Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2026
Tumor Mutational Burden as a Predictor of Immune-Related Adverse Events in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors: A Brief Report.
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Pecci Federica, Wang Xinan, Santo Valentina, Gariazzo Eleonora, Garbo Edoardo, Paoloni Francesco, Rossato de Almeida Guilherme, Aldea Mihaela, Di Federico Alessandro, Alessi Joao V, Canty Stephanie, Bruschi Giulia, Lotter William, Awad Mark M, Gusev Alexander, Florez Narjust, Christiani David C, Rodig Scott J, Nishino Mizuki, Jänne Pasi A, Sharon Elad, Ricciuti Biagio
Аннотация
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.
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.