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 Tumor Mutational Burden 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