Tumor mutational burden in lung cancer: a systematic literature review

Abstract

Purpose: To assess the association of tumor mutational burden (TMB) with clinical outcomes, other biomarkers and patient/disease characteristics in patients receiving therapy for lung cancer. Results: In total, 4,303 publications were identified; 81 publications were included. The majority of publications assessing clinical efficacy of immunotherapy reported an association with high TMB, particularly when assessing progression-free survival and objective response rate. High TMB was consistently associated with TP53 alterations, and negatively associated with EGFR mutations. High TMB was also associated with smoking, squamous cell non-small cell lung carcinoma, and being male. Methods: A systematic literature review based upon an a priori protocol was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane methodologies. Searches were conducted in EMBASE, SCOPUS, Ovid MEDLINE®, and Emcare (from January 2012 until April 2018) and in two clinical trial registries. Conference abstracts were identified in EMBASE, and in targeted searches of recent major conference proceedings (from January 2016 until April 2018). Publications reporting data in patients receiving therapy for lung cancer that reported TMB and its association with clinical efficacy, or with other biomarkers or patient/disease characteristics, were included. Results are presented descriptively. Conclusion: This systematic literature review identified several clinical outcomes, biomarkers, and patient/disease characteristics associated with high TMB, and highlights the need for standardized definitions and testing practices. Further studies using standardized methodology are required to inform treatment decisions.

Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer

“…When we set the cut-off at the upper 20 percentile (10.6 mt/mb), although patients with TMB-high still showed higher ORR (38.5 vs. 16%) and prolonged PFS (2.6 vs. 2.3 months) after ICB therapy, the differences were not significant. For TMB, recent systematic literature review of 81 prior publications concluded that standardized threshold for classifying TMB levels as low-and high-does not exist currently (29). In a large-scale study (n = 1,662) analyzing the association between TMB and clinical responses to checkpoint inhibitors in various cancer types (14), they used a top-20th percentile as a cutoff for TMB and suggested that that there may not be one universal definition of high TMB.…”

Current and future trends in non–small cell lung cancer biomarker testing: The American experience

“…10 For TMB, to our knowledge to date, the majority of studies have reported an association between high TMB and progression-free survival and the objective response rate when treated with immune checkpoint inhibitor therapy. 11 In addition, broader NGS-type panel testing can provide valuable information regarding the tumor's comutational profile, which may help to direct therapeutic choices in the future, such as the identification of inactivating STK11/LKB1 mutations in KRASmutated lung adenocarcinomas, which are predictive of primary resistance to immune checkpoint inhibitor therapy via PD-1 and/or PD-L1 blockade. 12 Therefore, as can be appreciated, the testing landscape for patients with advanced NSCLC in the United States has dramatically evolved over the past decade, expanding the number of biomarker-defined patient subgroups that are being matched with specific targeted therapies, thereby achieving superior clinical outcomes compared with previously relied on traditional cytotoxic chemotherapy.…”

Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer

“…TMB status can be assessed on tissue using whole-exome sequencing (WES) or targeted NGS of a more focused panel of genes [99,100]. Despite inconsistencies in the cut-offs definitions, high TMB appeared to be associated with greater clinical benefit (particularly ORR and PFS) among patients receiving immunotherapy for lung cancer [101]. However, the implementation of TMB assay into the clinic is hampered by several issues, including the tissue availability, which is limited to 34-59% of patients according to clinical trials [102][103][104].…”