EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non–Small Cell Lung Cancer: A Retrospective Analysis

Clinical Cancer Research, Год журнала: 2016, Номер 22(18), С. 4585 - 4593

Опубликована: Май 26, 2016

PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset patients derives clinical benefit. To determine activity PD-1/PD-L1 within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients.We identified 58 treated with inhibitors. Objective rates (ORR) were assessed using RECIST v1.1. PD-L1 expression CD8(+) tumor-infiltrating lymphocytes (TIL) by IHC.Objective responses observed 1 28 (3.6%) EGFR-mutant or ALK-positive versus 7 30 (23.3%) wild-type ALK-negative/unknown (P = 0.053). The ORR never- light- (≤10 pack years) smokers was 4.2% 20.6% heavy 0.123). In an independent cohort advanced (N 68) 27) patients, 24%/16%/11% 63%/47%/26% pre-tyrosine inhibitor (TKI) biopsies cutoffs ≥1%, ≥5%, ≥50% tumor staining, respectively. Among paired, pre- post-TKI-resistant 57), levels changed after resistance 16 (28%) patients. Concurrent (≥5%) high TILs (grade ≥2) pretreatment (2.1%) 5 resistant (11.6%) specimens not any ALK-positive, post-TKI specimens.NSCLCs harboring mutations ALK rearrangements associated low ORRs to Low concurrent microenvironment may underlie these observations. Clin Cancer Res; 22(18); 4585-93. ©2016 AACRSee related commentary Gettinger Politi, p. 4539.

Язык: Английский

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A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC

Journal of Thoracic Oncology, Год журнала: 2018, Номер 13(8), С. 1138 - 1145

Опубликована: Июнь 1, 2018

Язык: Английский

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PD-L1 Expression in Lung Cancer

Journal of Thoracic Oncology, Год журнала: 2016, Номер 11(7), С. 964 - 975

Опубликована: Апрель 30, 2016

Язык: Английский

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PD-L1 Distribution and Perspective for Cancer Immunotherapy—Blockade, Knockdown, or Inhibition

Frontiers in Immunology, Год журнала: 2019, Номер 10

Опубликована: Авг. 27, 2019

Cancer immunotherapy involves in blocking the interactions between PD-1/PD-L1 immune checkpoint with antibodies and has shown unprecedented positive outcomes clinics. Particularly, PD-L1 antibody therapy efficiency membrane efficacy treating some advanced solid cancers. However, this limited effects on many tumors, suspecting to be revelent located other cellular compartments, where they play additional roles are associated poor prognosis. In review, we highlight advances of 3 current strategies based immunotherapy, summarize distribution PD-L1, review versatile functions intracellular PD-L1. The function may indicate why not all blockade is able fully stop biological effectively inhibit tumor growth. regard, gene silencing have advantages over suppression sources functions. Apart from cancer cells, host cells such as APC DC can also enhance T cell immunity, leading clearance. Moreover, molecular regulation expression being elucidated, which helps identify potential therapeutic molecules target production improve clinical outcomes. Based our understandings distribution, regulation, function, prospect that more effective PD-L1-based will combination therapies.

Язык: Английский

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Lung Cancer Staging and Prognosis

Cancer treatment and research, Год журнала: 2016, Номер unknown, С. 47 - 75

Опубликована: Янв. 1, 2016

Язык: Английский

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Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway

Acta Pharmacologica Sinica, Год журнала: 2020, Номер 42(1), С. 1 - 9

Опубликована: Март 9, 2020

Язык: Английский

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The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer

International Journal of Oncology, Год журнала: 2016, Номер 49(4), С. 1360 - 1368

Опубликована: Июль 26, 2016

Negative regulation of the signal mediated by programmed cell death protein 1 (PD-1)/programmed death-ligand (PD-L1) pathway can effectively inhibit function T and B cells, which play a key role in immune response. Recently, emerging evidence has suggested that expression PD-L1 is related to mutation status epidermal growth factor receptor (EGFR). Moreover, activation EGFR signaling induce PD-L1. In present study, we demonstrated activated upregulate through interleukin 6/Janus kinase/signal transducer activator transcription 3 (IL-6/JAK/STAT3) non-small lung cancer (NSCLC) cells. Cells treated with tyrosine kinase inhibitors (EGFR-TKIs) downregulate IL-6/JAK/STAT3 pathway, subsequently reduces Furthermore, silencing NSCLC cells correlated inhibition proliferation enhanced tumor apoptosis. summary, our research indicates involved via NSCLC. The study suggests potential combined targeted therapy immunotherapy treatment

Язык: Английский

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PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review

Lung Cancer, Год журнала: 2017, Номер 112, С. 200 - 215

Опубликована: Авг. 10, 2017

Tumors can evade immune detection by exploiting inhibitory checkpoints such as the programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathway. Antibodies that block this pathway offer a promising new approach to treatment in advanced/metastatic non-small lung cancer (NSCLC). A systematic review of literature was conducted assess association PD-L1 with important patient and disease characteristics, prognostic significance expressing NSCLC tumors, value predictive biomarker response anti-PD-1/PD-L1 treatments NSCLC. total 35 eligible studies were selected for analysis. Methods used determine tissue varied considerably; different antibodies, antibody methods, staining cut-offs. Immunohistochemistry most frequent type assay. Overall, study evidence did not support an between expression gender, age, smoking history, tumor histology (adenocarcinoma vs. squamous carcinoma), performance status, pathologic grade or EGFR/KRAS/ALK mutational status. In several studies, high associated shorter survival compared low expression. Most indicated patients more likely experience benefit agents (nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab) advanced Variability methods suggests need standardized use well-validated diagnostic assays. Although considerable research links tumors NSCLC, its factor requires study. As continue, is play role selecting deriving from monotherapy directing lower levels (with unmet medical need), alternative treatments, combination immunotherapies.

Язык: Английский

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PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

Modern Pathology, Год журнала: 2016, Номер 29(9), С. 1104 - 1112

Опубликована: Май 21, 2016

Язык: Английский

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KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma

Cancer Immunology Immunotherapy, Год журнала: 2017, Номер 66(9), С. 1175 - 1187

Опубликована: Апрель 27, 2017

It was reported that PD-L1 expression correlated with genetic alterations. Whether regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated correlation between KRAS mutation functional significance of PD-1/PD-L1 blockade KRAS-mutant adenocarcinoma. We found associated both human adenocarcinoma cell lines tissues. up-regulated through p-ERK but not p-AKT signaling. also KRAS-mediated up-regulation induced apoptosis CD3-positive T cells which reversed anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker inhibitor could recover anti-tumor immunity decrease survival rates NSCLC co-culture system vitro. However, Pembrolizumab combined did show synergistic effect on killing tumor system. Our study demonstrated induce signaling Blockade pathway may be a promising therapeutic strategy for

Язык: Английский

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