Tumor mutational burden as a predictor of immune-related adverse events in patients with advanced non-small cell lung cancer receiving immune checkpoint inhibitors: a Brief Report.

F. Pecci Xinan Wang Valentina Santo E. Gariazzo E. Garbo Francesco Paoloni G. D. De Almeida M. Aldea A. Di Federico J. Alessi S. Canty Giulia Bruschi W. Lotter M. Awad Alexander Gusev N. Florez David C. Christiani S. Rodig M. Nishino P. Jänne E. Sharon B. Ricciuti

Aug 2026 · Journal of Thoracic Oncology · pp. 104136 · 0 citations

Medicine

Abstract

Background

Tumor mutational burden (TMB) has been established as a predictor of response to immune checkpoint inhibitors (ICI) ± 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 ICI±chemotherapy who had available TMB assessed by OncoPanel next-generation sequencing. Baseline TMB was correlated with irAEs using both logistic regression and Cox-proportion hazard model. Multiplex immunofluorescence (mIF) 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 ICI±chemotherapy, 63.4% were treated with ICI alone, 61.4% were treated in first-line. A total of 421 (34.7%) patients developed irAEs. Higher baseline TMB was associated with a increased risk of developing irAEs (adjusted OR [aOR] 1.04, p<0.001) and earlier irAEs onset (aHR 1.02, p=0.002). Baseline TMB≥90th percentile (19 mut/Mb) was the strongest predictor of both increased irAEs risk (aOR 2.14, p<0.001) and earlier irAEs onset (aHR 1.58, p=0.004), compared to TMB<90th percentile. Using a 6, 9, and 12 weeks landmark analysis, adjusting for age, sex, ECOG-PS, PD-L1, and treatment type, TMB ≥90th percentile was associated with a higher risk of irAEs at 6,9, and 12 weeks. Tumors with TMB≥90th percentile were enriched of CD8+ cells (p=0.04) compared to tumors with TMB<90th percentile.

Conclusion

These findings indicate that high TMB, particularly TMB≥19 mut/Mb, is associated with increased risk and earlier irAEs onset, independently from longer immunotherapy exposure. This association appears biologically driven by tumors enriched in CD8+ cells, supporting the role of elevated TMB as an irAEs biomarker.

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