Related Experiment Video
Updated: Nov 30, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?
John H Strickler1, Brent A Hanks1,2,3, Mustafa Khasraw4,2
1Duke Cancer Institute, Duke University, Durham, North Carolina.
Abstract:
Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung cancer, but the broad applicability of TMB-H as a biomarker of response across all solid tumors is unclear. The FDA has approved the PD-1 inhibitor, pembrolizumab, as a therapy for all solid tumors with TMB equal to or greater than 10 mutations/megabase as measured by the FoundationOne CDx assay. This approval was based on an exploratory analysis of the KEYNOTE-158 study, which was a single-arm, phase II multi-cohort study of pembrolizumab for select, previously treated advanced solid tumors. Here, we elucidate the caveats of using TMB as a biomarker with a universal threshold across all solid tumors. While we recognize the importance of this and other FDA pan-cancer approvals, several questions about TMB as a predictive biomarker remain unanswered. In this perspective, we discuss clinical trial evidence in this area. We review the relationship between TMB and the tumor immune microenvironment. We highlight the risks of extrapolating evidence from a limited number of tumor histologies to all solid tumors, and we propose avenues for future research.
Insights
High tumor mutational burden (TMB) shows promise for predicting response to cancer immunotherapies like PD-1/PD-L1 inhibitors. However, its universal applicability across all solid tumors requires further investigation and raises concerns about a one-size-fits-all threshold.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Research
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized cancer treatment.
- Most patients exhibit resistance to ICIs, creating a need for predictive biomarkers.
- High tumor mutational burden (TMB-H) is a potential biomarker, but its efficacy across diverse solid tumors is uncertain.
Purpose of the Study:
- To critically evaluate the use of tumor mutational burden (TMB) as a universal predictive biomarker for PD-1/PD-L1 blockade across all solid tumors.
- To discuss the limitations and caveats associated with applying a single TMB threshold for patient selection.
- To explore the relationship between TMB, the tumor immune microenvironment, and clinical response.
Main Methods:
- Review of clinical trial evidence, including data from the KEYNOTE-158 study.
- Analysis of the FDA's pan-cancer approval of pembrolizumab based on TMB.
- Exploration of the association between TMB and tumor immune microenvironment characteristics.
Main Results:
- The FDA approved pembrolizumab for solid tumors with TMB ≥ 10 mutations/megabase, based on exploratory analyses.
- Evidence suggests that TMB's predictive value may vary significantly across different tumor types.
- Extrapolating TMB data from limited histologies to all solid tumors carries risks.
Conclusions:
- A universal TMB threshold may not be reliably predictive of response to ICI therapy across all solid tumors.
- Further research is needed to refine TMB as a biomarker and understand its interplay with the tumor immune microenvironment.
- Developing robust, tumor-specific biomarkers is crucial for optimizing ICI treatment strategies.
More Related Videos
07:47Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
09:32Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
