caa a22 4500 555159396 CHVBK 20190320043559.0 cr unu---uuuuu 190202e20190101xx s 000 0 eng 10.1093/annonc/mdy495 doi (SERVAL)BIB_352758F0496B 30395155 pmid 000459677700009 isiid Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic [Elektronische Daten] [T.A. Chan, M. Yarchoan, E. Jaffee, C. Swanton, S.A. Quezada, A. Stenzinger, S. Peters] Treatment 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. In 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. High 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. TMB, 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. Chan T.A. aut Yarchoan M. aut Jaffee E. aut Swanton C. aut Quezada S.A. aut Stenzinger A. aut Peters S. aut Annals of oncology 30/1(2019-01-01), 44-56 30:1<44-56 2019 30 1 article serval SERVAL 700 1- Chan T.A. aut SERVAL 700 1- Yarchoan M. aut SERVAL 700 1- Jaffee E. aut SERVAL 700 1- Swanton C. aut SERVAL 700 1- Quezada S.A. aut SERVAL 700 1- Stenzinger A. aut SERVAL 700 1- Peters S. aut SERVAL 773 0- Annals of oncology 30/1(2019-01-01), 44-56 30:1<44-56 2019 30 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article