scholarly journals The Role of Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Haowei Wang ◽  
Fei Zhou ◽  
Meng Qiao ◽  
Xuefei Li ◽  
Chao Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Tumor Dna

BackgroundThe use of circulating tumor DNA (ctDNA) to reflect clinical benefits of advanced non-small cell lung cancer (NSCLC) patients during immune checkpoint inhibitor (ICI) therapy remains controversial. This study aimed to determine the association of pre-treatment and early dynamic changes of ctDNA with clinical outcomes in advanced NSCLC patients treated with ICIs.MethodsElectronic databases (PubMed, Embase, Web of Science, and Cochrane) were systematically searched to include relevant studies published in English up to November 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS) and the secondary outcome was objective response rate (ORR) with RECIST criteria.ResultsA total of 1017 patients from 10 studies were identified. The baseline ctDNA levels (detected versus not detected) showed no significant association with clinical outcomes regarding OS (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.93-1.51), PFS (HR, 0.98; 95% CI, 0.80-1.21), and ORR (odds ratio [OR], 0.89; 95% CI, 0.54-1.46). Interestingly, when taken early longitudinal assessment of ctDNA into consideration, the early reduction of the concentration of ctDNA was associated with significant improvements of OS (HR, 0.19; 95% CI, 0.10-0.35), PFS (HR, 0.30; 95% CI, 0.22-0.41) and ORR (OR, 0.07; 95% CI, 0.03-0.18). Further subgroup analyses revealed that the reduction magnitude did not significantly impact the association between ctDNA and clinical outcomes, suggesting that both patients with decreased ctDNA or a ≥50% reduction of ctDNA was associated with improved OS, PFS and ORR.ConclusionEarly reduction of ctDNA was associated with improved OS, PFS and ORR in advanced NSCLC patients treated with ICIs.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, CRD42021226255.

scholarly journals 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

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.

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

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.

Fusion detection and longitudinal circulating tumor DNA (ctDNA) profiling in ALK+ non-small cell lung cancer (NSCLC) patients.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e21031-e21031 ◽  
Author(s):  
Aurélie Swalduz ◽  
Sandra Ortiz-Cuaran ◽  
Virginie Avrillon ◽  
Solène Marteau ◽  
Séverine Martinez ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Tumor Dna ◽  
Fusion Detection

Impact of SWI/SNF complex mutations in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors: Immuno-oncology biomarker study in LC-SCRUM-Japan (LC-SCRUM-IBIS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9530-9530
Author(s):  
Kiyotaka Yoh ◽  
Shingo Matsumoto ◽  
Naoki Furuya ◽  
Kazumi Nishino ◽  
Shingo Miyamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

9530 Background: The SWI/SNF chromatin remodeling complex is reported to be involved in sensitivity and resistance to immune checkpoint inhibitor (ICI). However, their role in non-small cell lung cancer (NSCLC) remains unclear. We examined the relationship between SWI/SNF complex mutations and clinical outcomes of ICI in patients with NSCLC. Methods: Of 1017 lung cancer patients enrolled in LC-SCRUM-IBIS, 350 patients were analyzable for whole-exome sequencing (WES). WES data were used to analyze the presence of mutations in 29 major subunits of the SWI/SNF complexes. ARID1A and SMARCA4 mutations were also evaluated in a targeted NGS panel (Oncomine comprehensive assay, OCA). PD-L1 expression by 22C3, tissue tumor mutational burden (tTMB) by WES, STK11 and KEAP1 mutations by WES or OCA were also assessed. Durable clinical benefit (DCB) including CR, PR and SD > 6 mos to ICI, progression-free survival (PFS) and overall survival (OS) were compared in status of each of SWI/SNF complex mutations and other factors. Results: At least one mutation in any subunits of the SWI/SNF complex was present in 28% of NSCLC patients. The most common mutated subcomplexes were SMARCA4 (12%), BAF (7%: ARID1A, 4%), non-canonical BAF (3%), PBAF (3%), and SMARCA2 (2%). Of 101 NSCLC patients treated with PD-1/PD-L1 inhibitors, SMARCA4 mutations tended to be associated with lower DCB (16 vs 31%) and shorter median PFS (1.9 vs 3.6 m) and OS (7.4 vs 18.1m). Patients with ARID1A mutations tended to have better clinical outcomes (DCB, 40 vs 28%) compared to those without mutations. No significant associations were found between PD-L1 expression and SMARCA4 or ARID1A mutations. Patients with STK11/KEAP1 mutations had lower rate of PD-L1 expression (TPS > 50%) (18% vs 48%, P = 0.03) and worse clinical outcomes (DCB, 6 vs 33%) compared to those without mutations. There was no significant association between a tTMB status and clinical outcome. Conclusions: SMARCA4 and ARID1A mutations appear to affect clinical outcomes of ICI in NSCLC patients. These findings indicate that SWI/SNF complex mutations may serve as a predictive biomarker for ICI in NSCLC patients.

NGS to reveal heterogeneity between cerebrospinal fluid and plasma ctDNA among non-small cell lung cancer patients with leptomeningeal carcinomatosis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9022-9022 ◽  
Author(s):  
Ben-Yuan Jiang ◽  
Yangsi LI ◽  
Shaokun Chuai ◽  
Zhou Zhang ◽  
Jin-Ji Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cerebrospinal Fluid ◽  
Small Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Leptomeningeal Carcinomatosis ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Tumor Dna

9022 Background: In current clinical setting, NSCLC patients harboring specific driver mutation were usually treated guiding by prior profiling of the primary tumor when developed to brain metastasis. Some studies have shown that circulating tumor DNA (ctDNA) derived from cerebrospinal fluid (CSF) can reveal unique genomic alterations present in brain malignancies. We assessed CSF as a liquid biopsy media and compared to matched plasma. Methods: We performed capture-based ultra deep sequencing on ctDNA derived from matched CSF, plasma of 40 non-small cell lung cancer (NSCLC) patients with suspected leptomeningeal carcinomatosis (LC) using a panel consisting of 168 genes. Results: Among the 40 suspected LC cases, 35 were confirmed to have LC, ctDNA in CSF from the 5 non-LC cases are all undetectable. Circulating tumor DNA was detected in 93.8% of CSF and 66.7% of plasma. We compared mutation profiles and identified 86 and 46 SNVs from CSF and plasma, respectively, with 42 SNVs overlapping. Furthermore, ctDNA from CSF revealed many copy number variations (CNVs) that were not detected from plasma (189 CNVs vs. 3 CNVs). The average maximum allelic fraction (AF) of CSF ctDNA is significantly higher than in plasma (56.7% vs. 4.4% p < 10^-6). Twenty-eight patients were pre-treated with EGFR-TKIs and developed subsequent resistance. EGFR T790M and MET amplification were detected in 21% and 39% in CSF, respectively, showing a unique resistance profile among leptomeningeal metastases patients compared to the general population. Interestingly, 60% of CSF samples harbor TP53 loss of heterozygosity, only 11% of which were detected in the matched plasma samples. Such heterogeneity may reflect unique biological themes for brain metastatic tumor sub-clones. Furthermore, 26 patients received molecular targeted therapy based on the results from CSF, and 23 reported alleviation of symptoms at subsequent evaluations. Conclusions: Collectively, our data reveal that ctDNA derived from CSF provides a unique and more comprehensive characterization of genomic alterations of leptomeningeal carcinomatosis than plasma, supporting the importance of CSF as a liquid biopsy media.

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

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.

Retrospective analysis of efficacy of immune checkpoint inhibitors in BRCA-mutant non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21067-e21067
Author(s):  
Shaomu Chen ◽  
Si Li ◽  
Dongsheng Chen ◽  
Mingzhe Xiao
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Mutant Gene ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Type Group ◽  
Significant Difference ◽  
Nsclc Patients

e21067 Background: Efficacy of BRCA1/2 inhibitor in non-small cell lung cancer (NSCLC) is under investigation in serval clinical trials. Meanwhile immune checkpoint inhibitor (ICI) has become one of the standard therapies for advanced NSCLC, while its efficacy in BRCA mutant NSCLC is not clear. This study assessed the efficacy of anti-PD-(L)1/CTLA-4 in advanced BRCA-mutant NSCLC. Methods: Data of cohort OAK, POPLAR and Rizvi et al.,2018 was downloaded. Efficacy including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were reviewed for BRCA1/2 mutant and wild-type group. The impact of mutant gene ( BRCA1, BRCA2), histological types (adenocarcinoma, squamous) and tumor mutation burden ranges (TMB, > 10 SNVs/Mb, < 10 SNVs/Mb) was analyzed if information was available. Results: A total of 809 ICI-treated advanced NSCLC patients, including 53 (6.6%) with BRCA1/2 mutation, were identified. In OAK/POPLAR cohort (atezolizumab monotherapy, 2nd line or more), TMB in BRCA1/2 mutant group was significant higher (19.2 vs. 10.24, P=0.008) than group of wild-type. The ORR of mutant group was 21.9% (Table), median PFS was 2.5 months, median OS was 9.5 months. The ORR and PFS were comparable between mutant and wild-type groups, while OS of the mutant group was significantly shorter than that in wild-type group (mOS, 9.5 months vs. 14.1 months, P= 0.02). Within mutant group, no significant difference of ORR, PFS and OS were found between mutant gene ( BRCA1 vs. BRCA2), histological type (adenocarcinoma vs. squamous) and TMB range (>10 vs. <10). In Rizvi’s cohort (anti-PD-(L)1 /CTLA-4 mono- or combination therapy, 1st line or more), TMB in mutant group was also significant higher (22.2 vs. 9.1, P=0.04) than wild-type group. ORR, PFS for mutant and wild-type groups were 25.0% vs. 20.1%, 3.2 months vs. 3.4 months, without significant difference. Within mutant group, superior PFS was found in adenocarcinoma subgroup (mPFS, 5.5 months vs. 1.2 months (squamous subgroup), P = 0.008) and BRCA2-mutant subgroup tend to have superior PFS (mPFS 5.5 months vs. 1.8 months, P=0.08) than BRCA1-mutant subgroup. Conclusions: This retrospective multicohort analysis showed a trend of worse survival in BRAC-mutant NSCLC patients after ICI treatment compared to those in wild-type group, in spite of higher TMB level. Analysis with more samples are needed to provide more precise treatment reference. [Table: see text]

Soluble BTN2A1 as a potential predictive biomarker of immune checkpoint inhibitor efficacy in advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9561-9561
Author(s):  
Philippe Rochigneux ◽  
Anne Sophie Chretien ◽  
Delphine Rossille ◽  
Brice Chanez ◽  
Emilien Billon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Immune Checkpoints ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Plasmatic Concentration

9561 Background: Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune biomarkers of efficacy are still lacking. Preliminary data in leukemia and pancreatic cancer showed that soluble immune checkpoints are associated with a reduced overall survival (OS). This led us to explore the prognostic and predictive value of soluble immune checkpoints in non-small cell lung cancer (NSCLC) patients treated with chemotherapy or ICI. Methods: We analyzed 90 advanced NSCLC patients. The pilot cohort (Rennes University Hospital, France), included 48 patients treated with platinum doublets (n = 33) or ICI (n = 15) (LOC/11-16 protocol). The confirmation cohort (Paoli-Calmettes Institute) included 42 patients treated with ICI (nivolumab or pembrolizumab) in a longitudinal prospective setting (Immunosup trial, NCT03595813). In both cohorts, enzyme-linked immunosorbent assays (ELISA) were performed in baseline plasma samples for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3-A1 and BTN2A1. Soluble ICI levels were linked to clinical data using Kaplan-Meier, log-rank and Cox proportional-hazards models. Cut-points were determined using maxstat package for survival, R software R 3.6.2. Results: Five soluble immune checkpoints correlated and clustered together in unsupervised analysis (PD-1, PD-L1, global BTN3, BTLA, BTN3-A1), but were not associated with ICI efficacy. In patients treated with ICI, in the pilot and confirmation cohort, a high baseline plasmatic concentration of soluble BTN2A1 was significantly associated with an improved OS (confirmation cohort with a BTN2A1 cut-point of 3.55 ng/ml: HR = 0.30, 95%CI = 0.12-0.74, p = 0.0057, median OS in BTN2A1low = 7.6 months and median OS in BTN2A1hi = 19.5 months). On the contrary, in patients treated with chemotherapy, soluble BTN2A1 concentration was not associated with overall survival. Conclusions: In advanced NSCLC patients, a high baseline plasmatic concentration of soluble BTN2A1 was correlated with improved outcomes for ICI, but not for chemotherapy, suggesting that baseline soluble BTN2A1 level is a potential predictive biomarker of ICI efficacy. Additional studies are ongoing to confirm this finding.

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