Association Between Immune-Related Adverse Events During Anti-PD-1 Therapy and Tumor Mutational Burden

Importance: The clinical use of anti-PD-1 therapy is curbed by immune-related adverse events (irAEs). There is yet a lack of validated biomarkers that allows clinicians to predict the development of an irAE prior to therapy initiation.

Objective: To determine whether tumor mutational burden (TMB), which has been identified to be a potential biomarker for response to ICI therapy, is associated also with irAEs.

Design, Setting and Participants: A database study of adverse event reports that have been submitted to the FDA Adverse Event Reporting System (FAERS), ranging from July 2014 to March 2019.

Main Outcomes and Measures: Reporting odds ratio for any irAEs that developed during anti-PD-1 monotherapy (nivolumab or pembrolizumab) for any type of cancer.

Results: We identified 16,397 patients treated with anti-PD-1 monotherapy, who developed an adverse event. For 19 different cancer types there were at least 100 reports available. The most common therapeutic indications were melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma, head and neck cancer, and urothelial cancer. Out of all patients, 3,661 reported any irAE (22.3%; 95% CI, 21.7-23.0). The cancers with the highest proportion of reported irAEs were melanoma, Hodgkin’s lymphoma, NSCLC of the adenocarcinoma subtype, and NSCLC of the squamous cell carcinoma subtype. Pharmacovigilance analysis revealed a significant correlation between the odds of reporting an irAE and TMB across multiple cancer types treated with anti-PD-1 therapy (Pearson’s R = 0.704; P < 0.001).

Conclusion and Relevance: In this observational study, we show that irAEs are associated with TMB across multiple cancer types. Thus, TMB may be a useful biomarker to not only indicate therapy response, but also the risk of developing an irAE during anti-PD-1 therapy.