Plasma Biomarkers Screening by Multiplex ELISA Assay in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III–IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-α, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3–4 IrAEs in advanced NSCLC treated with ICIs.

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Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors

Journal of Translational Medicine ◽

10.1186/s12967-020-02679-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Li Wang ◽

Zhixuan Ren ◽

Bentong Yu ◽

Jian Tang

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Cancer Genomics ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

Abstract Introduction Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the expression of PD-L1, TMB, TIICs, MMR and MSI-H. However, there are no official biomarkers to guide the treatment of ICIs and to determine the prognosis. Therefore, it is essential to explore a systematic nomogram to predict the prognosis of ICIs treatment in NSCLC Methods In this work, we obtained gene expression and clinical data of NSCLC patients from the TCGA database. Immune-related genes (IRGs) were downloaded from the ImmPort database. The detailed clinical annotation and response data of 240 advanced NSCLC patients who received ICIs treatment were obtained from the cBioPortal for Cancer Genomics. Kaplan–Meier survival analysis was used to perform survival analyses, and selected clinical variables to develop a novel nomogram. The prognostic significance of FGFR4 was validated by another cohort in cBioPortal for Cancer Genomics. Results 3% of the NSCLC patients harbored FGFR4 mutations. The mutation of FGFR4 were confirmed to be associated with PD-L1, and TMB. Patients harbored FGFR4 mutations were found to have a better prolonged progression-free survival (PFS) to ICIs treatment (FGFR4: P = 0.0209). Here, we built and verified a novel nomogram to predict the prognosis of ICIs treatment for NSCLC patients. Conclusion Our results showed that FGFR4 could serve as novel biomarkers to predict the prognosis of ICIs treatment of advanced NSCLC. Our systematic prognostic nomogram showed a great potential to predict the prognosis of ICIs for advanced NSCLC patients.

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Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.665133 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qiao Yang ◽

Mingjing Chen ◽

Jiaoyang Gu ◽

Kai Niu ◽

Xianlan Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

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.

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Plasma Biomarkers and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: New Tools for Better Patient Selection?

Cancers ◽

10.3390/cancers11091269 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1269 ◽

Cited By ~ 6

Author(s):

Adrien Costantini ◽

Paul Takam Kamga ◽

Coraline Dumenil ◽

Thierry Chinet ◽

Jean-François Emile ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Circulating Tumor Dna ◽

Small Cell ◽

Small Cell Lung ◽

Plasma Biomarkers

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with non-small cell lung cancer (NSCLC). Although some patients can experience important response rates and improved survival, many others do not benefit from ICIs developing hyper-progressive disease or immune-related adverse events. This underlines the need to select biomarkers for ICIs use in order to better select patients. There is currently no universally validated robust biomarker for daily use of ICIs. Programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB) are sometimes used but still have several limitations. Plasma biomarkers are a promising approach in ICI treatment. This review will describe the development of novel plasma biomarkers such as soluble proteins, circulating tumor DNA (ctDNA), blood TMB, and blood microbiome in NSCLC patients treated with ICIs and their potential use in predicting response and toxicity.

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The role of ERBB4 mutations in the prognosis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors

Molecular Medicine ◽

10.1186/s10020-021-00387-z ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Xilin Hu ◽

Hanlin Xu ◽

Qianwen Xue ◽

Ruran Wen ◽

Wenjie Jiao ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Cancer Genomics ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

Abstract Background Immune checkpoint inhibitors (ICIs) have witnessed the achievements of convincing clinical benefits that feature the significantly prolonged overall survival (OS) of patients suffering from advanced non-small cell lung cancer (NSCLC), according to reports recently. Sensitivity to immunotherapy is related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, a further investigation into the novel biomarkers of the prognosis on ICIs treatment is required. In addition, there is an urgent demand for the establishment of a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients. Methods In this study, the gene mutation and clinical data of NSCLC patients was obtained from the TCGA database, followed by the analysis of the detailed clinical information and mutational data relating to two advanced NSCLC cohorts receiving the ICIs treatment from the cBioPortal of Cancer Genomics. The Kaplan–Meier plot method was used to perform survival analyses, while selected variables were adopted to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from the cBioPortal of Cancer Genomics. Results The mutation frequencies of TP53 and ERBB4 were 54% and 8% in NSCLC, respectively. The mutual exclusive analysis in cBioPortal has indicated that ERBB4 does show co-occurencing mutations with TP53. Patients with ERBB4 mutations were confirmed to have better prognosis for ICIs treatment, compared to those seeing ERBB4 wild type (PFS: exact p = 0.017; OS: exact p < 0.01) and only TP53 mutations (OS: p = 0.021). The mutation status of ERBB4 and TP53 was tightly linked to DCB of ICIs treatment, PD-L1 expression, TMB value, and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy. Conclusion ERBB4 mutations could serve as a predictive biomarker for the prognosis of ICIs treatment. The systematic nomogram was proven to have the great potential for evaluating the efficacy of ICIs therapy for advanced NSCLC patients.

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Incidence and risk factors for pneumonitis associated with immune checkpoint inhibitors in advanced-stage non-small cell lung cancer: A single center experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15089 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15089-e15089

Author(s):

Felipe Soto ◽

Linda Zhong ◽

Vickie R Shannon ◽

Nathaniel Wilson ◽

Abdulrazzak Zarifa ◽

...

Keyword(s):

Risk Factors ◽

Lung Cancer ◽

Lung Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Advanced Stage ◽

Small Cell Lung

e15089 Background: Conventional treatments for advanced-stage non-small cell lung cancer (NSCLC) confer a progression-free survival of only about 6 months. Immune checkpoint inhibitors (ICIs) have become standard therapies in the management of advanced NSCLC, but are associated with a variety of immune-related adverse events that may be dose-limiting (irAEs). Risk factors for ICI-related pneumonitis, a potentially fatal irAE, have not been well established. We sought to determine the incidence and risk factors for ICI-related pneumonitis in NSCLC in a cohort of patients treated with ICIs as standard of care or as part of a clinical trial. Methods: We performed a retrospective review of 525 patients with advanced NSCLC who received ICI therapy with PD-1 inhibitors, with or without CTLA-4 inhibitors, at MD Anderson Cancer Center between 2015 and 2018. Patients with incomplete data were excluded from the study. Clinical data was collected at the time of ICI therapy and at the time of irAE. The diagnosis of pneumonitis was based on clinical presentation, imaging findings, and microbiological results. We constructed a Fine-Gray competing risks regression model with pneumonitis as the outcome of interest and all-cause mortality as the competing risk. Results: In our initial data analysis based on available data shows a 9.7% raw incidence of pneumonitis (17/177). We found no association between age, race, gender, type of anti-PD-1 therapy, concurrent use of CTLA-4 inhibitors, tumor histology, cumulative radiation dose, or smoking pack-years with the risk for pneumonitis. Patients who were therapy-naïve at the initiation of ICI therapy (hazard ratio [HR] 3.3, 95% confidence interval [CI] 1.0-10.6, p = 0.04), and patients with prior lung disease (HR 2.7, 95% CI 0.8-8.5, p = 0.1) had around a three-fold increase in the risk for pneumonitis after accounting for the competing risk of mortality. Conclusions: NSCLC patients who are therapy-naïve or have prior lung disease on initiation of ICI therapy have a higher risk for pneumonitis. Other studies have shown an increase in pneumonitis in therapy-naïve patients, but the association with prior lung disease is novel. Further analysis on this cohort is ongoing.

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Real-world data on patients with metastatic non-small-cell lung cancer treated with checkpoint inhibitors in an Italian Teaching Hospital in 2015–2018

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220941586 ◽

2020 ◽

pp. 107815522094158

Author(s):

Marianna Veraldi ◽

Stefania Esposito ◽

Maria D. Naturale ◽

Marco Oradei ◽

Donato Cosco ◽

...

Keyword(s):

Lung Cancer ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Real World Data ◽

World Data

Background Non-small-cell lung carcinoma (NSCLC) accounts for 85–90% of all forms of lung cancer. Immuno-oncology represents a valid new approach but the high cost requires a specific evaluation of the health outcomes. This study describes the real-world efficacy, safety and cost profiles of the new anti-PD-1 immune-checkpoint inhibitors nivolumab and pembrolizumab on a cohort of 56 selected patients with advanced NSCLC. Methods A retrospective, observational analysis was conducted on patients treated with immune checkpoint inhibitors from September 2015 to September 2018 at Azienda Ospedaliera Universitaria “Mater Domini” in Catanzaro, Italy. Data sources were medical records, internal prescription cards and reports of adverse reactions. Results Fifty-six patients were diagnosed with advanced NSCLC, 64.3% characterized by a non-squamous histology, 30.3% squamous and 5.4% not specified. First-line treatment with pembrolizumab was administered to 11 patients for an average of 4.4 months, while 45 patients were treated with nivolumab for an average of 8.6 months. Data showed a survival rate of 95% after 6 months and 88% after 12 months. Most patients received immunotherapy as a second-line or subsequent treatment. In terms of prior therapy among all the patients, 43 had received platinum-based treatments. Indirect comparison with other real-world data studies showed variability in methodologies and an alignment in terms of results. Conclusion This study, based on real-world data, was a first step in the assessment of the impact of the introduction of a significant new class of treatments, i.e. immunotherapy, and covers patients, treatments and outcomes, as well as organizational and economic variables.

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The Role of ERBB4 Mutations in the Prognosis of Advanced Non-small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

10.21203/rs.3.rs-281496/v1 ◽

2021 ◽

Author(s):

Xilin Hu ◽

Ruran Wen ◽

Hanlin Xu ◽

Wenjie Jiao ◽

Kaihua Tian

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Cancer Genomics ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

Abstract Introduction: Recently, immune checkpoint inhibitors (ICIs) has been reported to achieved convincing clinical benefits and significantly prolonged the overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients. Sensitivity to immunotherapy was related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, novel biomarkers for the prognosis to ICIs treatment need to be further investigated, and it is an urgent demand to establish a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients.Methods: In this study, gene mutation and clinical data of NSCLC patients was obtained from the TCGA database. Then, we analyzed the detailed clinical information and mutational data of two advanced NSCLC cohorts received ICIs treatment from the cBioPortal for Cancer Genomics. The Kaplan-Meier plot method was used to perform survival analyses, selected variables were used to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from cBioPortal for Cancer Genomics.Results: Mutation frequencies of TP53 and ERBB4 was 54% and 8% in NSCLC, respectively. Mutual exclusive analysis in cBioPortal indicated that ERBB4 does show co-occurencing mutations with TP53. Patients harbored ERBB4 mutations were confirmed to have a better prognosis for ICIs treatment, compared to ERBB4 wild type (PFS: p=0.0360; OS: p=0.0378) and only TP53 mutations (OS: p=0.021). The mutation status of ERBB4 and TP53 are tightly linked to DCB for ICIs treatment, PD-L1 expression, TMB value and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy.Conclusion: ERBB4 mutations could serve as a predicting biomarker for prognosis of ICIs treatment. The systematic nomogram was proven to have a great potential to evaluate the efficacy of ICIs therapy for advanced NSCLC patients.

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Association Between Efficacy of Immune Checkpoint Inhibitors and Sex: An Updated Meta-Analysis on 21 Trials and 12,675 Non-Small Cell Lung Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.627016 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chongxiang Xue ◽

Shuyue Zheng ◽

Huijing Dong ◽

Xingyu Lu ◽

Xu Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

BackgroundMounting randomized clinical trials have proved that immune checkpoint inhibitors (ICIs) achieved better overall survival (OS) and progression-free survival (PFS) than chemotherapy drugs for advanced non-small cell lung cancer (NSCLC) patients. However, some literatures have indicated that different sexes might not have equal immune response. Also, no agreement reached on the issue whether therapeutic benefit of ICIs is related to sex.ObjectivesTo explore the association between efficacy of ICIs for NSCLC patients and their sexes and summarize overall treatment-related adverse events (TRAEs) in an exploratory manner.MethodsWe performed this systematic review and meta-analysis of all potentially relevant studies retrieved from PubMed, EMBASE, and the Cochrane Library until June 2021, for eligible randomized controlled trials (RCTs) comparing immunotherapy with chemotherapy in advanced NSCLC patients. Literature screening, summary data extraction was performed independently and in duplicate. The pooled hazard ratio (HR) and 95% confidence interval (CI) of OS, PFS and TRAEs were calculated, applying STATA software and random-effects models. This study was registered in international prospective register of systematic reviews (PROSPERO), number CRD42020210797.ResultsTwenty-one trials involving 12,675 NSCLC patients were included. For patients with advanced NSCLC, ICIs significantly prolonged the OS (males: HR 0.73, 95%CI 0.67-0.79; females: HR 0.73, 95%CI 0.61-0.85) and PFS (males: HR 0.62, 95%CI 0.55-0.70; females: HR 0.68, 95%CI 0.55-0.81) versus chemotherapy. Overall, there was no statistical difference between their sexes (OS: P = 0.97; PFS: P = 0.43), respectively. Owing to insufficient TRAEs data of different sexes, we only found immunotherapy for NSCLC patients had more all-grades (RR 0.88; 95%CI 0.82-0.95) and 3-5 grades (RR 0.60; 95%CI 0.47-0.75) AEs compared with chemotherapy.ConclusionOur findings indicated that the interaction between immunotherapy efficacy and different sexes was equally evident. Overall, patients with NSCLC could obtain more benefits from ICIs than chemotherapy regimen regardless of their sexes.Systematic Review RegistrationPROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020210797.

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