Advanced non-small cell lung cancer: the role of PD-L1 inhibitors.
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ABSTRACT:
SUBMITTER: Heigener DF
PROVIDER: S-EPMC5994502 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Advanced non-small cell lung cancer: the role of PD-L1 inhibitors.
Heigener David F DF Reck Martin M
Journal of thoracic disease 20180501 Suppl 13
PD-L1 and PD-1 inhibitors were both developed to combat a huge array of cancers. Both classes of agents block the PD-1/PD-L1 pathway. Unlike PD-1 inhibitors, PD-L1 inhibitors do also block the B-7.1-receptor and leave the PD-L2/PD-1 axis unaffected. Whether these differences enhance efficacy and tolerability is not clear yet. There are three PD-L1 inhibitors approved or in late clinical development: Atezolizumab, approved in 2<sup>nd</sup>-line treatment of non-small cell lung cancer, durvalumab ...[more]
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Project description:Objective: Immune checkpoint inhibitors, especially the programmed cell death receptor-1/ligand 1 (PD-1/L1) inhibitors, displayed promising efficacy in non-small cell lung cancer (NSCLC) patients. Incorporation of anti-PD-1/L1 antibodies into other therapeutic regimens (including CTLA-4 inhibitors, chemotherapy, EGFR-TKIs and IDO inhibitors) is currently in active clinical research. This meta-analysis summarized recent developments in four combination regimens of PD-1/L1 inhibitors. Methods: We searched PubMed, the Cochrane Library and the Embase database up to July 2018, on the combination therapy of PD-1/L1 inhibitors in NSCLC patients. Results: Seventeen trials were finally included in the current meta-analysis. The combined objective response rate s (ORR) for PD-1/L1 inhibitors in combination with CTLA-4 inhibitors, chemotherapy, EGFR-TKIs, and IDO inhibitors were 32% (19%-44%), 49% (46%-53%), 55% (28%-83%) and 35% (20%-50%) respectively. The combined ORR for first line PD-1/L1 inhibitors combination with CTLA-4 inhibitors, chemotherapy, and EGFR-TKIs were 35% (17%-53%), 51% (46%-56%) and 43% (-7%-93%) respectively, and the combined ORR in the second or more line setting were 36% (8%-65%), 17% (-13%-46%), 39% (19%-59%) and 35% (20%-50%) respectively. The pooled 6-month progression-free survival rate (6m PFSr) and 1-year overall survival rate (1y OSr) for combination therapy of PD-1/L1 inhibitors with CTLA-4 inhibitors or chemotherapy were 35% or 65% (6m PFSr) and 31% or 70% (1y OSr) respectively. Anti-PD-1/L1 drugs combined with anti-CTLA-4 drugs exhibited a more potent efficacy on PD-L1 positive patients (OR=0.33, 95%CI: 0.12-0.88). This trend was not observed in patients receiving combination therapy of PD-1/L1 inhibitors with chemotherapy (OR=0.96, 95%CI: 0.51-1.78). Conclusion: The included four combination regimens were potential treatment strategies and well tolerated for NSCLC patients. Further, the therapy lines and PD-L1 expression status were correlated with treatment efficacy.
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Project description:Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC) is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1) receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy), and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients.
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Project description:BackgroundSrc homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME).MethodsSixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME.ResultsSHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001).ConclusionHigh SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.
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Project description:BackgroundStudies have shown that integrating anlotinib with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors enhances survival rates among progressive non-small-cell lung cancer (NSCLC) patients lacking driver mutations. However, not all individuals experience clinical benefits from this therapy. As a result, it is critical to investigate the factors that contribute to the inconsistent response of patients. Recent investigations have emphasized the importance of lipid metabolic reprogramming in the development and progression of NSCLC.MethodsThe objective of this investigation was to examine the correlation between lipid variations and observed treatment outcomes in advanced NSCLC patients who were administered PD-1/PD-L1 inhibitors alongside anlotinib. A cohort composed of 30 individuals diagnosed with advanced NSCLC without any driver mutations was divided into three distinct groups based on the clinical response to the combination treatment, namely, a group exhibiting partial responses, a group manifesting progressive disease, and a group demonstrating stable disease. The lipid composition of patients in these groups was assessed both before and after treatment.ResultsSignificant differences in lipid composition among the three groups were observed. Further analysis revealed 19 differential lipids, including 2 phosphatidylglycerols and 17 phosphoinositides.ConclusionThis preliminary study aimed to explore the specific impact of anlotinib in combination with PD-1/PD-L1 inhibitors on lipid metabolism in patients with advanced NSCLC. By investigating the effects of using both anlotinib and PD-1/PD-L1 inhibitors, this study enhances our understanding of lipid metabolism in lung cancer treatment. The findings from this research provide valuable insights into potential therapeutic approaches and the identification of new therapeutic biomarkers.
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Project description:The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.
| S-EPMC4993158 | biostudies-other
Project description:BackgroundImmune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic.MethodsPaired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software.ResultsIn 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment.ConclusionThere was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.
| S-EPMC8085403 | biostudies-literature
Project description:IntroductionThere are currently three first-line immunotherapy options used as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand 1 (PD-L1) expression (≥50%). This manuscript aims to evaluate the available data on atezolizumab (AT), cemiplimab (CEMI), and pembrolizumab (PEMBRO) and to study the results obtained during pivotal trials, especially regarding patient subgroups.MethodsNominal group and Delphi techniques were used. Eight Spanish experts in lung cancer (the scientific committee of the project) analyzed the use of immunotherapy monotherapy as first-line treatment in patients with NSCLC and high PD-L1 expression. The expert scientific committee formulated several statements based on a scientific review and their own clinical experience. Subsequently, 17 additional Spanish lung cancer experts were selected to appraise the committee's statements through two Delphi rounds. They completed a Delphi round via an online platform and voted according to a scale from 1 (strongly disagree) to 10 (strongly agree). The statements were approved if ≥70% of experts voted 7 or more.ResultsA total of 20 statements were proposed covering the following areas: (1) general characteristics of pivotal clinical trials; (2) overall main outcomes of pivotal clinical trials; and (3) subgroup analysis. All statements reached consensus in the first round.ConclusionsAT, CEMI, and PEMBRO as monotherapy can be considered the standard of care in patients with advanced NSCLC and high PD-L1 expression (≥50%). Moreover, some differences noted among the drugs analyzed in this document might facilitate treatment decision-making, especially in clinically relevant patient subgroups, when using PD-1/PD-L1 inhibitors. The high level of agreement reached among experts supports the proposed statements.
| S-EPMC10420126 | biostudies-literature