inhibitors (1 of 3). Three patients were tested for PD-L1 staining in the allograft tissue and all of them were negative (0% staining) with no graft rejections observed. Four patients had tumor PD-L1 evaluated (2 patients tested positive with 1 patient obtained a CR). The median OS, PFS and duration of therapy were 1.2, 1.8 and 1.2 months respectively. Conclusions: In this pilot evaluation of PD-1/PD-L1 inhibitors in LT patients both preliminary efficacy (1 of 4) and allograft rejection (1 of 6) was exhibited. Larger, prospective trials are needed to elucidate optimal patient and immunosuppressive regimen selection in these patients.

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer

Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a noninvasive method to evaluate PD-L1 status in advanced NSCLC patients. CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform; Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody; Ventana), and quantified in tumor cells and WBCs. CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4 ml, and median of 60 CTCs/4 ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥1 PD-L1-positive CTCs and 11 patients (15%) showed ≥1% PD-L1-positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (sensitivity = 55%; specificity = 100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥1% PD-L1-positive immune infiltrates in tumor tissue and 39 patients (53%) showed ≥1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (sensitivity = 82%; specificity = 79%). We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in CTCs or immune cells (progression-free and overall survival), similar to the effects of PD-L1 expression in matched-patient tumors. These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.

Impact of Clinicopathologic Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients With Previously Treated Non–small-cell Lung Cancer

BackgroundThe current study aimed to comprehensively investigate the impact of various clinicopathologic features on the efficacy of programmed cell death-1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non–small-cell lung cancer (NSCLC). Patients and MethodsRandomized controlled trials that compared PD-1/PD-L1-inhibitor monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included. ResultsFive trials were included (n = 3025). For all studies, PD-1/PD-L1 inhibitors significantly prolonged overall survival (OS) (hazard ratio [HR], 0.70; P < .001) and progression-free survival (PFS) versus chemotherapy (HR, 0.86; P = .020). Subgroup analysis showed that anti-PD-1/PD-L1 monotherapy could markedly improve OS in elderly patients (HR, 0.69; P < .001), female patients (HR, 0.70; P < .001), never-smoking patients (HR, 0.73; P = .001), and patients with a histology of squamous cell carcinoma (HR, 0.67; P < .001), but not PFS in the elderly and female patient groups. Notably, PD-1/PD-L1 inhibitors cannot prolong both OS (HR, 0.76; P = .390) and PFS (HR, 0.74; P = .210) in patients with central nervous system (CNS) metastasis, whereas patients without CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy on OS (HR, 0.71; P < .001). ConclusionPD-1/PD-L1-inhibitor monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Subgroup analyses showed that most patients including elderly, females, never-smokers, and patients with squamous cell carcinomas do benefit. However, whether patients with CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy requires further validation.

P2.07-010 Impact of Clinicopathological Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients with Previously Treated Non-Small Cell Lung Cancer

The current study aimed to comprehensively investigate the impact of various clinicopathological features on the efficacy of programmed cell death 1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non-small cell lung cancer (NSCLC).

P2.07-025 Increased Antitumor Response to Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer

The role of anti-PD-1/PD-L1 inhibitor monotheapy has been demonstrated for advanced non-small cell lung cancer (NSCLC). However, its benefits in terms of response and progression-free survival are limited to small proportion of patients. The successful treatment of advanced NSCLC requires a combination of various treatment modalities. Therefore, this study evaluated whether subsequent chemotherapy administered after immunotherapy (PD-1/PD-L1 inhibitors) (SCAI) would have enhanced antitumor response in patients with NSCLC.