OA20.01 Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients

Background. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, and the majority of NSCLC patients are diagnosed at the advanced stage. Chemotherapy is still the main treatment at present, and the overall prognosis is poor. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs) as the representative have been extensively applied for treating various types of cancers. Tumor mutation burden (TMB) as a potential biomarker is used to screen appropriate patients for treatment of ICIs. To verify the predictive efficacy of TMB, a systematic review and meta-analysis were conducted to explore the association between TMB and ICIs. Method. PubMed, EMBASE, Cochrane Library, and son on were systematically searched from inception to April 2020. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were estimated. Results. A total of 11 studies consisting of 1525 nonsmall cell lung cancer (NSCLC) patients were included. Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046 ); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001 ); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001 ). Subgroup analysis values: pooled HRs for OS, 0.75 (95% CI 0.29 to 1.92, P = 0.548 ) for blood TMB (bTMB), 0.44 (95% CI 0.26 to 0.75, P = 0.003 ) for tissue TMB (tTMB); for PFS, 0.54 (95% CI 0.29 to 0.98, P = 0.044 ) and 0.43 (95% CI 0.26 to 0.71, P = 0.001 ), respectively. Conclusions. These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB. As opposed to bTMB, tTMB was thought more appropriate for stratifying NSCLC patients for ICI treatment.

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Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

npj Precision Oncology ◽

10.1038/s41698-021-00244-6 ◽

2022 ◽

Vol 6 (1) ◽

Author(s):

Shuhang Wang ◽

Pei Yuan ◽

Beibei Mao ◽

Ning Li ◽

Jianming Ying ◽

...

Keyword(s):

Copy Number ◽

Copy Number Gain ◽

Pathological Response ◽

Immune Microenvironment ◽

Tumor Mutation Burden ◽

Neoadjuvant Immunotherapy ◽

Mutation Burden ◽

Tumor Immune Microenvironment ◽

Nsclc Patients ◽

Insight Into

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

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Higher Tumor Mutation Burden Was a Predictor for Better Outcome for NSCLC Patients Treated with PD-1 Antibodies: A Systematic Review and Meta-analysis

SLAS TECHNOLOGY Translating Life Sciences Innovation ◽

10.1177/24726303211024557 ◽

2021 ◽

pp. 247263032110245

Author(s):

Yuhui Zheng ◽

Meihong Yao ◽

Yinghong Yang

Keyword(s):

Meta Analysis ◽

Progression Free Survival ◽

Cochrane Library ◽

Small Cell Lung ◽

Free Survival ◽

Tumor Mutation Burden ◽

Ovid Medline ◽

Mutation Burden ◽

The Cochrane Library ◽

Nsclc Patients

This study was conducted to evaluate the predictive efficacy of tumor mutation burden (TMB) in patients with non–small-cell lung cancer (NSCLC) receiving PD-1 antibodies. Embase, PubMed, Ovid Medline, and the Cochrane Library were systematically searched until May 24, 2020. The keywords included “PD-1,” “TMB,” and “NSCLC.” Overall survival (OS) and progression-free survival (PFS) were summarized and combined using the hazard ratio (HR) and 95% confidence interval. Twenty-one studies with 9883 patients were included in the meta-analysis. The overall relapse rate ranged from 39.3% to 64.3% in the higher TMB group as compared with 0% to 40% in the lower TMB group. The median OS ranged from 2.9 to 23 mo in the higher TMB group as compared with 4.3 to 16.2 mo in the lower TMB group. Patients with a higher TMB had a better OS as compared with patients with a lower TMB (HR = 0.61, P < 0.001). Similarly, a higher TMB was also a good predictor of PFS in patients treated with PD1/PDL1 antibodies (HR = 0.55, P < 0.001). Our results suggest that among NSCLC patients receiving PD1/PDL1 antibodies, patients with higher TMB could have a better survival outcome.

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The relationship between blood-based tumor mutation burden level and efficacy of PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis

BMC Cancer ◽

10.1186/s12885-021-08924-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

He Ba ◽

Lei Liu ◽

Qiang Peng ◽

Jie Chen ◽

Yao-dong Zhu

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Cell Lung Cancer ◽

Meta Analysis ◽

Inhibitor Therapy ◽

Sensitivity Analyses ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Nsclc Patients

Abstract Background The predictive role of blood-based tumor mutation burden (bTMB) for selecting advanced nonsmall cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs) is still under debate. Therefore, the purpose of this meta-analysis was to evaluate the efficacy of programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) inhibitors versus that of standard-of-care therapy in patients with NSCLC who were bTMB high and bTMB low. Methods PubMed, Embase, Cochrane, the Web of Science, and ClinicalTrials.gov were searched systematically from inception to February 2021 for studies of PD-1/PD-L1 inhibitors (durvalumab OR atezolizumab OR avelumab OR pembrolizumab OR Nivolumab) that provided hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS), or odds ratios (ORs) for objective response rate (ORR) in both bTMB high and bTMB low groups. Results A total of 2338 patients with advanced or metastatic NSCLC from six randomized controlled trials, which all used chemotherapy (CT) as a control, were included in this study. Compared with CT, PD-1/PD-L1 inhibitor therapy improved OS (HR 0.62, 95% CI 0.52–0.75, P < 0.01), PFS (HR 0.57, 95% CI 0.48–0.67, P < 0.01), and ORR (OR 2.69, 95% CI 1.84–3.93, P < 0.01) in bTMB-high NSCLC patients but not in bTMB-low patients (OS HR 0.86, 95% CI 0.69–1.07, P = 0.17; PFS HR 1.00, 95% CI 0.78–1.27, P = 0.98; ORR OR 0.63, 95% CI 0.49–0.80, P = 0.03). Subgroup analyses showed that these results were consistent across all subgroups (line of therapy, therapy regimen, type of NGS panel, PD-L1 expression, and cutoff value). Meta-regression analysis showed that the proportion of patients with squamous cell histology had no statistical effect on clinical outcomes. Sensitivity analyses illustrated that all results were stable. Conclusions The efficacy of PD-1/PD-L1 inhibitor therapy in advanced NSCLC patients may be dependent on bTMB level. Patients with high bTMB tend to obtain significantly better OS, PFS, and ORR from PD-1/PD-L1 inhibitor therapy than from CT. However, because of multiple limitations, including those related to reproducibility, the results are exploratory and should be interpreted with caution.

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Barriers to tumor mutation burden (TMB) testing in NSCLC patients in the US and EU.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e24192 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e24192-e24192

Author(s):

William H Angel ◽

Ciny Edathanal ◽

Mahaletchumy Krishnam ◽

Pieter De Richter ◽

Ayse Levent

Keyword(s):

Tumor Mutation Burden ◽

Mutation Burden ◽

The Us ◽

Nsclc Patients

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A non-linear association between blood tumor mutation burden and prognosis in NSCLC patients receiving atezolizumab

OncoImmunology ◽

10.1080/2162402x.2020.1731072 ◽

2020 ◽

Vol 9 (1) ◽

pp. 1731072 ◽

Cited By ~ 3

Author(s):

Wei Nie ◽

Jie Qian ◽

Mi-Die Xu ◽

Kai Gu ◽

Fang-Fei Qian ◽

...

Keyword(s):

Tumor Mutation Burden ◽

Linear Association ◽

Mutation Burden ◽

Non Linear ◽

Nsclc Patients

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Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib

Scientific Reports ◽

10.1038/s41598-020-57624-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hidenobu Ishii ◽

Koichi Azuma ◽

Kazuko Sakai ◽

Yoshiko Naito ◽

Norikazu Matsuo ◽

...

Keyword(s):

Somatic Mutations ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Nsclc Patients

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Evaluation of Prognostic Utility of Tumor Mutation Burden for NSCLC response to Immune Checkpoint Blockade Therapy: A Single Institute Study

10.1101/19013433 ◽

2019 ◽

Author(s):

Jean R. Clemenceau ◽

Sung Hak Lee ◽

Peter Bazeley ◽

Alex Millinovich ◽

Jian Jin ◽

...

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Cleveland Clinic ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

High Status ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Prognostic Utility ◽

Nsclc Patients

IMPORTANCEThe role of Tumor Mutation Burden (TMB) as a prognostic and/or predictive biomarker for Immune Checkpoint Blockade (ICB) therapy in a real-world clinical setting is still unclear.OBJECTIVETo assess whether TMB status provided by a clinically and commercially available tumor genomic profiling (TGP) assay is associated with overall survival of Non-Small Cell Lung Cancer (NSCLC) patients treated with ICB from a single institute.DESIGN, SETTING, AND PARTICIPANTSOutcomes and genetic testing data were collected for 188 NSCLC patients treated within the Cleveland Clinic system between August 2012 and July 2017.MAIN OUTCOMES AND MEASURESOverall survival (OS) from time receiving ICB therapy.RESULTSAmong 188 patients with NSCLC (median age, 62 years; 49.5% female), 86 (45.7%) received ICB therapy. Patients were grouped into three categories based on the status of TMB (in mutations/Mb): high (>= 20/Mb), intermediate (>=5 to <= 20/Mb), and low (<5/Mb). In patients treated with ICB, TMB high status was not significantly associated with improved OS from therapy initiation (HR: 0.90 [95% CI, 0.52-2.49, P>0.8], median OS difference: 9.7 months).CONCLUSIONS AND RELEVANCEAmong patients with NSCLC from a single institute in a longitudinal database of clinical data including TGP results, exploratory analyses do not show statistical significance for the prognostic utility of TMB. These findings indicate that there is a need for more prospective data on the use of TMB status as a guide for ICB therapy in a routine care setting.

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Intergrated Analysis of ELMO1, Serves As a Link between Tumor Mutation Burden and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

SSRN Electronic Journal ◽

10.2139/ssrn.3350534 ◽

2019 ◽

Author(s):

Hong Peng ◽

Yi Zhang ◽

Zhiwei Zhou ◽

Yu Guo ◽

Xiaohui Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Tumor Mutation Burden ◽

Mesenchymal Transition ◽

Mutation Burden

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Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽

10.2217/epi-2020-0093 ◽

2020 ◽

Author(s):

Qijie Zhao ◽

Jinan Guo ◽

Yueshui Zhao ◽

Jing Shen ◽

Parham Jabbarzadeh Kaboli ◽

...

Keyword(s):

Transcription Factor ◽

Signaling Pathways ◽

Underlying Mechanism ◽

Comprehensive Analysis ◽

The Cancer Genome Atlas ◽

Gastrointestinal Cancers ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

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