Programmed Death-ligand 1 Expression Status Research Articles

A CT-derived deep neural network predicts for programmed death ligand-1 expression status in advanced lung adenocarcinomas.

BackgroundProgrammed death ligand-1 (PD-L1) expression remains a crucial predictor in selecting patients for immunotherapy. The current study aimed to non-invasively predict PD-L1 expression based on chest computed tomography (CT) images in advanced lung adenocarcinomas (LUAD), thus help select optimal patients who can potentially benefit from immunotherapy.MethodsA total of 127 patients with stage III and IV LUAD were enrolled into this study. Pretreatment enhanced thin-section CT images were available for all patients and were analyzed in terms of both morphologic characteristics by radiologists and deep learning (DL), so to further determine the association between CT features and PD-L1 expression status. Univariate analysis and multivariate logical regression analysis were applied to evaluate significant variables. For DL, the 3D DenseNet model was built and validated. The study cohort were grouped by PD-L1 Tumor Proportion Scores (TPS) cutoff value of 1% (positive/negative expression) and 50% respectively.ResultsAmong 127 LUAD patients, 46 (36.2%) patients were PD-L1-positive and 38 (29.9%) patients expressed PD-L1-TPS ≥50%. For morphologic characteristics, univariate and multivariate analysis revealed that only lung metastasis was significantly associated with PD-L1 expression status despite of different PD-L1 TPS cutoff values, and its Area under the receiver operating characteristic curve (AUC) for predicting PD-L1 expression were less than 0.700. On the other hand, the predictive value of DL-3D DenseNet model was higher than that of the morphologic characteristics, with AUC more than 0.750.ConclusionsThe traditional morphologic CT characteristics analyzed by radiologists show limited prediction efficacy for PD-L1 expression. By contrast, CT-derived deep neural network improves the prediction efficacy, it may serve as an important alternative marker for clinical PD-L1 detection.

Prognostic Value of KRAS Mutation Subtypes and PD-L1 Expression in Patients With Lung Adenocarcinoma

BackgroundThe prognostic value of different KRAS (Kirsten rat sarcoma viral oncogene) mutation subtypes and their association with programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma (LADC) remain unclear. We examined the association of KRAS mutation subtypes with clinical outcomes and PD-L1 expression status. Patients and MethodsPatients diagnosed with KRAS-mutated LADC were evaluated for PD-L1 expression, cancer staging, overall survival (OS), and relapse-free survival. ResultsA cohort of 254 KRAS-mutated LADC patients (median follow-up, 17 months) was studied. The 3 major subtypes of KRAS mutations were G12C (46.1%), G12V (21.7%), and G12D (15.7%). We found that all these subtypes had no impact on cancer stages, brain metastasis at diagnosis, OS, and relapse-free survival. Among this cohort, 33% of 94 patients who had PD-L1 staining data available had PD-L1–positive disease (≥ 1% of tumor cells). PD-L1 expression status was not significantly different among the 3 major mutation subtypes. Of interest, among patients with G12C mutation, positive PD-L1 expression was associated with significantly shorter OS (median survival, 5.7 vs. 12.8 months, P = .007). In multivariable analysis, PD-L1 positivity remained as an adverse factor for OS, with hazard ratio of 4.44 (P = .0007). PD-L1 status did not affect OS in other subtypes of mutations. ConclusionKRAS mutation subtype is not associated with patient clinical outcomes or PD-L1 expression status. However, PD-L1 positivity appears to negatively affect OS in LADC patients with G12C mutation. Further study is needed to confirm our observation and to determine if programmed cell death 1/PD-L1 antagonist may affect the clinical outcome of patients with different KRAS mutation subtypes.

Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial

BackgroundMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti–programmed death-ligand 1 (PD-L1)) became the first approved treatment for...

Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement.

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (≥50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2–2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2–2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations.

Potential role of the PD-L1 expression and tumor-infiltrating lymphocytes on neuroblastoma.

The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway has garnered much attention for its roles in clinical oncology. The aim of this study was to examine the clinical impact of the PD-L1 expression and tumor-infiltrating lymphocytes (TILs) on neuroblastoma. We evaluated the PD-L1 expression and TIL status in 31 patients with neuroblastoma who underwent a biopsy or resection by an immunohistochemical analysis. Furthermore, we performed the serial analysis of the PD-L1 status before and after chemotherapy in 15 patients. Among the 31 cases, 11 (35%) showed a positive PD-L1 expression. The survival analysis showed a trend toward an association between PD-L1 positivity and a decreased overall survival. PD-L1 positivity tended to be associated with higher levels of tumor markers. In the serial analysis of the PD-L1 status, positivity was noted in 8 of 15 patients before chemotherapy and 6 after chemotherapy. Notably, all four patients with a positive PD-L1 status both before and after chemotherapy had recurrence, and 3 of them died during the follow-up period. Our findings suggest that the PD-L1 tumor expression might be a good biomarker for the treatment of neuroblastoma patients, especially for advanced neuroblastoma.

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials.

Background:Inhibitors targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have unprecedented effects in cancer treatment. However, the objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 blockade monotherapy have not been systematically evaluated.Methods:We searched Embase, PubMed, and Cochrane database from inception to July 2019 for prospective clinical trials on single-agent PD-1/PD-L1 antibodies (avelumab, atezolizumab, durvalumab, cemiplimab, pembrolizumab, and nivolumab) with information regarding ORR, PFS, and OS.Results:Totally, 28,304 patients from 160 perspective trials were included. Overall, 4747 responses occurred in 22,165 patients treated with PD-1/PD-L1 monotherapy [ORR, 20.21%; 95% confidence interval (CI), 18.34–22.15%]. Compared with conventional therapy, PD-1/PD-L1 blockade immunotherapy was associated with more tumor responses (odds ratio, 1.98; 95% CI, 1.52–2.57) and better OS [hazard ratio (HR), 0.75; 95% CI, 0.67–0.83]. The ORRs varied significantly across cancer types and PD-L1 expression status. Line of treatment, clinical phase and drug target also impacted the response rates in some tumors. A total of 2313 of 9494 PD-L1 positive patients (ORR, 24.39%; 95% CI, 22.29–26.54%) and 456 of 4215 PD-L1 negative patients (ORR, 10.34%; 95% CI, 8.67–12.14%) achieved responses. For PD-L1 negative patients, the ORR (odds ratio, 0.92; 95% CI, 0.70–1.20) and PFS (HR, 1.15; 95% CI, 0.87–1.51) associated with immunotherapy and conventional treatment were similar. However, PD-1/PD-L1 blockade monotherapy decreased the risk of death in both PD-L1 positive (HR, 0.66; 95% CI, 0.60–0.72) and PD-L1 negative (HR, 0.86; 95% CI, 0.74–0.99) patients compared with conventional therapy.Conclusion:The efficacies associated with PD-1/PD-L1 monotherapy vary significantly across cancer types and PD-L1 expression. This comprehensive summary of clinical benefit from immunotherapy in cancer patients provides an important guide for clinicians.

Consistency Analysis of Programmed Death-Ligand 1 Expression between Primary and Metastatic Non-Small Cell Lung Cancer: A Retrospective Study.

Background: Programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) is considered as a predictive biomarker of anti-PD-1/PD-L1 cancer therapies. However, the correlation of PD-L1 expression status between the primary and paired metastatic NSCLC is still not clear. The current study aims to address this specific issue.Materials and Methods: The PD-L1 expression of the primary and paired metastatic lesions from 110 patients with NSCLC was retrospectively evaluated by immunohistochemical assay using Anti-PD-L1 antibody, Clone 22C3. The results were assessed by the Tumor Proportion Score (TPS) using cutoff values of <1%, 1%-49% and ≥50%. Meanwhile, the Cohen's kappa coefficient (k) of agreement was calculated.Results: An overall concordance rate of the PD-L1 expression between the primary and metastatic lesions was 61% (63/103) (k = 0.39, and P < 0.001). If using TPS considering 1% and 50% as a threshold, the inconsistent rate was 28/103 (27.2%) paired specimens (k = 0.46, and P < 0.001) and 14/103 (13.6%) paired specimens (k = 0.53, and P < 0.001), respectively. Moreover, the concordance of the PD-L1 expression between primary and metastatic tumor was also analyzed according to the clinical stages within the untreated group of patients. We observed that for patients with stage I-III NSCLC, the concordance rate of the PD-L1 expression between primary and metastatic lesions was 81.3% and 100% when using 1% and 50% as threshold, respectively. While in stage IV patients, the concordance rate of the PD-L1 expression between the primary and metastatic lesions drops to 71.4% and 85.7%, respectively.Conclusion: The PD-L1 expression was dynamic as tumor developed, which was valuable in selecting the proper type of sample for accurately evaluating the prognosis of using pembrolizumab as first or second line treatment.

Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan

ObjectivesTo describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Materials and methodsJapanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). ResultsIn this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. ConclusionThe real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab.

Prognostic significance of PD-L1 expression and evaluation of microsatellite instability status in patients with retroperitoneal leiomyosarcomas

Background. Leiomyosarcoma is one of the most common types of soft tissue sarcomas. Radical surgical resection with subsequent adjuvant chemotherapy remain the most effective treatment approach. Immunotherapy based on inhibition of PD-L1 (programmed death ligand 1) or its receptor PD1 (programmed death 1) is considered a promising treatment option. Level of PD-L1 expression in tumor cells and presence of microsatellite instability (МSI) could be considered prognostic and predictive markers of disease progression and effectiveness of immunotherapy.The study objective is to determine PD-L1 expression level and МSI status in patients with retroperitoneal leiomyosarcomas and evaluate their effect on overall and recurrence-free survival.Materials and methods. The study included 57 patients with retroperitoneal leiomyosarcomas who underwent surgical or combination treatment. Analysis of clinical and morphological characteristics was performed; results of surgical treatment were researched. Evaluation of PD-L1 expression and MSI status was performed using immunohistochemical and molecular genetic analysis.Results. PD-L1 expression and MSI status were evaluated in 41 patients of 57. In 10 (24 %) of 41 cases, positive PD-L1 expression was observed (expression level 3–50 %). In 1 (2.4 %) patient, the primary tumor and metastatic lesion had low MSI level (MSI-low, MSI-L). Median follow-up was 31 months. In patients with positive PD-L1 expression, higher Ki-67 proliferative index was observed compared to patients with PD-L1 negative tumors (58.8 and 47.8 % respectively; р = 0.02), as well as significantly lower median overall survival for grade II tumors (30 and 105 months; p = 0.043). In grade III leiomyosarcomas, a trend towards lower median overall survival in patients with PD-L1‑negative tumors (31.0 months) compared to patients with PD-L1 expression (61.2 months) (р = 0.11) was observed.Conclusion. Among patients with retroperitoneal leiomyosarcomas, positive expression of PD-L1 was observed in 24 % (10 / 41) of cases and MSI-low status was found in 2.4 % (1 / 41) of cases. In patients with grade 2 tumors, positive PD-L1 expression is associated with significantly lower overall survival. PD-L1 expression in patients with retroperitoneal leiomyosarcomas could be considered a prognostic marker and a potential therapeutic target.

Analysis of Programmed Death-Ligand 1 Expression, Stromal Tumor-Infiltrating Lymphocytes, and Mismatch Repair Deficiency in Invasive Micropapillary Carcinoma of the Breast

Abstract Introduction: Invasive micropapillary carcinoma (IMPC) of the breast is a rare and aggressive subtype of invasive ductal carcinomas, associated with poor prognosis and without a well-established treatment. Programmed death-ligand 1 (PD-L1) expression, high tumor-infiltrating lymphocytes (TILs), and microsatellite instability have recently been linked to susceptibility to immunotherapies against PD-1/PD-L1 axis. No exhaustive data is available on the status of these predictive markers in IMPCs of the breast. The aim of our study is to analyze PD-L1 expression, stromal TIL (sTIL), and mismatch repair (MMR) gene status in IMPCs of the breast, to extend the therapeutic possibilities of these rare aggressive tumors. Materials and Methods: Thirty-seven cases of IMPCs diagnosed in two European institutions between 2003 and 2017 with detailed clinical and pathologic data were analyzed. sTILs were assessed in hematoxylin and eosin-stained sections. MMR deficiency was tested by either immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6, and PMS2) or capillary electrophoresis for microsatellite instability using a standardized panel of five loci (Bat25, Bat26, D2S123, D5S346, and D17S250). For PD-L1, expression in both tumor cells (TCs) and immune cells (ICs) was determined using the antibody clone SP263. Results: The median sTILs was 3% (mean: 6%, range: 0–40). Thirty-one cases (84%) showed ≤10% of sTILs and only one case had 40% of sTILs. Higher median TILs were more frequently observed in lymph node metastases. PD-L1 expression (≥1%) was observed in 4 (11%) and 14 (38%) cases in TCs and ICs, respectively. None of the tumors showed PD-L1 expression in &amp;gt;1% of TCs. Only three cases showed expression in &amp;gt;10% of ICs. All cases were microsatellite stable by either IHC or polymerase chain reaction analyses. Conclusions: IMPCs of the breast are microsatellite-stable and immune desert tumors with low PD-L1 expression, thus arguing against the use of immune-checkpoint inhibitors in these patients. Active immunotherapy strategies attempting to stimulate self-immune system to attack tumor are needed.

Programmed death ligand-1/programmed death-1 inhibition therapy and programmed death ligand-1 expression in urothelial bladder carcinoma

After two decades of unchanged paradigms, the treatment strategies for advanced urothelial bladder cancer have been revolutionized by emerging programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) inhibition therapy. Increased evidence is demonstrating the efficacy of PD-L1/PD1 inhibition therapy in both second-line and first-line settings. However, the percentage of patients who benefit from anti-PD-L1/anti-PD1 therapy is still low. Many questions have been raised in the development of biomarker-driven approaches for disease classification and patient selection. In this perspective, we discuss PD-L1/PD1 expression in urothelial bladder carcinoma, review approved anti-PD-L1/anti-PD1 agents for bladder cancer treatment and current ongoing studies investigating combination treatment strategies, and explore PD-L1 expression status for the evaluation of bladder cancer immunotherapy.

Programmed death ligand 1 (PD-L1) expression in parathyroid tumors.

IntroductionPD-L1 is associated with prognosis and immunotherapeutic response in patients with malignancies. In previous studies, PD-L1 expression was detected in many endocrine tumors. However, the PD-L1 expression status in parathyroid tumors is unknown.MethodsWe included 26 parathyroid carcinoma and 37 adenoma samples, as well as the corresponding patient information. PD-L1 was stained using the FDA-approved PD-L1 IHC 22C3 pharmDx and Ventana PD-L1 (SP263) assays, and staining was assessed by the estimated percentages of positive tumor cells and immune cells, respectively.ResultsWe classified the PD-L1 expression in the parathyroid tumors into four groups: (0) <1%, (1) 1–4%, (2) 5–9% and (3) ≥10% positive. With the SP263 clone, 37 (carcinoma:adenoma = 18:19) samples scored 0, 13 (carcinoma:adenoma = 4:9) scored 1, 7 (carcinoma:adenoma = 1:6) scored 2 and 6 (carcinoma:adenoma = 3:3) scored 3. However, in the series of cases using the 22C3 clone, 45 (carcinoma:adenoma = 20:25) samples scored 0, 10 (carcinoma: adenoma = 3:7) scored 1, 5 (carcinoma:adenoma = 1:4) scored 2, and 3 (carcinoma:adenoma = 2:1) scored 3. Concerning tumor-infiltrating immune cells, 57 samples were negative and six were positive with SP263, and 59 were negative and four were positive with 22C3. Moreover, PD-L1 expression was negatively correlated with the Ki-67 index and mitotic rate in parathyroid tumors depending on the different clones. However, the results indicated only moderate consistency between the SP263 and 22C3 clones in parathyroid tumors.ConclusionWe found deficient PD-L1 expression in the majority of parathyroid tumors. However, the PD-L1 expression score in parathyroid tumors depended greatly on the antibody clone used.

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients

The purpose of this study was to evaluate the prognostic impact of major histocompatibility complex (MHC) class I expression and programmed death-ligand 1 (PD-L1) expression in patients with head and neck squamous cell carcinoma (HNSCC). A total of 158 patients with HNSCC were evaluated retrospectively. The expression of MHC class I and PD-L1 was analyzed in tumor specimens using immunohistochemistry. The association between MHC class I/PD-L1 expression and clinical outcome was evaluated by Kaplan-Meier and Cox regression analyses. Among 158 patients, 103 (65.2%) showed positive PD-L1 expression, and 20 (12.7%) showed no detectable expression of MHC class I. The frequency of PD-L1 positive expression with concomitant MHC class I loss was 7.0%. In the PD-L1-positive group, MHC class I loss was associated with a significantly worse survival compared with MHC class I positivity (median overall survival 39.3 months vs. not reached; P = 0.005), whereas MHC class I status provided no prognostic impact in the PD-L1 negative group. Neither PD-L1 nor MHC class I alone showed a significant difference in overall survival. The loss of MHC class I expression in PD-L1-positive HNSCC was associated with a poor clinical outcome. This suggested that MHC class I expression status might be useful for the prognosis of tumor progression in HNSCC when combined with PD-L1 expression status. External validation with enough numbers of participants in such subgroup should be needed for validation.

Novel circulating tumor cell-based blood test for the assessment of PD-L1 protein expression in treatment-na\xefve, newly diagnosed patients with non-small cell lung cancer

We evaluated the analytical and clinical performance of a novel circulating tumor cell (CTC)-based blood test for determination of programmed death ligand 1 (PD-L1) protein expression status in real time in treatment-naïve non-small cell lung cancer (NSCLC) patients. CTCs were detected in 86% of patients with NSCLC (I–IV) at the time of diagnosis, with a 67% PD-L1 positivity rate (≥ 1 PDL + CTC). Among 33 NSCLC patients with PD-L1 results available via both tissue immunohistochemistry (IHC) and CTC assays, 78.9% were positive according to both methods. The CTC test identified an additional ten cases that were positive for PD-L1 expression but that tested negative via IHC analysis. Detection of higher PD-L1 expression on CTCs compared to that in the corresponding tissue was concordant with data obtained using other platforms in previously treated patients. The concordance in PD-L1 expression between tissue and CTCs was approximately 57%, which is higher than that reported by others. In summary, evaluation of PD-L1 protein expression status on CTCs isolated from NSCLC patients is feasible. PD-L1 expression status on CTCs can be determined serially during the disease course, thus overcoming the myriad challenges associated with tissue analysis.

Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial

A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. F Hoffmann-La Roche Ltd and Genentech Inc.

Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma.

Purpose: Immunotherapy may be a potential alternative for patients with sinonasal squamous cell carcinoma (SNSCC). Data regarding potential immunotherapy targets, such as programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), in SNSCC are limited. In this study, we assessed the prevalence and prognostic value of PD-L1 expression and TILs in p16-negative and p16-positive SNSCC.Patients and methods: Tissues from 96 patients with SNSCC were stained using immunohistochemistry against PD-L1, CD8, and Foxp3 to assess the immune environment. The correlations between PD-L1 expression, TILs, and p16 status were analyzed. Additionally, PD-L1, CD8, and Foxp3 expressions, as well as p16 status, were analyzed in relation to patient clinicopathological variables and prognosis.Results: Twenty-nine (30.2%) patients with SNSCC showed PD-L1 expression in >5% of tumor cells. PD-L1 expression was significantly correlated with poor differentiation and a high level of TILs. PD-L1 expression and the CD8+ and Foxp3+ T-cell infiltrates in p16-negative patients (n=78, 81.2%) and p16-positive patients (n=18, 18.8%) were not significantly different. PD-L1 expression and p16 status were not associated with overall survival (OS) and disease-free survival (DFS). Patients with high CD8+ or Foxp3+ cell infiltration had better clinical outcomes. A multivariate analysis confirmed that CD8 TILs were a significant independent and favorable prognostic factor for OS (p=0.023) and DFS (p=0.008).Conclusion: TILs can play a prognostic role in SNSCC. We did not find differences in immune marker expression between p16-positive and p16-negative SNSCC tissues. The high correlation between PD-L1 expression and TILs indicates that the PD-1/PD-L1 pathway is a promising immunotherapeutic target for SNSCC.

A multicenter, open-label, phase I study of nivolumab alone or in combination with gemcitabine plus cisplatin in patients with unresectable or recurrent biliary tract cancer.

306 Background: This phase 1 study evaluated the safety and efficacy of the immune checkpoint inhibitor nivolumab (monotherapy or combined with chemotherapy) in Japanese patients with biliary tract cancer (BTC). Methods: In the monotherapy cohort (N = 30), patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg, 2-week intervals). In the combined therapy cohort (N = 30), chemonaïve patients with unresectable/recurrent BTC received nivolumab (240 mg, 2-week intervals) plus cisplatin-gemcitabine chemotherapy. The primary objective was tolerability and safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) (central assessment). Results: The most frequently reported nivolumab-related adverse events were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%) in the monotherapy cohort, and malaise (8/30, 27%) and decreased appetite (7/30, 23%) in the combined therapy cohort. Median duration of follow-up for efficacy (Table) was 5.1 months (mo; monotherapy cohort) and 8.2 mo (combined therapy cohort). In the monotherapy cohort, median OS and median PFS were longer in patients with programmed death-ligand 1 (PD-L1) ≥ 1% (including the patient who responded) than in those with PD-L1 &lt; 1% (Table). In the combined therapy cohort, the ORR was higher, but median OS and median PFS were lower, in patients with PD-L1 ≥ 1% than in those with PD-L1 &lt; 1% (Table). Conclusions: Nivolumab was well tolerated, with a manageable safety profile and signs of clinical activity, in this phase 1 study in patients with unresectable/recurrent BTC. PD-L1 expression status may predict clinical activity of nivolumab in advanced BTC. Clinical trial information: JapicCTI-153098. [Table: see text]

Mapping heterogeneity in glucose uptake in metastatic melanoma using quantitative 18F-FDG PET/CT analysis

BackgroundMetastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. However, a large subgroup of patients does not benefit. Tumour metabolic alterations may well be involved in the efficacy of both targeted and immunotherapy. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. The aim of this retrospective study was to provide insight into quantitative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters and corresponding intra- and inter-patient heterogeneity in tumour 18F-FDG uptake among metastatic melanoma patients. Consecutive, newly diagnosed stage IV melanoma patients with a baseline 18F-FDG PET/CT scan performed between May 2014 and December 2015 and scheduled to start first-line systemic treatment were included. Volume of interests (VOIs) of all visible tumour lesions were delineated using a gradient-based contour method, and standardized uptake values (SUVs), metabolically active tumour volume (MATV) and total lesion glycolysis (TLG) were determined on a per-lesion and per-patient basis. Differences in quantitative PET parameters were explored between patient categories stratified by BRAFV600 and RAS mutational status, baseline serum lactate dehydrogenase (LDH) levels and tumour programmed death-ligand 1 (PD-L1) expression.ResultsIn 64 patients, 1143 lesions ≥ 1 ml were delineated. Median number of lesions ≥ 1 ml was 6 (range 0–168), median maximum SUVpeak 9.5 (range 0–58), median total MATV 29 ml (range 0–2212) and median total TLG 209 (range 0–16,740). Per-patient analysis revealed considerable intra- and inter-patient heterogeneity. Maximum SUVs, MATV, number of lesions and TLG per patient did not differ when stratifying between BRAFV600 or RAS mutational status or PD-L1 expression status, but were higher in the patient group with elevated LDH levels (> 250 U/l) compared to the group with normal LDH levels (P < 0.001). A subset of patients with normal LDH levels also showed above median tumour 18F-FDG uptake.ConclusionsBaseline tumour 18F-FDG uptake in stage IV melanoma is heterogeneous, independent of mutational status and cannot be fully explained by LDH levels. Further investigation of the prognostic and predictive value of quantitative 18F-FDG PET parameters is of interest.

Differential Prognostic Impact of Strong PD-L1 Expression and 18F-FDG Uptake in Triple-negative Breast Cancer.

Triple-negative breast cancers (TNBC) is an aggressive disease and often associated with early distant metastases, which negate the role of adjuvant radiotherapy. We studied the clinical utility of programmed death ligand-1 (PD-L1) and other available factors in predicting clinical outcome in TNBC. Of the 539 patients with newly diagnosed TNBC between 2004 and 2011, we analyzed 117 patients who had both tumor samples which PD-L1 protein expression could be evaluated using immunohistochemistry and initial staging F-fluorodeoxyglucose (FDG) positron emission tomography (PET) data to find available immunologic or metabolic factors. Median follow-up duration was 53 months. Strong PD-L1 expression was significantly associated with increased risk of recurrence along with tumor hypermetabolism. The systemic recurrence rate was significantly higher in the strong PD-L1 group than the weak PD-L1 group (35% vs. 11%; P=0.002); whereas there was no difference in locoregional failures (8% vs. 8%). Meanwhile, tumor hypermetabolism seemed to relate with an increase in overall recurrences (26% vs. 8%; P=0.019), not with specific type (locoregional, 9% vs. 3% [P=0.289]; systemic, 22% vs. 8% [P=0.051]). The relationship between PD-L1 expression and survival outcomes retained significance even after adjusting potential risk factors. PD-L1 and tumor metabolism might have role of predicting an increase in treatment failures. Especially, strong PD-L1 expression status was related to distant metastasis-dominant recurrence pattern which needs for intensive systemic therapy.

P2.04-01 Associations Histological Subtype of Lung Adenocarcinoma and Programmed Death Ligand 1 (PD-L1) Expression in Tumor Cells.

The analysis by immunohistochemistry (IHC) of the programmed cell death-ligand 1 (PD-L1) protein expression is the most extensively explored biomarker for response to immunotherapy in non-small cell lung cancer (NSCLC). However, there are differences concerning diverse IHC assays and cut-off criteria: Pembrolizumab with the 22C3 assay with cut-off ranges of >1%, 1-49% and >50%; and Nivolumab with the 28-8 assay and ranges of <1%, 1-5%, 5 -10% and >10%. Furthermore, there is lack of information regarding the association between the histological subtype of adenocarcinoma and PD-L1 expression. In this work, we assessed the frequency of PD-L1 expression according with to histological subtype of adenocarcinoma. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx immunohistochemistry assay (Dako North America, Inc.). We correlated histological subtype of adenocarcinoma with the frequency and intensity of PD-L1 expression, smoking history, EGFR and ALK status. Tissue samples from one hundred and sixty-two were analyzed, of which 33 (20.4%) were excluded due to insufficient material for PD-L1asessment. Among them, 106 patients (71,55%) were female, the median age was 63 years (range 31-86 years), 69 (53.5%) were never-smokers with no exposition to wood smoke or asbestos (79,61.2% and 117, 90.7% respectively). Among the 129 adenocarcinomas, 31.0% were acinar histological subtype; 27.1% solid, 17.1% papillary, 3.9% lepidic, 1.6% micropapillary and 54.3% had a moderated tumor differentiation grade. According to PD-L1 score, 49 (38%) of the patients were classified as negative (PD-L1<1%), 71(55%) as poor PD-L1 expression (1 - 49%), and 9 (7%) as strong PD-L1 expression (≥50%). According to the IASLC/ATS adenocarcinoma histological subtype was associated with PD-L1 expression (p=0.003). Solid and acinar adenocarcinomas were more likely to present strong PD-L1 expression (55.6% and 33.3%, respectively) compared to lepidic, papillary, micropapillary and unspecified tumors, which presented a strong PD-L1 expression in up to 11.1%. Median PFS to first line therapy was 10.3 (95% CI: 6.1–14.5) months. Tobacco exposure was the only factor independently associated with an increase in the hazard of progression to first line therapy (either CT or TKI) from any cause among NSCLC patients (HR, 95% CI: 1.56-12.1). The median OS was 41.9 (95% CI: 10.9–72.9) months. Median OS differences were not found among PD-L1 (negative vs. positive: 60.6 vs. 31.3 months, p=0.685). Patients with adenocarcinoma tumors, solid histological subtype and poor differentiation grade can be more benefited with a PD-1 based immunotherapy. PD-L1 score can be a predictor factor for the response to first line chemotherapy.