First-in-Human Human Epidermal Growth Factor Receptor 2–Targeted Imaging Using ⁸⁹Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer

Abstract

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with Zr. Patients underwent PET/CT with 74 MBq ofZr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Six patients with HER2-positive metastatic breast cancer were enrolled and administeredZr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases,Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity.

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

“…4,23,30 While these early imaging studies were successful, highly expressed non-internalizing targets only represent a fraction of clinically relevant oncology targets since many cell-surface cancer targets are internalizing. For instance, clinical imaging of human epidermal growth factor receptor 2 (HER2)-expressing tumors has been actively pursued via directly labeled antibodies, 40,41 antibody fragments 42 and affibodies 43 in an effort to improve patient selection and response monitoring for HER2-targeted cancer therapies. 44 Fewer examples exist in which internalizing targets have been pretargeted, 20,39 likely due to risk of time-dependent cell surface depletion of TCO moieties available for click reaction through antibody-bound receptor internalization, thereby decreasing image contrast.…”

CD146‐Targeted Multimodal Image‐Guided Photoimmunotherapy of Melanoma

“…We established subcutaneous (s.c.) melanoma Adv. [29] Ex vivo biodistribution studies demonstrated an average tumor uptake of 19.52 ± 6.13%ID g −1 at 96 h ( Figure 2D). 2019, 6, 1801237 models using the A375 cell line, and evaluated the biodistribution profiles and tumor detection efficacy of 89 Zr-Df-YY146 via PET imaging at 4, 24, 48, 72, and 96 h post-injection (p.i.)…”

Current Landscape and Emerging Fields of PET Imaging in Patients with Brain Tumors

“…For identifying EGFR overexpression, PET ligands such as [ 11 C] (Figure 3) [159,160]. First-in-human studies suggest that targeting PD-1 with [ 89 Zr]nivolumab [163] or PD-L1 with [ 89 Zr]atezolizumab [164] is useful as imaging biomarkers to non-invasively evaluate the expression of these immune checkpoints in patients with extra-and intracranial cancer [164,165].…”

“…For identifying EGFR overexpression, PET ligands such as [ 11 C]erlotinib, [ 11 C]PD153035, and [ 89 Zr]Zr-DFO-nimotuzumab have been used [156-158]. The most relevant PET tracers for imaging of HER2 overexpression are [ 64 Cu]DOTA-trastuzumab and [ 89 Zr]pertuzumab(Figure 3)[159,160].…”