Bomze D, et al. - Researchers examined how immune-related adverse events (irAEs) reported during anti-programmed cell death 1 [PD-1] therapy are associated with tumor mutational burden (TMB) by comparing large-scale surveillance data of irAEs with the median TMB across multiple cancer types. From the US Food and Drug Administration Adverse Event Reporting System, they retrieved data of a total of 47,304 adverse events in 16,397 patients who were reported as treated with anti–PD-1 monotherapy for 19 different cancer types. During anti–PD-1 therapy, cancers with a high TMB, such as melanoma and non–small cell lung cancer, were noted to be associated with a higher irAE reporting odds ratios. This strongly suggests a correlation of these cancers with a higher risk of irAEs than cancers with a low TMB. The different neoantigenic load across cancer types may possibly explain this finding. Additionally, studies have shown crossreaction of T cells that react against a neoantigen, against the corresponding wild-type protein. Antigen spreading may be another contributing mechanism, where tumor cell death releases antigens, including neoantigens, that prime lymphocytes against the wild-type antigens in healthy tissue. In view of the results, there seemed an association between irAEs and improved response to anti–PD-1 treatment, which is linked via an underlying neoantigenic potential that stems from a high TMB. Furthermore, a longer course of anti–PD-1 treatment was required by patients with cancers with a high TMB. However, the development of most irAEs, reported during anti–PD-1 therapy, was noted within the first few weeks of treatment. This finding suggests no influence of duration on the statistical outcome. In conclusion, for assessing patients’ risk of irAEs during anti–PD-1 therapy, a high TMB may be a useful biomarker, which seems particularly relevant for vulnerable patient groups.