112 Chapter 6 ABSTRACT Background We investigated the safety and feasibility of programmed cell death ligand-1 (PD-L1) positronemitting-tomography (PET) imaging with the 89Zr-labeled anti-PD-L1 antibody avelumab before start of avelumab treatment in patients with non-small cell lung cancer (NSCLC). Secondary aims were to correlate [89Zr]Zr-DFO-avelumab accumulation with avelumab treatment outcome and baseline tumor PD-L1 expression. Methods In this phase I-II study (NCT03514719), 24 NSCLC patients were enrolled. After protocol amendment, only patients with early stage (stage Ia-IIIa) NSCLC (n=20) were enrolled. Patients with stage IV NSCLC (n=4) enrolled prior to this amendment, were only evaluated for imaging purposes. Dose and time point optimization of [89Zr]Zr-DFO-avelumab PET/CT was performed in the first 13 patients who received 2mg, 10mg or 50mg avelumab followed by PET/CT at day 2 and 4 post injection. Remaining patients received the selected [89Zr]Zr-DFO-avelumab dose at the optimal timepoint. All patients underwent a chest CT and [18F]FDG PET/CT during standard clinical work-up. Patients with early-stage NSCLC were planned to receive 2 cycles of avelumab (10mg/kg Q2W) prior to surgery, with CT-evaluation every 3 months post-surgery for 1 year. [89Zr]Zr-DFO-avelumab uptake was measured in [8F]FDG-positive tumor lesions, as well as in spleen, bone marrow and blood pool. PD-L1-expression was determined on baseline tumor biopsy. Tracer-uptake was correlated to PD-L1 expression and pathological response, as determined on surgical specimen. Results [89Zr]Zr-DFO-avelumab PET/CT with pre-medication (antihistaminic (clementine) and paracetamol) was considered safe and feasible. The administration of 10mg protein dose was considered optimal for [89Zr]Zr-DFO-avelumab PET/CT imaging at day 4 post injection. [89Zr]ZrDFO-avelumab did correlate to absolute PD-L1 percentage (Pearson r 0.86, p=0.014; Spearman ρ 0.62, p= 0.14). In total, 19/20 (95%) patients with early-stage NSCLC initiated avelumab treatment. There were no delays or conversions of surgical procedures. Six patients (32%) had pathologic response, including two patients with major pathologic response. [89Zr]Zr-DFO-avelumab tumorto-blood ratio was correlated to pathological response (Spearman ρ 0.56, p= 0.036). Conclusions [89Zr]Zr-DFO-avelumab PET/CT imaging in patients with NSCLC is feasible and neo-adjuvant avelumab treatment was considered safe. [89Zr]Zr-DFO-avelumab uptake was correlated with pathological response to avelumab treatment.