Abstract BACKGROUND Recent phase 2 data showed that the small molecule regorafenib with antiangiogenic properties has promising effectivity in glioblastoma patients at first progression. Following antiangiogenic therapy with bevacizumab, amino acid PET provides valuable additional diagnostic information regarding bevacizumab-related effects on MRI (e.g., pseudoresponse). In contrast, only a little is known about regorafenib. Thus, we evaluated prospectively the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the assessment of regorafenib-related treatment effects. METHODS Twenty-two patients with progressive malignant glioma (median number of relapses, 2; range, 1-4) were included. Up to now, 10 of 22 patients were eligible for data evaluation and underwent regorafenib therapy (median number of cycles, 2; range, 1-5 cycles). FET PET and MRI were performed at baseline and after the second cycle. After the second cycle, MRI was performed every 8 weeks. In case of a suspicious MRI after the second cycle, a FET PET scan was added. MRI changes were evaluated according to the RANO criteria. Maximum tumor-to-brain ratios (TBRmax) were calculated. Pseudoresponse was considered if (i) the follow-up MRI showed an improvement (i.e., at least “partial response” according to RANO criteria) despite subsequent clinical progression, and (ii) an increase of TBRmax>25% occurred. Pseudoresponse was confirmed if (i) the subsequent MRI follow-up showed progression, and/or (ii) the clinical status worsened, or the patient died. RESULTS In 4 of 10 patients, FET PET provided clinically relevant additional information. In two patients, pseudoresponse could be confirmed. Furthermore, in one patient with stable disease according to MRI, increasing TBRmax (+138%) enabled earlier diagnosis of tumor progression (time benefit, 5 weeks). In another patient without signs of MRI response after 2 cycles, decreasing TBRmax (-23%) indicated metabolic response and was associated with a significant clinical improvement. CONCLUSIONS FET PET seems to add valuable diagnostic information for regorafenib therapy monitoring.