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Background: PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans. Methods: PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1–2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland–Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC. Results: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was − 10.9% and − 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively. Conclusions: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations. [ABSTRACT FROM AUTHOR]

Simple Summary: The uptake on a 89Zr-immuno-PET scan is not just the result of the binding of a radiolabeled antibody with its target (i.e., target engagement) but also includes background factors such as non-specific binding (for example, catabolism of antibodies inside endothelial cells). In this study, we wanted to isolate target engagement. We used data from five previously performed 89Zr-immuno-PET studies with immune-targeting 89Zr-radiolabeled antibodies. First, via Patlak analysis, we separated reversible from irreversible uptake, and by using a baseline of target-negative organs, we further defined target-specific irreversible uptake. Second, we compared different mass doses (ratios of labeled and unlabeled antibody) and looked for saturation effects. Evidence for target engagement was based on the following two things: (1) when the target-specific irreversible uptake exceeded the baseline, and (2) when the signal showed saturation. We found target engagement for the different antibodies in several lymphoid organs, for example, in the spleen, while the brain had close to zero target engagement. We propose a new baseline for bone marrow and brain. In conclusion, we promote the use of Patlak analysis for 89Zr-immuno-PET studies, or similar simplified outcomes such as a tissue-to-blood ratio. Introduction: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([89Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [89Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. Method: 89Zr-immuno-PET data from five [89Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2–3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (Ki). To identify target engagement, Ki values were compared to ns-baseline Ki values previously reported, and the effect of increasing mass doses on Ki was investigated. Results: All mAbs, except ipilimumab, showed Ki values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing Ki values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed Ki values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. Ki values were near zero in brain tissue for all mass doses of all mAbs. Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the Ki values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior. [ABSTRACT FROM AUTHOR]

Purpose: Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration. Methods: Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing. Results: Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50–0.85]; 604 mg: 0.56 [IQR 0.42–0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures. Conclusions: [89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies. Trial registration: ClinicalTrials.gov, NCT03780725. Registered 19 December 2018 [ABSTRACT FROM AUTHOR]

Introduction: Pre‐invasive squamous lesions of the central airways can progress into invasive lung cancers. Identifying these high‐risk patients could enable detection of invasive lung cancers at an early stage. In this study, we investigated the value of 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET) scans in predicting progression in patients with pre‐invasive squamous endobronchial lesions. Methods: In this retrospective study, patients with pre‐invasive endobronchial lesions, who underwent an 18F‐FDG PET scan at the VU University Medical Center Amsterdam, between January 2000 and December 2016, were included. Autofluorescence bronchoscopy (AFB) was used for tissue sampling and was repeated every 3 months. The minimum and median follow‐up was 3 and 46.5 months. Study endpoints were the occurrence of biopsy proven invasive carcinoma, time‐to‐progression and overall survival (OS). Results: A total number of 40 of 225 patients met the inclusion criteria of which 17 (42.5%) patients had a positive baseline 18F‐FDG PET scan. A total of 13 of 17 (76.5%) developed invasive lung carcinoma during follow‐up, with a median time to progression of 5.0 months (range, 3.0–25.0). In 23 (57.5%) patients with a negative 18F‐FDG PET scan at baseline, 6 (26%) developed lung cancer, with a median time to progression of 34.0 months (range, 14.0–42.0 months, p < 0.002). With a median OS of 56.0 months (range, 9.0–60.0 months) versus 49.0 months (range, 6.0–60.0 months) (p = 0.876) for the 18F‐FDG PET positive and negative groups, respectively. Conclusions: Patients with pre‐invasive endobronchial squamous lesions and a positive baseline 18F‐FDG PET scan were at high‐risk for developing lung carcinoma, highlighting that this patient group requires early radical treatment. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) has one of the highest cancer-related mortality rates worldwide. In a subgroup of NSCLC, tumor growth is driven by epidermal growth factor receptors (EGFR) that harbor an activating mutation. These patients are best treated with EGFR tyrosine kinase inhibitors (EGFR TKI). Identifying the EGFR mutational status on a tumor biopsy or a liquid biopsy using tumor DNA sequencing techniques is the current approach to predict tumor response on EGFR TKI therapy. However, due to difficulty in reaching tumor sites, and varying inter- and intralesional tumor heterogeneity, biopsies are not always possible or representative of all tumor lesions, highlighting the need for alternative biomarkers that predict tumor response. Positron emission tomography (PET) studies using EGFR TKI-based tracers have shown that EGFR mutational status could be identified, and that tracer uptake could potentially be used as a biomarker for tumor response. However, despite their likely predictive and monitoring value, the EGFR TKI-PET biomarkers are not yet qualified to be used in the routine clinical practice. In this review, we will discuss the currently investigated EGFR-directed PET biomarkers, elaborate on the typical biomarker development process, and describe how the advances, challenges, and opportunities of EGFR PET biomarkers relate to this process on their way to qualification for routine clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: [F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [F]FAZA studies and to assess the validity of simplified analytical methods. Methods: Dynamic 70-min [F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients. Continuous arterial blood sampling, together with manual arterial and venous sampling, was performed to derive metabolite-corrected plasma input functions. Volumes of interest (VOIs) were defined for tumour, healthy lung muscle and adipose tissue generating [F]FAZA time-activity curves (TACs). TACs were analysed using one- and two-tissue compartment models using both metabolite-corrected blood sampler plasma input functions (BSIF) and image-derived plasma input functions (IDIF). Results: The reversible two-tissue compartment model with blood volume parameter (2T4k+V) best described kinetics of [F]FAZA in tumours. Volumes of distribution (V) obtained using IDIF correlated well with those derived using BSIF ( R = 0.82). Venous samples yielded the same radioactivity concentrations as arterial samples for times >50 min post-injection (p.i.). In addition, both plasma to whole blood ratios and parent fractions were essentially the same for venous and arterial samples. Both standardised uptake value (SUV), normalised to lean body mass, and tumour to blood ratio correlated well with V ( R = 0.77 and R = 0.87, respectively, at 50-60 min p.i.), although a bias was observed at low V. Conclusion: The 2T4k+V model provided the best fit to the dynamic [F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods. [ABSTRACT FROM AUTHOR]

Introduction: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Methods: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Results: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC.Conclusion: The novel positron emission tomography (PET) imaging tracer, [18F]F-AraG, targets activated T-cells, offering a potential means to improve our understanding of immune-oncological processes. The aim of this study was to determine the optimal pharmacokinetic model to quantify tumour lesion [18F]F-AraG uptake in patients with non-small cell lung cancer (NSCLC), and to validate simplified measures at different time intervals against the pharmacokinetic uptake parameter.Ten patients with early-stage NSCLC and three patients with advanced NSCLC underwent a dynamic PET scan of minimal 60 min. Venous and/or arterial blood sampling was obtained at maximum seven time points. Tumour lesion time activity curves and metabolite-corrected input functions were analysed using single-tissue reversible (1T2k), two-tissue irreversible (2T3k) and two-tissue reversible (2T4k) plasma input models. Simplified uptake measures, such as standardised uptake value (SUV) and tumour-to-blood (TBR) or tumour-to-plasma ratio (TPR), were evaluated for different time intervals.Whole-blood and plasma radioactivity concentrations showed rapid clearance of [18F]F-AraG. Metabolite analysis revealed a low rate of metabolism, at 70 min p.i., on average, 79% (SD = 9.8%) of the total radioactivity found in blood corresponded to intact [18F]F-AraG. The time activity curves were best fitted by the 2T3k model. Strong positive correlations were found for SUV (body weight (BW), lean body mass (LBM) or body surface area (BSA) corrected), TBR and TPR for any time interval between 20 and 70 min p.i. against the 2T3k-derived Ki. The correlation of TBR at 60–70 min p.i. with 2T3K-derived Ki (r (df = 20) = 0.87, p < 0.01), was stronger than for SUVBW (r (df = 20) = 0.80, p < 0.01).Tumour lesion [18F]F-AraG uptake in patients with NSCLC is characterised by a 2T3k model. TBR and TPR show most potential for simplified quantification of tumour lesion [18F]F-AraG uptake in patients with NSCLC. [ABSTRACT FROM AUTHOR]

• An overview of relevant PET imaging targets in the tumor microenvironment. • Features and clinical validation of immunoPET tracers in NSCLC. • Challenges and upcoming opportunities for immunoPET. Immune oncology therapy (IO) has now become an important treatment option for patients with a non-small cell lung cancer (NSCLC). However, a substantial proportion of patients still fails to benefit from IO. Predictive biomarkers and biomarkers that provide insights in the biological processes at the tumor microenvironment (TME) level could enhance the beneficial impact of IO, and lead to improved drug development strategies. Immune positron emission tomography (immunoPET) has the potential to provide such biomarkers, by using highly-specific, radiolabeled tracers to investigate key targets in the TME with PET imaging. This review will highlight developments in immunoPET biomarkers, and the corresponding tracers and radionuclides used in cancer, and more specifically NSCLC. We will focus on available clinical tracers as well as those under development, providing an overview of each TME target, and the available clinical validation. Recent advances that could improve immunoPET in the upcoming years will be discussed. [ABSTRACT FROM AUTHOR]

Summary: Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([11C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [11C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs. [Copyright &y& Elsevier]