Related Experiment Video
Updated: Aug 7, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Tumor Mutational Burden as a Predictor of Immune-Related Adverse Events in Patients With Advanced NSCLC Receiving
Federica Pecci1, Xinan Wang2, Valentina Santo1
1Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Introduction:
Tumor mutational burden (TMB) has been established as a predictor of response to immune checkpoint inhibitors (ICIs) with or without chemotherapy in advanced non-small cell lung cancer (NSCLC). However, less is known about its role as a predictor of immune-related adverse events (irAEs).
Methods:
This monocentric cohort study included patients with advanced NSCLC receiving ICIs with or without chemotherapy who had available TMB assessed by OncoPanel next-generation sequencing. Baseline TMB was correlated with irAEs using both logistic regression and Cox proportional hazards models. Multiplex immunofluorescence was used to assess immune cells density (CD8+, PD-1+, CD8+PD-1+, FOXP3+) in tumor tissue according to TMB.
Results:
Among 1215 patients with advanced NSCLC receiving ICIs with or without chemotherapy, 63.4% were treated with ICI alone and 61.4% were treated in the first line. A total of 421 patients (34.7%) developed irAEs. Higher baseline TMB was associated with an increased risk of developing irAE (adjusted odds ratio = 1.04, p < 0.001) and earlier irAE onset (adjusted hazard ratio = 1.02, p = 0.002). Baseline TMB more than or equal to the 90th percentile (19 mut/Mb) was the strongest predictor of both increased irAE risk (adjusted odds ratio = 2.14, p < 0.001) and earlier irAE onset (adjusted hazard ratio = 1.58, p = 0.004), compared with TMB less than the 90th percentile. Using 6-, 9-, and 12-week landmark analyses, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, PD-L1, and treatment type, TMB more than or equal to the 90th percentile was associated with a higher risk of irAE at 6, 9, and 12 weeks. Tumors with TMB more than or equal to the 90th percentile were enriched with CD8+ cells (p = 0.04) compared with tumors with TMB less than the 90th percentile.
Conclusion:
These findings indicate that a high TMB, particularly TMB more than or equal to the 19 mut/Mb, is associated with an increased risk and earlier irAE onset, independent of longer immunotherapy exposure. This association seems to be biologically driven by tumors enriched in CD8+ cells, supporting the role of elevated TMB as an irAEs biomarker.
