139 Summary, general discussion and future perspectives non-responding patients. Currently the only registered biomarker for ICI response is the presence of PD-L1 expression in the tumor and immune infiltrate as measured by immunohistochemistry. The limitations of PD-L1 immunohistochemistry have stimulated the development of new biomarkers. In Chapter 4, we reviewed the use of molecular imaging to visualize whole-body tumor PD-L1 expression (PD-L1 PET-imaging). Our first experience with PD-L1 PET-imaging was with 89Zr-labeled durvalumab (anti PD-L1) before start of durvalumab treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN, PINCH study: NCT03829007). In this prospective multicenter phase II clinical trial, 37 patients with R/M SCCHN were included in one of four university medical centers in the Netherlands. In Chapter 5, we reported that [89Zr]Zr-DFOdurvalumab administration was considered feasible and safe. PET/CT imaging was performed at day 5 after [89Zr]Zr-DFO-durvalumab administration. In a dose finding study in 14 patients, a protein dose of 10 mg durvalumab resulted in superior tumor-to-blood ratios and tumor visualization compared to dose cohort 2 and 50 mg. all patients received durvalumab treatment in a fixed dose of 1500mg iv once every 4 weeks. The evaluation of 24 patients that received the optimal protein dose [89Zr]Zr-DFO-durvalumab showed that tumor accumulation of the tracer was not associated with progression free survival. On a lesion level, there was a near significant correlation between [89Zr]Zr-DFO-durvalumab uptake and durvalumab treatment response at 12 weeks. We did not find a correlation between [89Zr]Zr-DFO-durvalumab uptake and the PD-L1 expression as determined by immunohistochemistry. Additionally, we performed PD-L1 PET-imaging using 89Zr-labeled avelumab (anti PD-L1) before start of avelumab treatment in patients with non-small cell lung cancer (NSCLC, PINNACLE study: NCT03514719). We focused on patients with early-stage NSCLC who were treated with neo-adjuvant avelumab before surgical resection with curative intent. This was the first study to perform PD-L1 PET-imaging in the neo-adjuvant setting, which allowed us to determine the correlation between [89Zr]Zr-DFO-avelumab-uptake and pathological response to avelumab treatment. Despite a limited number of patients, we showed a correlation between [89Zr]ZrDFO-avelumab accumulation and pathological response. (Chapter 6). Meanwhile, other PD-1 and PD-L1 PET-imaging studies have been performed. We reflect on the results of these studies in Chapter 7, and critically review on the clinical use of this imaging technique as a tool to select patients with ICI treatment. In conclusion, molecular PET imaging with [18F]FDG and 89Zr-labeled girentuximab, durvalumab and avelumab have provided us with unique insight in the inter- and intra-patient and tumor heterogeneity. Furthermore, the imaging studies described in this thesis led to new insights on the in vivo biodistribution of therapeutic antibodies, and clues to further optimize treatment regimens. 8
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