The emerging development of tumor mutational burden in patients with NSCLC

2020 ◽  
Author(s):  
Yu Zhang ◽  
Lifeng Wang ◽  
Rutian Li ◽  
Baorui Liu
Keyword(s):  
Racial Differences ◽  
Response Prediction ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Predictors Of Response ◽  
Tumor Mutational Burden ◽  
Multiple Biomarkers ◽  
History Of ◽  
Innovative Concept

Immunocheckpoint inhibitors (ICIs) which target PD-1 and CTLA-4 have dramatically changed the history of non-small-cell lung cancer treatment. Multiple biomarkers especially tumor mutational burden (TMB) have been raised to be potential predictors of response to ICIs. However, great value of TMB has been observed in patients who receive ICIs monotherapy instead of ICIs combination therapy from latest exploratory studies. Thus, the innovative concept of TMB needs to be identified. This study uncovers specific aspects of TMB including signatures of TMB, factors related with variation, racial differences, heterogeneity between tissue TMB and blood-based TMB. Additionally, more and more factors are found valuable in clinical trials, suggesting that more markers should be further investigated as interesting candidates for response prediction beyond TMB.

scholarly journals Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB2 harmonization project comparing three NGS panels

2021 ◽  
Vol 9 (5) ◽  
pp. e001904
Author(s):  
Javier Ramos-Paradas ◽  
Susana Hernández-Prieto ◽  
David Lora ◽  
Elena Sanchez ◽  
Aranzazu Rosado ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Value ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Reproducibility Study ◽  
Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.MethodsWe evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.ResultsBoth panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.ConclusionsBoth panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

scholarly journals In-house Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-small Cell Lung Cancer and Melanoma Patients

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1271 ◽  
Author(s):  
Heeke ◽  
Benzaquen ◽  
Long-Mira ◽  
Audelan ◽  
Lespinet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Melanoma Patients

Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

scholarly journals Tumor Mutational Burden and PD-L1 Expression in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China

2020 ◽  
Vol Volume 13 ◽  
pp. 5191-5198
Author(s):  
Yuhui Ma ◽  
Quan Li ◽  
Yaxi Du ◽  
Wanlin Chen ◽  
Xing Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Southwestern China ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer

Cancer Cell ◽  
2018 ◽  
Vol 33 (5) ◽  
pp. 853-861.e4 ◽  
Author(s):  
Matthew D. Hellmann ◽  
Margaret K. Callahan ◽  
Mark M. Awad ◽  
Emiliano Calvo ◽  
Paolo A. Ascierto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals First-Line Nivolumab Plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers

2019 ◽  
Vol 37 (12) ◽  
pp. 992-1000 ◽  
Author(s):  
Neal Ready ◽  
Matthew D. Hellmann ◽  
Mark M. Awad ◽  
Gregory A. Otterson ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
Low Dose ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Free Survival ◽  
Mutational Burden ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
First Line Treatment

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Sign in / Sign up

Export Citation Format

Share Document