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The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation.

ABSTRACT: Over the past few years, immune checkpoint inhibitors (ICIs) have greatly improved the survival for patients with non-small cell lung cancer (NSCLC) without driver mutations. Compared with wild-type tumors, tumors with epidermal growth factor receptor (EGFR) mutations show more heterogeneity in the expression level of programmed cell death-ligand 1 (PD-L1), tumor mutational burden (TMB), and other immune microenvironment characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In previous studies, no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation. Here, we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations. We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations, the characteristics of potential responders, and provided insights into areas worth further investigations in future studies.

SUBMITTER: Ma L

PROVIDER: S-EPMC8696228 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation.

Ma Lin L Diao Bowen B Huang Zhaoqin Z Wang Bin B Yu Jinming J Meng Xiangjiao X

Cancer communications (London, England) 20211026 12

Over the past few years, immune checkpoint inhibitors (ICIs) have greatly improved the survival for patients with non-small cell lung cancer (NSCLC) without driver mutations. Compared with wild-type tumors, tumors with epidermal growth factor receptor (EGFR) mutations show more heterogeneity in the expression level of programmed cell death-ligand 1 (PD-L1), tumor mutational burden (TMB), and other immune microenvironment characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mut ...[more]

PMID: 34699691

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Project description:BackgroundWith a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC.ObjectivesThere are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations.DesignRetrospective observational study.MethodsWe conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression.ResultsA total of 62 patients were included in this analysis. The median age was 68.0 years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3-8.0] and 3.8 (IQR: 3.0-4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6 months, p = 0.047). This finding was not shown in patients with wild-type KRAS.ConclusionOur analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS.

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.

Project description:BackgroundTo date, immunotherapy has improved the 5-year survival rate of patients with advanced non-small cell lung cancer (NSCLC) from 4% to 15%. However, only 30%-50% of the NSCLC patients respond to immune checkpoint inhibitors (ICIs) immunotherapy. Therefore, screening patients for potential benefit with precise biomarkers may be of great value.MethodsFirst, an immunotherapy NSCLC cohort was analyzed to identify the gene mutations associated with the prognosis of ICI treatment. Further analyses were conducted using NSCLC cohort in The Cancer Genome Atlas (TCGA) project to validate the correlations between the specific gene mutations and tumor immunogenicity, antitumor immunity, and alterations in the tumor-related pathways using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Gene set enrichment analysis (GSEA).ResultsIn the immunotherapy NSCLC cohort (n = 266), significantly longer overall survival (OS) rates were observed in the PAK7-mutant type (PAK7-MT) group (n = 13) than the PAK7-wild type (PAK7-WT) group (n = 253) (P = 0.049, HR = 0.43, 95%CI = 0.23-0.79). In the TCGA cohort, PAK7 mutations were correlated with the higher tumor mutation burden (TMB) (14.18 vs. 7.13, P <0.001), increased neoantigen load (NAL) (7.52 vs. 4.30, P <0.001), lower copy number variation (CNV), and higher mutation rate in the DNA damage response (DDR)-related pathways. In addition, PAK7 mutations were also positively correlated with immune-related genes expressions and infiltrating CD8+ T cells (0.079 vs. 0.054, P = 0.005). GSEA results showed that several tumor-related pathways varied in the PAK7-MT group, suggesting the potential mechanisms that regulate the tumor immune-microenvironment.ConclusionsThis study suggested that the PAK7 mutations might be a potential biomarker to predict the efficacy of immunotherapy for NSCLC patients. Considering the heterogeneity among the patients and other confounding factors, a prospective clinical trial is proposed to further validate the impact of PAK7 mutation on the immunotherapy outcomes in NSCLC.

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The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation.

Publications

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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