Tumor Mutational Burden (TMB) by Whole Exome Sequencing measures the total number of mutations that result in altered proteins (neo-antigens), a pan-tumor biomarker that indicates a cancer may respond more effectively to immunotherapies. The Caris TMB assay quantifies the number of non-synonymous, somatic mutations identified per megabase (Mb) of the genome coding area of DNA (1 megabase is 1,000,000 DNA basepairs) and reports results as Low or High.
Non-synonymous mutations are changes in DNA that result in amino acid changes in the protein.1,2 The new protein changes result in new shapes (neo-antigens) that are considered to be foreign to the immune system.1,3 Immune checkpoint inhibitors are able to stimulate and allow the immune system to detect these neo-antigens and destroy the tumor.2 Germline (inherited) mutations are not included in Tumor Mutational Burden because the immune system has a higher likelihood of recognizing these alterations as normal.4
TMB has emerged as an important biomarker when considering immunotherapy in solid tumors. This is highlighted by the FDA accelerated approval of pembrolizumab (KEYTRUDA®) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This approval is based on the results of the KEYNOTE-158 trial, which achieved an overall response rate of 29% (95% CI: 21, 39), with a 4% complete response rate and 25% partial response rate.5
Caris has collaborated with the Friends of Cancer Research TMB Harmonization Project to systematically characterize and standardize TMB testing and reporting to a common industry standard.6 Based on this collective work and exciting KEYNOTE-158 result and drug approval, Caris has updated the TMB high/low threshold to reflect greater than or equal to 10 mutations per megabase across all solid tumors, aligning the testing results to pembrolizumab for TMB-H cases.5
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