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Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89Zr-lumretuzumab, 89Zr-MMOT0530A, 89Zr-bevacizumab and 89Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions.

In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3′-deoxy-3’L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. Discussion: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. Trial registration:Clinicaltrials.govidentifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC Background: Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help understand these findings, we performed a first-in-human positron emission tomography (PET) imaging study with the anti-PD-L1 antibody atezolizumab labeled with zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal organ distribution and evaluate tumor tracer uptake in relation to PD-L1 IHC in archival and post-tracer tumor specimen and ultimately to treatment response. Methods: Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), bladder cancer (BC) or triple-negative breast cancer (TNBC) received 10 mg unlabeled atezolizumab plus 37 MBq 89Zr-atezolizumab (~1 mg) followed by up to 4 PET scans (1 hour, days 2, 4 and 7 post-injection (pi)). Next, after obtaining a tumor biopsy for PD-L1 IHC 8-10 days after tracer injection, patients received atezolizumab (1200 mg) i.v. once every 3 weeks until disease progression ([NCT02453984][1] and [NCT02478099][2]). Response was assessed every 6 weeks with RECIST1.1. Normal organ tracer uptake was calculated as percentage of the injected dose/kg (%ID/kg) 4 and 7 days pi, tumor tracer uptake as maximum standardized uptake value (SUVmax) and %ID/kg 7 days pi. Tumor biopsy PD-L1 expression was assessed in tumor cells (TC) and tumor infiltrating immune cells (IC) by HistoGeneX IHC with the SP142 assay (Ventana). Results: In this ongoing trial, 16/25 patients completed the PET series and received atezolizumab at least until the first response assessment. The median follow-up of these patients is 16 weeks (6-40+, NSCLC=6, BC=8, TNBC=2). The highest normal organ 89Zr-atezolizumab uptake was seen in the spleen (16.3±3.6 %ID/kg 4 days and 17.9±3.6 %ID/kg 7 days pi), and uptake in other lymphatic organs (single normal lymph nodes and tonsil) and sites of (chronic) inflammation ( e.g. chronic sinusitis and bursitis) were detected. Uptake in liver, kidney and intestine was similar to other antibodies with 7.3±1.6, 5.5±2.0 and 4.7±2.4 %ID/kg, respectively, 7 days pi. Tumor SUVmax ranged between 1.6 and 46.0 (1.8-12.4 %ID/kg), with an up to 9-fold difference within patients, and 4-fold difference between patients. In 4 biopsied lesions with IC/TC 0, 89Zr-atezolizumab uptake calculated as SUVmax was 10.0±3.6 (7.1±1.6 %ID/kg). At this time only 4 biopsies had a IHC score of 2+ on either IC or TC, and there were no biopsies with a score of 3+, limiting the ability to determine correlation of PD-L1 IHC to imaging data. Conclusion: 89Zr-atezolizumab imaging showed high uptake in normal spleen, other normal lymphoid organs and regions of inflammation. Uptake in tumor lesions was heterogeneous within and between patients and even PD-L1 IHC 0 tumors showed clear tracer uptake. Citation Format: Frederike Bensch, Elly van der Veen, Annelies Jorritsma, Marjolijn Lub-de Hooge, Ronald Boellaard, Sjoukje Oosting, Carolien Schröder, Jeroen Hiltermann, Anthonie van der Wekken, Harry Groen, Bernard Fine, Nathan McKnight, Sandra Sanabria Bohorquez, Simon Williams, Luisa Veronese, Christoph Mancao, Adrienne H. Brouwers, Elisabeth de Vries. First-in-human PET imaging with the PD-L1 antibody 89Zr-atezolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT017. doi:10.1158/1538-7445.AM2017-CT017 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02453984&atom=%2Fcanres%2F77%2F13_Supplement%2FCT017.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02478099&atom=%2Fcanres%2F77%2F13_Supplement%2FCT017.atom

An important role is reserved for nuclear imaging techniques in the imaging of neuroendocrine tumors (NETs). Somatostatin receptor scintigraphy (SRS) with In-111-DTPA-octreotide is currently the most important tracer in the diagnosis, staging and selection for peptide receptor radionuclide therapy (PRRT). In the past decade, different positron-emitting tomography (PET) tracers have been developed. The largest group is the 68 Gallium-labeled somatostatin analogs (Ga-68-SSA). Several studies have demonstrated their superiority compared to SRS in sensitivity and specificity. Furthermore, patient comfort and effective dose are favorable for Ga-68-SSA. Other PET targets like (F-18-[C-11]-5-hydroxy- L-tryptophan (C-11-5-HTP) and 6-F-18-L-3,4-dihydroxyphenylalanine (F-18-DOPA) were developed recently. For insulinomas, glucagon-like peptide-1 receptor imaging is a promising new technique. The evaluation of response after PRRT and other therapies is a challenge. Currently, the official follow-up is performed with radiological imaging techniques. The role of nuclear medicine may increase with the newest tracers for PET. In this review, the different nuclear imaging techniques and tracers for the imaging of NETs will be discussed. (C) 2015 S. Karger AG, Basel