scholarly journals High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Xi Chen ◽  
Haiying Kong ◽  
Linxiang Luo ◽  
Shuiyun Han ◽  
Tao Lei ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
Hodgkin Lymphoma ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Classical Hodgkin Lymphoma ◽  
Formalin Fixed Paraffin Embedded ◽  
Inhibitor Treatment

Abstract Purpose We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. Methods Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I–II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. Results All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. Conclusions PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

Gls-010, a novel anti-PD-1 mAb in Chinese patients with relapsed or refractory classical Hodgkin lymphoma: Preliminary impressive result of a phase II clinical trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8033-8033
Author(s):  
Yuqin Song ◽  
Jun Zhu ◽  
Ningjing Lin ◽  
Mingzhi Zhang ◽  
Hai Bai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Genetic Alterations ◽  
Phase Ii Clinical Trial ◽  
Chinese Patients ◽  
Favorable Result ◽  
Classical Hodgkin Lymphoma ◽  
Impressive Result

8033 Background: classical Hodgkin lymphoma (cHL) are characterized by genetic alterations at the 9p24·1 locus and PD-L1 ligand overexpression. GLS-010 is a novel fully human anti-PD-1 mAb and exhibited favorable result in previous Phase I study. This multi-center, single-arm Phase II clinical trial is aimed to further evaluate the safety and efficacy profile of GLS-010 in Chinese patients (pts) with relapsed or refractory cHL. Methods: All pts enrolled received GLS-010 240mg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. The primary endpoint was objective response rate (ORR) by independent review committee (IRC) per Lugona 2014. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: 85 pts with relapsed or refractory cHL who had received at least 2 lines of prior systemic chemotherapies were enrolled and treated. As of August 2 2019, data cutoff, pts received a median of 8 treatment cycles (1 cycle include 2 injections), with 12 pts discontinued and 73 pts were still in treatment. At a median follow-up of 6.57 months, an ORR was reported in 78 of 85 patients (91.76%, 95%CI, 83.77-96.62), by an IRC assessment, including 30(35.3%) pts with a complete response (CR) and 48 pts (56.5%) with a partial response (PR). Median duration of response (DoR) and progression free survival (PFS) were not reached yet. Treatment-related adverse events (TRAEs) of any grade occurred in 77 (90.6%) of 85 patients, most of which were Grade 1-2.The most common TRAEs were fever (26/85, 30.6%), neutrophil count decreased (16/85, 18.82%), white blood cell count decreased (15/85, 17.65%). ≥ Grade 3 TRAEs occurred in 23 (27.06%) pts, most commonly, hepatic function abnormal (5/85, 5.88%), hyperuricaemia (4/85, 4.71%). Conclusions: GLS-010 showed impressive anti-tumor activity (ORR = 91.96%) and manageable safety profile in Chinese patients with relapsed or refractory cHL, which could be a new safe and effective treatment option in this setting. Clinical trial information: NCT03655483 .

scholarly journals Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure

2016 ◽  
Vol 34 (31) ◽  
pp. 3733-3739 ◽  
Author(s):  
Philippe Armand ◽  
Margaret A. Shipp ◽  
Vincent Ribrag ◽  
Jean-Marie Michot ◽  
Pier Luigi Zinzani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Progression Free Survival ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Genetic Alterations ◽  
Brentuximab Vedotin ◽  
Response To Treatment ◽  
Classical Hodgkin Lymphoma ◽  
Programmed Death ◽  
Programmed Death 1

Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti–PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.

scholarly journals Clinical Correlations of Programmed Cell Death Ligand 1 Status in Liquid and Standard Biopsies in Breast Cancer

2020 ◽  
Vol 66 (8) ◽  
pp. 1093-1101 ◽  
Author(s):  
William Jacot ◽  
Martine Mazel ◽  
Caroline Mollevi ◽  
Stéphane Pouderoux ◽  
Véronique D’Hondt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Sites

Abstract Background Data regarding the prognostic value of programmed cell death ligand 1 (PD-L1) expression on circulating tumor cells (CTCs) are lacking. However, CTCs could represent an alternative approach to serial biopsies, allowing real-time monitoring of cancer phenotype. Methods We evaluated, in a dedicated prospective clinical trial, the clinicopathological correlations and prognostic value of PD-L1(+)-CTCs in 72 patients with metastatic breast cancer (MBC). Results Eighteen of 56 patients with available archival tissue presented at least one positive (≥1%) PD-L1 tumor sample. Baseline CTCs and PD-L1(+)-CTCs were detected in 57 (79.2%) and 26 (36.1%) patients. No significant correlation was found between PD-L1 tumors and CTC expression. In univariate analysis, triple negative (TN) phenotype, number of metastatic treatments, >2 metastatic sites, ≥5 CTCs and PD-L1(+)-CTCs were significantly associated with progression-free survival, while tissue PD-L1 expression was not. In multivariate analysis, TN phenotype, number of metastatic treatments and of metastatic sites were the only 3 variables independently associated with progression-free survival. Progesterone receptor negativity, TN phenotype, >2 metastatic sites and ≥5 CTCs were significantly associated with overall survival in univariate analysis. In multivariable analysis, TN phenotype and >2 metastatic sites were the only 2 independent variables. Conclusions Unlike PD-L1(+)-tumor, PD-L1(+)-CTCs correlate to survival in MBC. Reappraisal of the role of PD-L1 expression by tumor tissue and by CTCs under anti-PD-1/PD-L1 treatment is necessary to evaluate its predictive value and potential role as a stratifying factor in strategies and trials for MBC patients with MBC. Clinical trial registration NCT02866149

scholarly journals Programmed cell death protein-1 (PD-1)-expression in the microenvironment of classical Hodgkin lymphoma at relapse during anti-PD-1-treatment

Haematologica ◽  
2018 ◽  
Vol 104 (1) ◽  
pp. e21-e24 ◽  
Author(s):  
Stephanie Sasse ◽  
Katharina Reddemann ◽  
Arjan Diepstra ◽  
Ilske Oschlies ◽  
Antje Schnitter ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Hodgkin Lymphoma ◽  
Classical Hodgkin Lymphoma ◽  
Cell Death Protein

scholarly journals Gls-010, a Novel Anti-PD-1 Mab in Chinese Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: Preliminary Impressive Results of a Phase II Clinical Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Yuqin Song ◽  
Jun Zhu ◽  
Ningjing Lin ◽  
Mingzhi Zhang ◽  
Hai Bai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Objective Response ◽  
Genetic Alterations ◽  
Phase Ii Clinical Trial ◽  
Chinese Patients ◽  
Classical Hodgkin Lymphoma ◽  
Effective Treatment Option

Introduction: Classical Hodgkin lymphoma (cHL) is characterized by genetic alterations in 9p24.1, leading to overexpression of PD-L1 ligand. GLS-010 is a novel fully human anti-PD-1 monoclonal antibody (mAb) and exhibited favorable results in previous Phase I study. The aim of this study was to evaluate the safety and efficacy profile of GLS-010 in Chinese patients (pts) with relapsed or refractory cHL. Methods: In this multi-center, single-arm Phase II clinical trial, pts with relapsed or refractory cHL after at least 2 lines of prior systemic chemotherapies were enrolled and treated with GLS-010 240mg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. Efficacy was assessed with the primary endpoint of objective response rate (ORR) by independent review committee (IRC) per Lugano 2014. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: As of April 18, 2020, a total of 85 pts with relapsed or refractory cHL received a median of 14.5 treatment cycles (1 cycle include 2 injections). The pretreatment characteristics of the pts are shown in Table 1. At a median follow-up of 15.8 months, 28.2% (24/85) of pts discontinued treatment. As shown in Table 2, treatment-related adverse events (TRAEs) of any grade occurred in 79 (92.9%) of 85 patients, most of which were Grade 1-2. The most common TRAEs were fever (27/85, 31.8%), neutrophil count decreased (17/85, 20%) and alanine aminotransferase (ALT) increased (17/85, 20%). Grade ≥3 TRAEs occurred in 25 (29.4%) pts, most commonly, hepatic function abnormal (5/85, 5.88%) and hyperuricaemia (4/85, 4.71%). For all the 85 pts, ORR was 90.59% (77/85, 95%CI: 82.30-95.85) with 32.9% (28/85) of patients achieving a CR and 57.6% (49/85) of patients achieving a PR (Table 3). Median duration of response (DoR) and progression free survival (PFS) were not reached yet. Conclusions: GLS-010 showed impressive anti-tumor activity (ORR=90.59%) and manageable safety profile in Chinese patients with relapsed or refractory cHL, and could be a new safe and effective treatment option. Disclosures Meng: Guangzhou Gloria Biosciences Co., Ltd.: Current Employment.

Sign in / Sign up

Export Citation Format

Share Document