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Aim: The tumor antigen MSLN is frequently overexpressed in PC and OC. A 89Zr-PET study (NCT01832116) with MMOT0530A, an anti-MSLN antibody, was initiated in conjunction with a phase 1 study of the antibody-drug conjugate DMOT4039A (containing MMOT0530A linked to the anti-mitotic agent MMAE, NCT01469793). This imaging study aims to investigate antibody tumor uptake, whole body distribution and organ pharmacokinetics and to explore the relation between uptake and MSLN expression and response to DMOT40392A treatment in patients with unresectable PC or platinum-resistant OC. Methods: Before receiving DMOT4039A, patients were injected with 37 MBq 89Zr-MMOT0530A +/- additional unlabeled MMOT0530A, followed by PET/CT imaging 2, 4 and 7 days post injection (pi). Tracer uptake was quantified with standardized uptake value (SUV) and expressed as mean (±SD). MSLN expression was determined in archival tumor tissue with an exploratory immunohistochemical (IHC) assay. Results: 7 PC and 4 OC patients were included. MSLN expression varied from 0 to 3+. The optimal antibody protein dose resulting in sufficient circulating tracer was 10 mg MMOT0530A and the optimal imaging time was 4 or 7 days pi. Tumor tracer uptake was observed in 37 quantifiable tumor lesions (all patients) with mean SUV of 10.7 (±6.3) on PET 4 days pi. The mean SUV per patient (1-8 lesions/patient) was 10.9 (±5.7), with 9.2 (±4.5) in PC and 11.9 (±7.4) in OC lesions on PET 4 days pi. Within patients, a mean 2.4-fold (±1.10) difference in tumor uptake between lesions was found. Two measurable lesions on diagnostic CT (according to RECIST 1.1) were not visible on PET. Uptake in blood, liver, kidneys, spleen and intestine reflected normal antibody distribution with mean SUV at day 4 pi of 5.6, 7.8, 6.1, 4.1 and 3.2, respectively, while low uptake was observed in muscle, lung, brain and bone (0.6, 1.0, 0.2 and 0.7, respectively). Tracer tumor uptake was lower in the 2 patients with IHC scores 0 and 1. Best response on DMOT4039A was stable disease in ten patients. An association between iPET tumor uptake and clinical response could not be determined. Conclusions: 89Zr-MMOT0530A-PET shows antibody uptake in primary and metastatic PC and OC tumor lesions. This technique can potentially guide antibody-based therapy development.

Vascular endothelial growth factor (VEGF) is often over expressed in ovarian cancer (OVCA), promoting ascites and effusions. Preclinical studies of inhibition of VEGF and its receptors (VEGFR) show activity in OVCA xenografts. Clinical interest in evaluating VEGF (R) inhibition was triggered when the Gynecologic Oncology Group demonstrated single agent activity of the VEGF targeted antibody, bevacizumab (BEV) in recurrent OVCA. Since that time, BEV and small molecular VEGFR inhibitors have been studied in numerous phase II and III trials in OVCA. Randomized BEV trials are the most mature with results reported in first line (GOG218, ICON7), platinum sensitive recurrent disease (OCEANS trial) and platinum resistant recurrent disease (AURELIA trial) settings. All trials gave concurrent chemotherapy + BEV with some providing maintenance BEV after chemotherapy. All have shown a biological effect of the addition of BEV with higher response rates and longer progression free survival (PFS) in BEV arms. To date, no trial has shown overall survival (OS) improvement, although mature analyses for OS are awaited. Quality of life data have not suggested a benefit with BEV and toxicity is greater. Results of phase III trials of VEGFR inhibitors cedarinib, pazopanib and nintedanib are awaited. The BEV results lead to several important questions: 1) in the absence of significant OS improvement to date, is there sufficient patient benefit from PFS increases to warrant incorporation of BEV into ovarian cancer treatment? And when over the course of the disease should the agent be given? 2) Is the use of BEV cost effective and affordable? 3) Which patient subset is benefiting most? Subgroup analysis of the ICON7 study, suggests that patients with greater bulk disease (Stage III> 1 cm residual and Stage IV) seem to derive more PFS benefit. Indeed in this subgroup, overall survival also was improved. However, in the GOG0218 trial, the hazard ratio for PFS was observed to be better in patients with < 1 cm residual. Some have suggested VEGF A plasma levels may be predictive of BEV benefit, but no results from the BEV OVCA trials are yet published. In summary, clinical results to date show significant PFS improvements from BEV in 4 trials, but it is unclear if this will translate into improved OS and how best and in whom BEV should be used in OVCA management. Disclosure: The author has declared no conflicts of interest.

Background Breast cancer screening imaging techniques with mammography or MRI have a suboptimal sensitivity. Vascular endothelial growth factor (VEGF)-A, is overexpressed in most malignant breast tumors. Zirconium-89 (89Zr) labeled bevacizumab provides a noninvasive tool to visualize tumor VEGF-A in patients. Therefore we performed a feasibility study to determine whether this 89Zr-bevacizumab PET technique allows detection of breast cancer lesions. Methods Newly diagnosed breast cancer patients, scheduled to undergo mastectomy or lumpectomy, underwent a PET/CT scan of the upper thoracic region (including breasts and axillae) 4 days after 37 MBq/ 5mg 89Zr-bevacizumab tracer administration. 89Zr-bevacizumab uptake in breast tumor, normal glandular tissue and axillary lymph nodes (ALN), was quantified as the maximum standard uptake value (SUVmax). PET images were visually compared with standard breast imaging techniques. When sufficient tissue was available, VEGF-A levels were assessed with Enzyme-Linked Immuno Sorbent Assay (ELISA). Data are presented as mean ± standard deviation and range. Statistical analysis was performed using the paired t-Test test (SPSS, version 18.0). A double sided p-value Results Twenty-five of 26 breast tumors (size: 25.1 mm ± 19.8, range 4-80) in 23 patients were visualised. 89Zr-bevacizumab uptake was higher in breast tumors than normal breast tissue (SUVmax in breast tumors 1.8 ± 1.2, range 0.5-5.6 versus 0.59 ± 0.37, range 0.27-1.69 in ipsilateral and 0.51 ± 0.26, range 0.20-1.12 in contralateral normal breast tissue; p Conclusions 89Zr-bevacizumab uptake was shown in 96.1% of primary breast tumors. Future breast cancer studies will include fluorescent labeled bevacizumab. (ClinicalTrials.gov identifier: NCT00991978). Disclosure All authors have declared no conflicts of interest.