Hypermutation, Mismatch Repair Deficiency, and Defining Predictors of Response to Checkpoint Blockade
Abstract
Mutational burden is positively correlated with tumor neoantigen load and studies have demonstrated an association between high tumor mutational burden (TMB) and response to checkpoint blockade. On the basis of a phase II study, the anti-PD-1 therapy, pembrolizumab, was given FDA approval for use in any solid tumor with a high TMB (i.e., >10 mutations/megabase) as assessed by the FoundationOne companion diagnostic. This was an important step in expanding a potentially efficacious treatment option to patients who are likely to benefit and have limited other therapies available. Following this approval, there has been debate regarding the wide applicability of this approval and the most appropriate use of TMB as a predictive biomarker, with several studies questioning the predictive utility of TMB in this context. We discuss the scientific rationale and utility of using TMB as a tool to predict response to immunotherapy as well as address this biomarker's limitations.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 15, 2021
- Source ID
- 10.1158/1078-0432.ccr-21-3031
Entities
People
- Colin C Pritchard
- Laura S Graham
- Michael T Schweizer
Organizations
- National Health and Medical Research Council
- United States Department of Defense
- University of Colorado
- University of Washington