Quantitative imaging biomarkers of immune-related adverse events in immune-checkpoint blockade-treated metastatic melanoma patients. A pilot study

To develop quantitative molecular imaging biomarkers of immune-related adverse event (irAE) development in malignant melanoma (MM) patients receiving immune-checkpoint inhibitors (ICI) imaged with ${}^{18}$F-FDG PET/CT. ${}^{18}$F-FDG PET/CT images of 58 MM patients treated with anti-PD-1 or anti-CTLA-4 ICI were retrospectively analyzed for indication of irAE. Three target organs, most commonly affected by irAE, were considered: bowel, lung, and thyroid. Patient charts were reviewed to identify which patients experienced irAE, irAE grade, and time to irAE diagnosis. Target organs were segmented using a convolutional neural network (CNN), and novel quantitative imaging biomarkers --- SUV percentiles (SUV${}_{X\%}$) of ${}^{18}$F-FDG uptake within the target organs --- were correlated with the clinical irAE status. Area under the receiver-operating characteristic curve (AUROC) was used to quantify irAE detection performance. Patients who did not experience irAE were used to establish normal ranges for target organ ${}^{18}$F-FDG uptake. A total of 31% (18/58) patients experienced irAE in the three target organs: bowel (n=6), lung (n=5), and thyroid (n=9). Optimal percentiles for identifying irAE were bowel (SUV${}_{95\%}$, AUROC=0.79), lung (SUV${}_{95\%}$, AUROC=0.98), and thyroid (SUV${}_{75\%}$, AUROC=0.88). Optimal cut-offs for irAE detection were bowel (SUV${}_{95\%}$>2.7 g/mL), lung (SUV${}_{95\%}$>1.7 g/mL), and thyroid (SUV${}_{75\%}$>2.1 g/mL). Normal ranges (95% confidence interval) for the SUV percentiles in patients without irAE were bowel [1.74, 2.86 g/mL], lung [0.73, 1.46 g/mL], and thyroid [0.86, 1.99 g/mL]. Increased ${}^{18}$F-FDG uptake within irAE-affected organs provides predictive information about the development of irAE in MM patients receiving ICI and represents a potential quantitative imaging biomarker for irAE. Some irAE can be detected on ${}^{18}$F-FDG PET/CT well before clinical symptoms appear.