Impact Of PD-L1 Expression Research Articles

KEYNOTE-006 study of pembrolizumab (pembro) versus ipilimumab (ipi) for advanced melanoma: Efficacy by PD-L1 expression and line of therapy.

9513Background: In KEYNOTE-006 (NCT01866319), pembro (MK-3475) provided superior OS and PFS and a lower grade 3-5 treatment-related AE rate over ipi in patients (pts) with advanced melanoma and ≤ 1 prior therapy. We assessed the impact of PD-L1 expression and prior therapy on outcomes in KEYNOTE-006. Methods: Pts were randomized to pembro 10 mg/kg Q2W or Q3W or ipi 3 mg/kg Q3W. Pembro was given for 24 mo or until progression, intolerable toxicity, or investigator decision. Ipi was given for 4 cycles or until progression, intolerable toxicity, or investigator decision. PD-L1 was assessed by IHC using the 22C3 antibody; positivity was defined as ≥ 1% staining in tumor and adjacent immune cells. Response was assessed at wk 12, Q6W until wk 48, then Q12W. Survival follow-up was every 12 wk. Primary end points were OS and PFS (RECIST v1.1, central review). Data cutoff date was Mar 3, 2015. Pembro arms were pooled for this analysis. Results: Of the 834 pts enrolled, 80% were PD-L1+, 18% were PD-L1–, and 2% were...

Immunohistochemical Expression Pattern of Programmed Cell Death Ligand 1 Might be Both Good and Bad Prognostic Factor in Adult T-Cell Leukemia/ Lymphoma

IntroductionProgrammed death ligand 1 (PD-L1) is expressed both on neoplastic cells and on tumor-infiltrating non-neoplastic cells in several types of lymphoma. The programmed death-1 (PD-1)/PD-L1 pathway inhibits antitumor immunity. However, little is known about the functions of this pathway in adult T-cell lymphoma/leukemia (ATLL). The purpose of this study was to investigate the association between clinicopathological features and PD-L1 expression in ATLL.MethodsWe reviewed 134 biopsy samples diagnosed as ATLL including 61 cases in the international peripheral T-cell lymphoma study and 73 cases submitted to the Department of Pathology at Kurume University for consultations.PD-L1 immunohistochemical staining (IHC) was performed on formalin fixed paraffin embedded samples. According to staining patterns of PD-L1 IHC, we categorized cases of ATLL into several groups. First, cases with ATLL cells with distinct and circumferential membranous and/or cytoplasmic staining of PD-L1 were defined as neoplastic PD-L1 positive ATLL (nPD-L1(+) ATLL) whereas cases without such staining pattern of PD-L1 in ATLL cells were classified as neoplastic PD-L1 negative ATLL (nPD-L1(-) ATLL). Second, among nPD-L1(-) ATLL group, cases with non-ATLL cells with PD-L1 positivity were defined as microenvironmental PD-L1 positive ATLL (miPD-L1(+) ATLL) whereas cases without PD-L1 positive non-ATLL cells were difined as PD-L1 negative ATLL (PD-L1(-) ATLL).Clinical features analyzed in this study were age at the diagnosis, sex, Shimoyama classification, Eastern Cooperative Oncology Group performance status, LDH, presence or absence of hypercalcemia, Ann Arbor stage, Japan Clinical Oncology Group prognostic index, and complete response (CR) or CR uncertain as therapeutic effect. Morphological variant, and immunohistochemical expression in neoplastic cells of PD-1, CD30, CCR4, and FoxP3 were included in pathological features. The numbers of PD-1 positive tumor-infiltrating lymphocytes (TILs) were counted in each sample as quantitative analysis.Clinicopathological features of the patients were statistically compared using chi-square tests or Fisher's exact tests. Wilcoxon rank sum tests were performed to compare the number of PD-1 positive TIL counts between different groups. The Kaplan-Meier method was used to estimate the overall survival (OS). To compare the survival curves, we performed the log-rank test. Univariate and multivariate analyses were used to evaluate the influence of prognostic factors on the OS by the Cox proportional hazards models.ResultsThe percentage of nPD-L1(+) ATLL and nPD-L1(-) ATLL were 7.5% (10/134) and 92.5% (124/134), respectively. Among nPD-L1(-) ATLL, miPD-L1(+) ATLL were 58.2% (78/134) whereas PD-L1(-) ATLL were 34.3% (46/134).Statistical comparison of clinicopathological features between nPD-L1(+) ATLL and nPD-L1(-) ATLL showed significant difference in overall survival (OS) although significant difference was not observed in other clinicopathological features. NPD-L1(+) ATLL had inferior overall survival (OS) compared with nPD-L1(-) ATLL (p = 0.0098) (Figure1). The PD-L1 expression in neoplastic cells maintained prognostic value for OS in univariate analysis (p = 0.026) and multivariate analysis (p = 0.034).Statistical comparison of clinicopathological features between miPD-L1(+) ATLL and PD-L1(-) ATLL showed statistically significant differences in the positive rate of hypercalcemia (10%, 8/78 in miPD-L1(+) ATLL vs 24%, 11/46 in PD-L1(-) ATLL, p = 0.045), the positive rate of skin lesion (23%, 18/77 in miPD-L1(+) ATLL vs 7%, 3/46 in PD-L1(-) ATLL, p = 0.02), and the number of PD-1 positive TILs (3.60/hpf in average in miPD-L1(+) ATLL vs 0.28/hpf in PD-L1(-), p = 0.0007). MiPD-L1(+) ATLL had superior overall survival (OS) compared with PD-L1(-) ATLL (p = 0.0043) (Figure 2). The expression of PD-L1 in non-ATLL cells maintained prognostic value for OS in univariate analysis (p = 0.0056) and multivariate analysis (p = 0.002).ConclusionThis study, for the first time, described the impact of PD-L1 expression on clinicopathological features of ATLL. More effective immunotherapy for the PD-1/PD-L1 pathway may be selected according to PD-L1 expression in ATLL. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract CT104: Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001)

Abstract Background: Preliminary KEYNOTE-001 data showed that the PD-1 inhibitor pembro has manageable safety and antitumor activity in previously treated and treatment-naive advanced non-small cell lung cancer (NSCLC). In a training set of 182 pts, 129 of whom had measurable disease and tumor evaluable by an IHC clinical trial assay (CTA) for PD-L1 expression, ORR was higher in pts with membranous PD-L1 expression in ≥50% of tumor cells (proportion score [PS] ≥50%) vs PS <50%. We aimed to verify the relationship between PD-L1 expression and ORR in an independent validation set of NSCLC pts enrolled in KEYNOTE-001 and to assess the impact of PD-L1 expression in the combined training and validation sets. Methods: Advanced or metastatic NSCLC pts received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed every 9 wk. Treatment decisions were managed per investigator-assessed irRC. Efficacy evaluation was per centrally assessed RECIST v1.1. PD-L1 expression was determined by the CTA. Before analysis, ORR and PD-L1 data from the validation set were merged in pts with measurable disease and CTA-evaluable tumors. Duration of response (DOR), PFS, and OS were assessed in all treated pts from the training and validation sets with CTA-evaluable tumors. Results: In all 495 pts from the training and validation sets, irrespective of PD-L1 expression, ORR was 19.4%, median DOR was 12.4 mo, median PFS was 3.7 mo, and median OS was 12.0 mo. 9% experienced grade 3-5 treatment-related AEs; 4% discontinued due to a treatment-related AE. There was 1 treatment-related death (pneumonitis). Of the 313 pts in the validation set, ORR in the 204 pts evaluable by the CTA was 45.2% in those with PS ≥50% (Table). The relationship between ORR and PD-L1 expression was observed in previously treated and treatment-naive pts (Table). In the 356 pts evaluable by the CTA in the total population, PFS and OS were longer in pts with PS ≥50% (Table). Median OS was not reached in pts with PS ≥50%, regardless of prior treatment. Median (range) DOR was similar in pts with PS ≥50% (12.4 mo [2+ to 22.8+]), 1-49% (10.3 mo [1.4+ to 10.3]), and <1% (NR [0.9+ to 10.8+]). Conclusion: Pembro provides durable antitumor efficacy and safety in pts with treatment-naive and previously treated NSCLC. These data validate that membranous PD-L1 expression in ≥50% of tumor cells identifies pts with advanced NSCLC who are particularly likely to obtain clinical benefit from pembro. Proportion Score (PS)≥50%1-49%<1%ORR in evaluable pts in the validation set,% (95% CI)Totaln = 73n = 103n = 2845.2 (33.5-57.3)16.5 (9.9-25.1)10.7 (2.3-28.2)Previously treatedn = 57n = 77n = 2243.9 (30.7-57.6)15.6 (8.3-25.6)9.1 (1.1-29.2)Treatment naiven = 16n = 26n = 650.0 (24.7-75.3)19.2 (6.6-39.4)16.7 (0.4-64.1)Survival in evaluable pts in the total population, mo, median (95% CI)PFSTotaln = 119n = 161n = 766.3 (2.9-12.5)3.3 (2.1-4.1)2.3 (2.1-4.0)Previously treatedn = 99n = 127n = 686.1 (2.1-12.5)2.3 (2.1-3.4)2.2 (2.0-4.1)Treatment naiven = 20n = 34n = 812.5 (2.4-12.5)4.3 (3.1-6.4)3.5 (2.1-4.2)OS [NR, not reached.]Totaln = 119n = 161n = 76NR (13.7-NR)8.8 (6.8-12.4)8.8 (5.5-12.0)Previously treatedn = 99n = 127n = 68NR (9.3-NR)7.3 (5.8-12.1)8.6 (5.5-12.0)Treatment naiven = 20n = 34n = 8NR (NR-NR)16.2 (8.6-16.2)10.4 (3.4-NR) Citation Format: Edward B. Garon, Naiyer Rizvi, Rina Hui, Natasha B. Leighl, Ani S. Balmanoukian, Joseph P. Eder, Amita Patnaik, Charu Aggarwal, Matthew A. Gubens, Leora Horn, Enric Carcereny, Myung-Ju Ahn, Enriqueta Felip, Jong-Seok Lee, Jin Zhang, Reshma A. Rangwala, Gregory M. Lubiniecki, Charlotte M. Roach, Kenneth Emancipator, Leena Gandhi. Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2015-CT104

Impact of Pdl1 Expression on Clinical Outcomes in Subtypes of Sarcoma

ABSTRACT Aim: Sarcomas are rare heterogenous mesenchymal tumors that have limited treatment options. Novel targeted therapies are needed for shifting the paradign of care in sarcomas. Programmed death protein 1 and its ligand PD1/PDL1 axis is an important immunlogical target for cetain tumors and targeting the PDL1 axis may help cause tumor regression . To evaluate the PDL1 expression in subtypes of sarcoma namely osteosarcoma, leiomyosarcoma and Ewings sarcoma and then correlate it with clinicval outcomes. Methods: We evaluated PDL1 expression in three specific subtypes of sarcomas including 161 samples of osteosarcoma, 46 smples of leiomyosarcoma and 33 samples of Ewing sarcoma. Immunohistochemical staining was performed with rabbit primary antibody against PDL1 (CD274/B7-H1) on formalin-fixed paraffin-embedded core sections on tissue microarrays. PDL1 positivity was scored as percentage of cells and immunostain intensity. We also correlated the PDL1 wih clnical outcomes and perfomed subset analyses .We will also perform validation of the PDL1 expression through gene expression analysis using bioinformatics. Results: Of 161 samples of osteosarcoma 36% were positive for PDL1 expression, whilst 97% of 46 samples of leiomyosarcomas and 39% of 33 samples of Ewing's sarcomas were positive for PDL1 expression. PDL1 expression was then correlated with clinical outcomes, gender, age and treatment responses. We are also validating the PDL1 expression by using gene expression data through bioinformatics. .These results will be presented at the meeting. Conclusions: Sarcomas show significant PDL1 expression that may hold potential for justification of a clinical trial with targeted PDL1 inhibitors in the future. Disclosure: All authors have declared no conflicts of interest.