Sarah Verhoeff

15 General introduction and outline of this thesis OUTLINE OF THIS THESIS PET-imaging can serve as a complementary tool to guide the development of effective anticancer treatment strategies providing information regarding tumor (glucose) metabolism, tumor biology, tumor heterogeneity (e.g., target expression within and between tumors), tumormicroenvironment, and drug delivery. The aim of this thesis is to explore the potential of molecular PET-imaging to steer treatment of cancer patients. We studied the clinical application of molecular PET-imaging in three clinical trials among patients with consecutively metastatic clear cell renal cell carcinomas (mccRCC), head and neck cancer (SCCHN) and non-small cell lung cancer (NSCLC). IMPACT-RCC study The primary objective of the IMaging PAtients for Cancer drug SelecTion (IMPACT) - RCC study was to assess the added value of [18F]FDG PET and [89Zr]Zr-girentuximab PET to predict the time to progression under watchful waiting (WW) in patients with a good or intermediate prognosis mccRCC eligible for WW. In this study, we first evaluated the performance of baseline [18F]FDG and [89Zr]Zr-girentuximab PET/CT compared to conventional CT, to accurately determine disease status (chapter 2). We report the lesion-detection for all three imaging modalities and describe the observed differences between patients regarding the number of tumor lesions, lesion size and involved organ sites. The heterogeneity of mccRCC patients is reflected by the heterogenous [18F]FDG and [89Zr]Zr-girentuximab tumor-uptake within and between mccRCC patients. These imaging techniques provide unique insight in the tumor biology of the individual patients and may therefore facilitate personalized medicine. In chapter 3, we determined the value of [18F]FDG and [89Zr]Zr-girentuximab PET/CT in predicting the duration of a period of watchful waiting (WW). Moreover, we evaluated a model of clinical parameters to identify patients eligible for WW, and whether this model could be improved with knowledge of the baseline [18F]FDG- and/or [89Zr]Zr-girentuximab-uptake. As an introduction to the studies on PD-L1 PET-imaging, we explored the current available biomarkers for response and evaluated the preclinical and clinical experiences with molecular imaging to predict treatment response of immune checkpoint inhibitors (chapter 4) PINCH study The PINCH (PD-L1 ImagIng to prediCt durvalumab treatment response in SCCHN) trial, is a multicenter phase 1-2 study designed to assess the potential of [89Zr]Zr-DFO-durvalumab PETimaging to visualize tumor PD-L1 expression and predict disease control rate for durvalumab treatment in patients with advanced SCCHN. 1