Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Abstract

BackgroundTreatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.Materials and methodsIn this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity.ResultsHigh TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established.ConclusionsTMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

“…More than 50% of solid cancers sooner or later escape control of standard treatments. Those tumors with high mutational burden are easily treated with immunotherapy, which is almost ineffective in another half of cases in which specific driver genes are supposed to lead therapy resistance . However, molecular‐based recommended therapies have almost unfulfilled expectation.…”

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions

“…Fifty‐four trials were identified in the search, which have a total estimated enrollment of over 11 000 patients, and their projected primary completion dates suggest that patient TMB data will continue to accumulate through 2019 and beyond. Of the 54 trials, 37 investigate immune checkpoint inhibitors and TMB, and findings show that integration of TMB as a biomarker for response to immune checkpoint inhibitors in clinical trials is diversifying from mostly melanoma and NSCLC trials into a range of other tumor types, including endometrial, colorectal, urothelial, and breast cancers . These findings underlie expectations that diagnostic assessment of TMB could provide benefit across many tumor types.…”

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…Despite the current uncertainty regarding molecular markers such as MDM2 amplification and EGFR alterations that may predict HPD , the use of genomic aberrations as biomarkers for immunotherapy response pattern has been previously established . Indeed, although genomics and immunotherapy are often considered as separate fields, in reality, they are tightly linked .…”

“…Indeed, although genomics and immunotherapy are often considered as separate fields, in reality, they are tightly linked . There are various genomic aberrations that correlate with immunotherapy response, including (but not limited to) (A) mismatch repair gene defects that result in high microsatellite instability (MSI), (B) high tumor mutational burden (TMB), (C) PBRM1 and CDK12 mutations, and (D) PD‐L1 amplification . Other biomarkers include high PD‐L1 protein expression, gut microbiome, and POLE , ATM (TMB‐mediated), ATR (TMB‐mediated), and CDK12 mutations, which have been shown to predict response to immunotherapy .…”