Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence. (2nd October 2019)

• Record Type: Journal Article
• Authors: Klempner, Samuel J.; Fabrizio, David; Bane, Shalmali; Reinhart, Marcia; Peoples, Tim; Ali, Siraj M.; Sokol, Ethan S.; Frampton, Garrett; Schrock, Alexa B.; Anhorn, Rachel; Reddy, Prasanth
• Is Part Of: Oncologist. Volume 25:Number 1(2020)
• Page Start: e147
• Page End: e159
• Publication Date: 2019-10-02
• Subjects: Programmed cell death 1 receptor -- Antibodies/therapeutic use -- DNA mutational analysis -- Genes -- Neoplasm -- Sequence analysis -- DNA; Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2019-0244
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract: : Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)—the number of somatic mutations per DNA megabase (Mb)—has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next‐generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole‐exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression‐free survival in patients with non‐small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. Abstract : Optimization of treatment with immune checkpoint inhibitors requires additional predictive biomarkers to establish which patients are most likely to benefit from such therapies. This review summarizes methodology and clinical data supporting tumor mutational burden as immunotherapy biomarker and complement to treatment selection.