133 Understanding immune checkpoint inhibitors through PET-imaging studies implications for the interpretation of data from radiolabeled ICI PET imaging studies. This should be kept in mind depending on the respective research question. It should further be noted that there are differences in the design of the studies (Table 1). [89Zr]Zr-pembrolizumab and [89Zr]Zr-nivolumab PET imaging were only performed in NSCLC patients, while [89Zr]Zr-atezolizumab PET imaging was performed on a heterogenous patient population (e.g., bladder cancer, NSCLC and triple-negative breast cancer). The variable PD-L1 expression and ICI treatment response across patients with different tumor types may impact the potential correlation of 89Zr-labeled ICI to clinical response. Also, PET analyses differed. Lesion tracer-uptake was quantified using peak standard uptake values (SUVpeak) in the NSCLC patients, while in the study of Bensch et al.18 only SUV max values are reported. The cut-off of 2 cm to correct for partial volume effect, was performed in all studies. The interpretation and relevance of traceruptake in the smaller lesions is unsure but should be noted if we want to translate per lesion data to patient level. Ultimately, all collected PET-data, preferably including metabolic features assessed by [18F]FDG PET/CT, should be combined in a data warehouse to identify the best approach for analyses and may help to compare across different antibody-based PET imaging studies16. In future [89Zr]Zr-labeled ICI trials, it should be evaluated whether the differences in 89Zr-labeled ICI uptake is correlated with overall survival, progression-free survival, and objective responses according to RECIST v1.1 using a diagnostic CT scan. Furthermore, baseline and ontreatment biopsies should be included in a mechanism-based trial program. Here, multiplex immunohistochemistry can be used to quantify and localize corresponding immune cell subsets and their immune checkpoint expression in biopsy samples17. This will add biological relevance to the found heterogeneity on radiolabeled ICI imaging. More importantly, this may also shed light on the question why patients with a biopsy-based low PD-L1 expression by immunohistochemistry are able to respond to ICI therapy. Table 1. Radiolabeled ICI PET/CT imaging studies Clinical trial Imaging technique (PET) Tumor type Patients Results Niemeijer et al. 9 NCT03065764 [89Zr]Zr-pembrolizumab NSCLC n=12 • [89Zr]Zr-pembrolizumab PET/CT is feasible and safe • [89Zr]Zr-pembrolizumab uptake higher in patients with treatment response • [89Zr]Zr-pembrolizumab uptake was not correlated to PD-1/PD-L1 expression 7
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