124 Chapter 6 So far, three phase II clinical trials studied neo-adjuvant nivolumab, atezolizumab and nivolumab +/- ipilimumab, in patients early-stage NSCLC, reporting major pathological response (MPR) in 45, 21 and 24-50%, respectively5-7. Interestingly, the MPR rates to nivolumab monotherapy differ considerably (45 vs 24%). The nivolumab studies differed in the percentage of stage I and II NSCLC, number of treatment cycles (2 and 3 2-weekly cycles) and the time between last treatment and surgery (2 vs 6 weeks)5,6. While our study was not powered nor designed to detect clinical benefit of neo-adjuvant avelumab, we observed pathological response in six patients, including two patients with MPR (11%) after surgery within 6 weeks of diagnosis (<2 weeks of last avelumab treatment). Potentially, the short time interval between last treatment and surgery impacts the observed pathological response rates. In agreement with these three studies, we did not find a relation between PD-L1 expression and MPR. While combination ipilimumab/nivolumab resulted in the highest MPR rates, future neo-adjuvant clinical trials with (combination) ICI or ICI in combination with chemotherapy should be awaited to determine the implications on safety and disease-free survival. Previous neo-adjuvant studies including the current study, have reported pathological response to ICI based on the percentage of viable cells, which is based on the induction of cell death and necrosis by neo-adjuvant chemotherapy20,21. Since the mechanism of action of ICI (e.g. priming and infiltration of tumor-specific T-cells) may not be reflected by these response criteria, it has been discussed whether T-cell infiltration rates should be used as a substitute marker for response to ICI treatment28. Alternatives includes the assessment of a so-called ‘immunoscore’, reporting the presence of immune cell components in the tumor micro-environment29,30. In conclusion, current study reports the first experience with PD-L1 PET-imaging in neo-adjuvant setting. In patients with early-stage NSCLC, tumor accumulation of [89Zr]Zr-DFO-avelumab was correlated with pathological response to neo-adjuvant avelumab treatment. This clinically relevant association should be confirmed in future PD-(L)1 imaging studies in the neo-adjuvant setting.