The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation.
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ABSTRACT:
SUBMITTER: Ma L
PROVIDER: S-EPMC8696228 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immune checkpoint inhibitors (ICIs) are new therapeutic strategies for non-small cell lung cancer (NSCLC). We aimed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized clinical trials comparing ICIs with control therapies in NSCLC. Data were pooled according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 12 trails comprising 6,919 NSCLC patients were included in this meta-analysis. ICIs therapies significantly improved progression-free survival (PFS) (HR, 0.838; P < 0.001), overall survival (OS) (HR, 0.747; P < 0.001) and objective response rates (ORR) (RR, 1.311; P < 0.001) in NSCLC. Prognostic benefit was observed irrespective of age, sex, treatment line, performance status and histology. Survival improvement of ICIs was limited for NSCLC patients with non-smoker (PFS, P = 0.468; OS, P = 0.317) or central nervous system (CNS) metastasis (PFS, P = 0.209; OS, P = 0.090), or positive EGFR mutation (PFS, P = 0.083; OS, P = 0.522) or PD-L1 expression level less than 5% (PFS, P = 0.370; OS, P = 0.047). The relative risks of all-grade and high-grade (≥3) anemia, neutropenia, leukopenia, thrombocytopenia, stomatitis, nausea, pyrexia, asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies. This meta-analysis provides clinical evidence that ICIs improve PFS, OS, and ORR in NSCLC with fewer adverse effects. Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker, no CNS metastasis, wild type EGFR, and high PD-L1 expression.
| S-EPMC6136858 | biostudies-other
Project description:Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.
| S-EPMC7407667 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.
| S-EPMC5870075 | biostudies-literature
Project description:In recent years, epidermal growth factor receptor tyrosine kinase inhibitors have been recommended by many guidelines as first-line drugs for advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations and no resistance. However, with the prolongation of medication time, most appear acquired resistance. In recent years, breakthroughs in inhibitors of programmed death-1 (PD-1) and its ligand (PD1 ligand, PD-L1) have rapidly changed the therapeutic model of NSCLC. Recent studies have shown that the efficacy of immune checkpoint inhibitors in EGFR-mutant NSCLC patients is not satisfactory, which might be caused by low PD-L1 expression, inhibitory immune microenvironment and low tumor mutation load. This review will elaborate the immune microenvironment of NSCLC patients with EGFR mutation, the latest study progression of immune checkpoint inhibitors and its combined with TKI, expecting to bring new hopes for the treatment of EGFR-mutant NSCLC patients.?.
| S-EPMC6105349 | biostudies-literature
Project description:BackgroundResistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study.MethodsPublic cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK (n = 853), MSKCC (n = 1662) and Van Allen (n = 57) and TCGA (n = 3210) cohorts were obtained and analyzed.ResultsThe expression of immune-checkpoint related genes, including programmed death-ligand 1 (CD274), lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death ligand 1 (PDCD1), and programmed cell death 1 ligand 2 (PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 (p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34-6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 (p = 0.007; HR, 2.53; 95% CI, 1.25-5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort (p = 0.02; HR, 2.53; 95% CI, 1.17-5.45) and merged cohort (p = 0.008; HR, 2.63; 95% CI, 1.29-5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC (p = 0.02; HR, 2.47; 95% CI, 1.16-5.26), but not in other type of tumors.ConclusionsWe identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.
| S-EPMC8366138 | biostudies-literature
Project description:In the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti-program death-1 (PD-1) and anti-program death-ligand 1(PD-L1) pathway (4) outline determinants of response to PD-1/PD-L1 therapy and (5) discuss potential future areas for research.
| S-EPMC5055165 | biostudies-literature
Project description:The present retrospective study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Patients with NSCLC harboring driver mutations who received ICIs (nivolumab or pembrolizumab) were reviewed in Hirosaki University and Aomori Prefectural Central Hospital. There were 139 patients who received molecular targeted drugs, including 24 patients treated with ICIs. Patient characteristics were as follows: Male/female, 5/19; median age 68 (range 39-82); smoking/non-smoking, 6/18; PS 0-1/2, 20/4; driver mutation status, EGFR/ALK/RET/ROS1: 21/1/1/1. The overall response rate was 16.7% [95% confidence interval (CI), 7.0-37.1%] and the disease control rate was 33.4% (95% CI, 18.9-55.1%). The median progression-free survival (PFS) time was 62 days (95% CI 52-81 days). In the patients who had been treated by the preceding tyrosine kinase inhibitor (TKI) for >1 year, the PFS time was 110 days. On the other hand, in the patients who had received a TKI for less than a year, the PFS time was 56 days, which was significantly shorter (P=0.012). To conclude, some of the patients with NSCLC harboring driver mutation could benefit from ICIs, and the duration of previous TKI treatment may be associated with the efficacy.
| S-EPMC6482391 | biostudies-literature
Project description:BackgroundDespite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC.MethodsBetween 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets.ResultsA total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2-8) courses of therapy. The study included nine patients (64.3%) who were PD-L1-high (>50%) and four (28.6%) who were PD-L1-low (<50%). The objective response rate was 14.3% (2/14). The median progression-free survival time was 2.18 months (95% confidence interval [CI] 1.13 months-not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months-NR). RNA expression levels of CD274 were similar between the ALK-positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK-positive group. Cytolytic activity scores including interferon-γ-related response were lower in the ALK-positive group in the NCCRI but not TCGA dataset.ConclusionsDespite high PD-L1-positive rates, ICIs show limited efficacy in ALK-positive NSCLC. Decreased interferon-γ-related response may underlie these findings.
| S-EPMC6825904 | biostudies-literature
Project description:The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm for multiple cancer types, including thoracic malignancies. In advanced non-small cell lung cancer (NSCLC), ICIs have shifted treatment paradigm and improved overall survival reaching almost one-third of patients alive at 5 years. ICIs therapies have also modified the therapeutic strategy in first-line setting in metastatic small-cell lung cancer (SCLC) patients as well as in malignant pleural mesothelioma (MPM) improving the overall survival compared with standard treatment. This phenomenon is of huge relevance as both SCLC and MPM were considered orphan diseases without any significant improvement in the therapeutic strategy in the first-line setting during the last 15 years. In this review, we aim to review the efficacy of ICI in thoracic malignancies either in monotherapy or in combination, according to predictive biomarkers, and to the US Food and Drug Administration and the European Medicines Agency approvals of treatment strategies. We address the efficacy of these agents, especially in NSCLC according to PD-L1 expression and histologic subtype.
| S-EPMC9489136 | biostudies-literature
Project description:Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). High level of Faecalibacterium prausnitzii has been associated with a positive response to ICI in multiple cancer types. Here, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In a mouse preclinical model, we show that the F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain is not associated with a change in fecal microbiota diversity or composition suggesting a direct effect on immune cells in the small intestine.
2024-07-10 | GSE234818 | GEO